The Janus face of CaMKII: from memory consolidation to neurotoxic switch in Alzheimer's disease.
Gespeichert in:
| Titel: | The Janus face of CaMKII: from memory consolidation to neurotoxic switch in Alzheimer's disease. |
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| Autoren: | Tang L; Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China., Liu F; Department of Endocrinology and Metabolism, The Fourth People's Hospital of Shenyang, China Medical University, Shenyang, 110000, China., Sun X; Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, China., Yang J; Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China., Liu Y; Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China., Pan X; Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China., Hao L; Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, China. lyhao@cmu.edu.cn., Lou F; Department of Neurology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, Liaoning, China. loufan1018@163.com.; Key Laboratory of Neurological Disease Big Data of Liaoning Province, Shenyang, 110001, Liaoning, China. loufan1018@163.com.; Shenyang Clinical Medical Research Center for Difficult and Serious Diseases of the Nervous System, Shenyang, 110001, Liaoning, China. loufan1018@163.com., Su J; Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, China. jysu@cmu.edu.cn. |
| Quelle: | Archives of toxicology [Arch Toxicol] 2025 Dec; Vol. 99 (12), pp. 4829-4868. Date of Electronic Publication: 2025 Sep 01. |
| Publikationsart: | Journal Article; Review |
| Sprache: | English |
| Info zur Zeitschrift: | Publisher: Springer-Verlag Country of Publication: Germany NLM ID: 0417615 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0738 (Electronic) Linking ISSN: 03405761 NLM ISO Abbreviation: Arch Toxicol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Berlin, New York, Springer-Verlag. |
| MeSH-Schlagworte: | Alzheimer Disease*/physiopathology , Alzheimer Disease*/pathology , Alzheimer Disease*/enzymology , Alzheimer Disease*/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Type 2*/metabolism , Memory Consolidation*/physiology, Humans ; Animals ; Amyloid beta-Peptides/metabolism ; Calcium Signaling ; Neuronal Plasticity ; Calcium/metabolism ; tau Proteins/metabolism ; Long-Term Potentiation |
| Abstract: | Competing Interests: Declarations. Conflict of interests: The authors report no declarations of interest. Alzheimer's disease (AD), a neurodegenerative "memory killer" demanding urgent global intervention, has long been shrouded in mystery regarding its core pathological mechanisms. Although the traditional amyloid-β (Aβ) hypothesis remains dominant, recent groundbreaking research has revealed that early activation of aberrant calcium (Ca 2 ⁺) signaling pathways serves as the "initiating trigger" of AD pathogenesis-preceding even the formation of classical Aβ plaques-a discovery that fundamentally overturns the existing cognitive framework. This study systematically deconstructs, for the first time, the cascading regulatory network of the Ca 2 ⁺/CaM-CaMKII signaling axis in AD pathology, elucidating its potential links with core AD mechanisms, including the Aβ hypothesis, tau hyperphosphorylation, Ca 2 ⁺ dyshomeostasis, synaptic dysfunction, and neuronal loss. Furthermore, this pathway not only triggers neurotoxic cascades through spatiotemporally specific regulation of synaptic Ca 2 ⁺ overload but also directly disrupts neuroplasticity-the physical basis of memory encoding-by reshaping the dynamic equilibrium between long-term potentiation (LTP) and long-term depression (LTD).Crucially, the research uncovers the dual role of CaMKII as a "molecular switch": while physiologically maintaining memory consolidation via Thr286 autophosphorylation, its pathological overactivation due to Ca 2 ⁺ dyshomeostasis leads to a "memory solidification-toxicity cycle." These findings establish a theoretical foundation for developing innovative therapies based on precise calcium signaling modulation-including Ca 2 ⁺ homeostasis intervention and CaMKII allosteric modulators-offering a potential breakthrough in overcoming the long-standing limitation of "symptom relief without targeting root causes" in AD treatment. (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.) |
| References: | Abeysinghe A, Deshapriya R, Udawatte C (2020) Alzheimer’s disease; a review of the pathophysiological basis and therapeutic interventions. Life Sci 256:117996. https://doi.org/10.1016/j.lfs.2020.117996. (PMID: 10.1016/j.lfs.2020.11799632585249) Abiria SA, Colbran RJ (2010) CaMKII associates with CaV1.2 L-type calcium channels via selected beta subunits to enhance regulatory phosphorylation. J Neurochem 112(1):150–161. https://doi.org/10.1111/j.1471-4159.2009.06436.x. (PMID: 10.1111/j.1471-4159.2009.06436.x19840220) Alshial EE, Abdulghaney MI, Wadan AS et al (2023) Mitochondrial dysfunction and neurological disorders: a narrative review and treatment overview. Life Sci 334:122257. https://doi.org/10.1016/j.lfs.2023.122257. (PMID: 10.1016/j.lfs.2023.12225737949207) Ames JB (2021) L-type Ca(2+) channel regulation by calmodulin and CaBP1. Biomolecules. https://doi.org/10.3390/biom11121811. (PMID: 10.3390/biom11121811349444558699282) Andersen JV, Markussen KH, Jakobsen E et al (2021) Glutamate metabolism and recycling at the excitatory synapse in health and neurodegeneration. Neuropharmacology 196:108719. https://doi.org/10.1016/j.neuropharm.2021.108719. (PMID: 10.1016/j.neuropharm.2021.10871934273389) Aravind P, Bulbule SR, Hemalatha N, Babu RL, Devaraju KS (2021) Elevation of gene expression of calcineurin, calmodulin and calsyntenin in oxidative stress induced PC12 cells. Genes Dis 8(1):87–93. https://doi.org/10.1016/j.gendis.2019.09.001. (PMID: 10.1016/j.gendis.2019.09.00133569517) Arbel-Ornath M, Hudry E, Boivin JR et al (2017) Soluble oligomeric amyloid-β induces calcium dyshomeostasis that precedes synapse loss in the living mouse brain. Mol Neurodegener 12(1):27. https://doi.org/10.1186/s13024-017-0169-9. (PMID: 10.1186/s13024-017-0169-9283271815361864) Arboleda-Velasquez JF, Lopera F, O’Hare M et al (2019) Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat Med 25(11):1680–1683. https://doi.org/10.1038/s41591-019-0611-3. (PMID: 10.1038/s41591-019-0611-3316860346898984) Arispe N, Rojas E, Pollard HB (1993) Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum. Proc Natl Acad Sci USA 90(2):567–571. https://doi.org/10.1073/pnas.90.2.567. (PMID: 10.1073/pnas.90.2.567838064245704) Azargoonjahromi A (2024) The duality of amyloid-β: its role in normal and Alzheimer’s disease states. Mol Brain 17(1):44. https://doi.org/10.1186/s13041-024-01118-1. (PMID: 10.1186/s13041-024-01118-13902043511256416) Bai R, Guo J, Ye XY, Xie Y, Xie T (2022) Oxidative stress: the core pathogenesis and mechanism of Alzheimer’s disease. Ageing Res Rev 77:101619. https://doi.org/10.1016/j.arr.2022.101619. (PMID: 10.1016/j.arr.2022.10161935395415) Baltaci SB, Mogulkoc R, Baltaci AK (2019) Molecular mechanisms of early and late LTP. Neurochem Res 44(2):281–296. https://doi.org/10.1007/s11064-018-2695-4. (PMID: 10.1007/s11064-018-2695-430523578) Baracaldo-Santamaría D, Avendaño-Lopez SS, Ariza-Salamanca DF et al (2023) Role of calcium modulation in the pathophysiology and treatment of Alzheimer’s disease. Int J Mol Sci. https://doi.org/10.3390/ijms24109067. (PMID: 10.3390/ijms241090673724041310218981) Barcomb K, Hell JW, Benke TA, Bayer KU (2016) The CaMKII/GluN2B protein interaction maintains synaptic strength. J Biol Chem 291(31):16082–16089. https://doi.org/10.1074/jbc.M116.734822. (PMID: 10.1074/jbc.M116.734822272468554965558) Bartus RT, Dean RL 3rd, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217(4558):408–414. https://doi.org/10.1126/science.7046051. (PMID: 10.1126/science.70460517046051) Bayer KU, De Koninck P, Leonard AS, Hell JW, Schulman H (2001) Interaction with the NMDA receptor locks CaMKII in an active conformation. Nature 411(6839):801–805. https://doi.org/10.1038/35081080. (PMID: 10.1038/3508108011459059) Beauverger P, Ozoux ML, Bégis G et al (2020) Reversion of cardiac dysfunction by a novel orally available calcium/calmodulin-dependent protein kinase II inhibitor, RA306, in a genetic model of dilated cardiomyopathy. Cardiovasc Res 116(2):329–338. https://doi.org/10.1093/cvr/cvz097. (PMID: 10.1093/cvr/cvz09731038167) Beckendorf J, van den Hoogenhof MMG, Backs J (2018) Physiological and unappreciated roles of CaMKII in the heart. Basic Res Cardiol 113(4):29. https://doi.org/10.1007/s00395-018-0688-8. (PMID: 10.1007/s00395-018-0688-8299058926003982) Beghi S, Cavaliere F, Buschini A (2020) Gene polymorphisms in calcium-calmodulin pathway: focus on cardiovascular disease. Mutat Res Rev Mutat Res 786:108325. https://doi.org/10.1016/j.mrrev.2020.108325. (PMID: 10.1016/j.mrrev.2020.10832533339582) Beghi S, Furmanik M, Jaminon A et al (2022) Calcium signalling in heart and vessels: role of calmodulin and downstream calmodulin-dependent protein kinases. Int J Mol Sci. https://doi.org/10.3390/ijms232416139. (PMID: 10.3390/ijms232416139365557789783221) Bekdash RA (2021) The cholinergic system, the adrenergic system and the neuropathology of Alzheimer’s disease. Int J Mol Sci. https://doi.org/10.3390/ijms22031273. (PMID: 10.3390/ijms22031273335253577865740) Békés M, Langley DR, Crews CM (2022) Protac targeted protein degraders: the past is prologue. Nat Rev Drug Discov 21(3):181–200. https://doi.org/10.1038/s41573-021-00371-6. (PMID: 10.1038/s41573-021-00371-6350429918765495) Belder CRS, Schott JM, Fox NC (2023) Preparing for disease-modifying therapies in Alzheimer’s disease. Lancet Neurol 22(9):782–783. https://doi.org/10.1016/s1474-4422(23)00274-0. (PMID: 10.1016/s1474-4422(23)00274-037463598) Berry AS, Harrison TM (2023) New perspectives on the basal forebrain cholinergic system in Alzheimer’s disease. Neurosci Biobehav Rev 150:105192. https://doi.org/10.1016/j.neubiorev.2023.105192. (PMID: 10.1016/j.neubiorev.2023.1051923708693510249144) Bhattacharyya M, Karandur D, Kuriyan J (2020a) Structural insights into the regulation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a035147. (PMID: 10.1101/cshperspect.a035147319881407706568) Bhattacharyya M, Lee YK, Muratcioglu S et al (2020b) Flexible linkers in CaMKII control the balance between activating and inhibitory autophosphorylation. Elife. https://doi.org/10.7554/eLife.53670. (PMID: 10.7554/eLife.53670329023867538161) Blumenfeld J, Yip O, Kim MJ, Huang Y (2024) Cell type-specific roles of APOE4 in Alzheimer disease. Nat Rev Neurosci 25(2):91–110. https://doi.org/10.1038/s41583-023-00776-9. (PMID: 10.1038/s41583-023-00776-93819172011073858) Bohush A, Leśniak W, Weis S, Filipek A (2021) Calmodulin and its binding proteins in Parkinson’s disease. Int J Mol Sci. https://doi.org/10.3390/ijms22063016. (PMID: 10.3390/ijms22063016338095358001340) Boland B, Yu WH, Corti O et al (2018) Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing. Nat Rev Drug Discov 17(9):660–688. https://doi.org/10.1038/nrd.2018.109. (PMID: 10.1038/nrd.2018.109301160516456907) Bootman MD, Bultynck G (2020) Fundamentals of cellular calcium signaling: a primer. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a038802. (PMID: 10.1101/cshperspect.a038802314273726942118) Bourdenx M, Martín-Segura A, Scrivo A et al (2021) Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome. Cell 184(10):2696-2714.e25. https://doi.org/10.1016/j.cell.2021.03.048. (PMID: 10.1016/j.cell.2021.03.048338918768152331) Boyle AJ, Schultz C, Selvanayagam JB et al (2021) Calcium/Calmodulin-dependent protein kinase II delta inhibition and ventricular remodeling after myocardial infarction: a randomized clinical trial. JAMA Cardiol 6(7):762–768. https://doi.org/10.1001/jamacardio.2021.0676. (PMID: 10.1001/jamacardio.2021.0676338519668047802) Breijyeh Z, Karaman R (2020) Comprehensive review on Alzheimer’s disease: causes and treatment. Molecules. https://doi.org/10.3390/molecules25245789. (PMID: 10.3390/molecules25245789333025417764106) Bruni AC, Bernardi L, Gabelli C (2020) From beta amyloid to altered proteostasis in Alzheimer’s disease. Ageing Res Rev 64:101126. https://doi.org/10.1016/j.arr.2020.101126. (PMID: 10.1016/j.arr.2020.10112632683041) Burillo J, Marqués P, Jiménez B, González-Blanco C, Benito M, Guillén C (2021) Insulin resistance and diabetes mellitus in Alzheimer’s disease. Cells. https://doi.org/10.3390/cells10051236. (PMID: 10.3390/cells10051236340698908157600) Calvo-Rodriguez M, Kharitonova EK, Bacskai BJ (2020) Therapeutic strategies to target calcium dysregulation in Alzheimer’s disease. Cells. https://doi.org/10.3390/cells9112513. (PMID: 10.3390/cells9112513332336787699688) Campanari ML, García-Ayllón MS, Belbin O, Galcerán J, Lleó A, Sáez-Valero J (2014) Acetylcholinesterase modulates presenilin-1 levels and γ-secretase activity. J Alzheimers Dis 41(3):911–924. https://doi.org/10.3233/jad-140426. (PMID: 10.3233/jad-14042624699279) Cascella R, Cecchi C (2021) Calcium dyshomeostasis in Alzheimer’s disease pathogenesis. Int J Mol Sci. https://doi.org/10.3390/ijms22094914. (PMID: 10.3390/ijms22094914340663718124842) Chandra S, Vassar RJ (2024) Gut microbiome-derived metabolites in Alzheimer’s disease: regulation of immunity and potential for therapeutics. Immunol Rev. https://doi.org/10.1111/imr.13412. (PMID: 10.1111/imr.1341239440834) Chang CH, Lin CH, Lane HY (2020) D-glutamate and gut microbiota in Alzheimer’s disease. Int J Mol Sci. https://doi.org/10.3390/ijms21082676. (PMID: 10.3390/ijms21082676333793567795419) Chazin WJ, Johnson CN (2020) Calmodulin mutations associated with heart arrhythmia: a status report. Int J Mol Sci. https://doi.org/10.3390/ijms21041418. (PMID: 10.3390/ijms21041418320930797073091) Chen F, Zhao J, Meng F, He F, Ni J, Fu Y (2024a) The vascular contribution of apolipoprotein E to Alzheimer’s disease. Brain 147(9):2946–2965. https://doi.org/10.1093/brain/awae156. (PMID: 10.1093/brain/awae15638748848) Chen GF, Xu TH, Yan Y et al (2017) Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacol Sin 38(9):1205–1235. https://doi.org/10.1038/aps.2017.28. (PMID: 10.1038/aps.2017.28287131585589967) Chen J, Sitsel A, Benoy V, Sepúlveda MR, Vangheluwe P (2020) Primary active Ca(2+) transport systems in health and disease. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a035113. (PMID: 10.1101/cshperspect.a035113315011946996454) Chen LL, Fan YG, Zhao LX, Zhang Q, Wang ZY (2023) The metal ion hypothesis of Alzheimer’s disease and the anti-neuroinflammatory effect of metal chelators. Bioorg Chem 131:106301. https://doi.org/10.1016/j.bioorg.2022.106301. (PMID: 10.1016/j.bioorg.2022.10630136455485) Chen W, Cai W, Hoover B, Kahn CR (2022) Insulin action in the brain: cell types, circuits, and diseases. Trends Neurosci 45(5):384–400. https://doi.org/10.1016/j.tins.2022.03.001. (PMID: 10.1016/j.tins.2022.03.001353614999035105) Chen Y, Song S, Parhizkar S et al (2024b) APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread. Cell 187(2):428-445.e20. https://doi.org/10.1016/j.cell.2023.11.029. (PMID: 10.1016/j.cell.2023.11.02938086389) Chen Y, Zhao Y, Dai CL et al (2014) Intranasal insulin restores insulin signaling, increases synaptic proteins, and reduces Aβ level and microglia activation in the brains of 3xTg-AD mice. Exp Neurol 261:610–619. https://doi.org/10.1016/j.expneurol.2014.06.004. (PMID: 10.1016/j.expneurol.2014.06.00424918340) Chin D, Means AR (2000) Calmodulin: a prototypical calcium sensor. Trends Cell Biol 10(8):322–328. https://doi.org/10.1016/s0962-8924(00)01800-6. (PMID: 10.1016/s0962-8924(00)01800-610884684) Choi EH, Kim MH, Park SJ (2024) Targeting mitochondrial dysfunction and reactive oxygen species for neurodegenerative disease treatment. Int J Mol Sci. https://doi.org/10.3390/ijms25147952. (PMID: 10.3390/ijms251479523979611411719695) Cohen J, Mathew A, Dourvetakis KD et al (2024) Recent research trends in neuroinflammatory and neurodegenerative disorders. Cells. https://doi.org/10.3390/cells13060511. (PMID: 10.3390/cells130605113899501111240522) Cook SG, Buonarati OR, Coultrap SJ, Bayer KU (2021) CaMKII holoenzyme mechanisms that govern the LTP versus LTD decision. Sci Adv. https://doi.org/10.1126/sciadv.abe2300. (PMID: 10.1126/sciadv.abe2300342616478279502) Cortes-Canteli M, Iadecola C (2020) Alzheimer’s disease and vascular aging: JACC focus seminar. J Am Coll Cardiol 75(8):942–951. https://doi.org/10.1016/j.jacc.2019.10.062. (PMID: 10.1016/j.jacc.2019.10.062321309308046164) Coultrap SJ, Bayer KU (2012) CaMKII regulation in information processing and storage. Trends Neurosci 35(10):607–618. https://doi.org/10.1016/j.tins.2012.05.003. (PMID: 10.1016/j.tins.2012.05.003227172673461103) Coultrap SJ, Vest RS, Ashpole NM, Hudmon A, Bayer KU (2011) CaMKII in cerebral ischemia. Acta Pharmacol Sin 32(7):861–872. https://doi.org/10.1038/aps.2011.68. (PMID: 10.1038/aps.2011.68216859293846291) Crossley CA, Rajani V, Yuan Q (2023) Modulation of L-type calcium channels in Alzheimer’s disease: a potential therapeutic target. Comput Struct Biotechnol J 21:11–20. https://doi.org/10.1016/j.csbj.2022.11.049. (PMID: 10.1016/j.csbj.2022.11.04936514335) Cummings JL, Tong G, Ballard C (2019) Treatment combinations for Alzheimer’s disease: current and future pharmacotherapy options. J Alzheimers Dis 67(3):779–794. https://doi.org/10.3233/jad-180766. (PMID: 10.3233/jad-180766306895756398562) Czapski GA, Strosznajder JB (2021) Glutamate and GABA in microglia-neuron cross-talk in Alzheimer’s disease. Int J Mol Sci. https://doi.org/10.3390/ijms222111677. (PMID: 10.3390/ijms222111677347691068584169) D’Arcy MS (2024) Mitophagy in health and disease. Molecular mechanisms, regulatory pathways, and therapeutic implications. Apoptosis 29(9–10):1415–1428. https://doi.org/10.1007/s10495-024-01977-y. (PMID: 10.1007/s10495-024-01977-y38758472) Da Mesquita S, Fu Z, Kipnis J (2018a) The meningeal lymphatic system: a new player in neurophysiology. Neuron 100(2):375–388. https://doi.org/10.1016/j.neuron.2018.09.022. (PMID: 10.1016/j.neuron.2018.09.022303596036268162) Da Mesquita S, Louveau A, Vaccari A et al (2018b) Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 560(7717):185–191. https://doi.org/10.1038/s41586-018-0368-8. (PMID: 10.1038/s41586-018-0368-8300461116085146) de Carvalho MJ, Furini CR, Benetti F, Izquierdo I (2014) Hippocampal molecular mechanisms involved in the enhancement of fear extinction caused by exposure to novelty. Proc Natl Acad Sci USA 111(12):4572–4577. https://doi.org/10.1073/pnas.1400423111. (PMID: 10.1073/pnas.1400423111) De la Rosa A, Olaso-Gonzalez G, Arc-Chagnaud C et al (2020) Physical exercise in the prevention and treatment of Alzheimer’s disease. J Sport Health Sci 9(5):394–404. https://doi.org/10.1016/j.jshs.2020.01.004. (PMID: 10.1016/j.jshs.2020.01.004327806917498620) de la Torre JC (2004) Is Alzheimer’s disease a neurodegenerative or a vascular disorder? Data, dogma, and dialectics. Lancet Neurol 3(3):184–190. https://doi.org/10.1016/s1474-4422(04)00683-0. (PMID: 10.1016/s1474-4422(04)00683-014980533) Deane R, Sagare A, Hamm K et al (2008) ApoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J Clin Investig 118(12):4002–4013. https://doi.org/10.1172/jci36663. (PMID: 10.1172/jci36663190336692582453) Dissanayaka DMS, Jayasena V, Rainey-Smith SR, Martins RN, Fernando W (2024) The role of diet and gut microbiota in Alzheimer’s disease. Nutrients. https://doi.org/10.3390/nu16030412. (PMID: 10.3390/nu160304123833769610857293) Feng M, Zhou Q, Xie H et al (2024) Role of CD36 in central nervous system diseases. Neural Regen Res 19(3):512–518. https://doi.org/10.4103/1673-5374.380821. (PMID: 10.4103/1673-5374.38082137721278) Ferreira-Vieira TH, Guimaraes IM, Silva FR, Ribeiro FM (2016) Alzheimer’s disease: targeting the cholinergic system. Curr Neuropharmacol 14(1):101–115. https://doi.org/10.2174/1570159x13666150716165726. (PMID: 10.2174/1570159x13666150716165726268131234787279) Fišar Z, Hroudová J (2024) CoQ(10) and mitochondrial dysfunction in Alzheimer’s disease. Antioxidants (Basel). https://doi.org/10.3390/antiox13020191. (PMID: 10.3390/antiox1302019138397789) Fitz NF, Nam KN, Wolfe CM et al (2021) Phospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer’s disease. Nat Commun 12(1):3416. https://doi.org/10.1038/s41467-021-23762-0. (PMID: 10.1038/s41467-021-23762-0340997068184801) Fu WY, Wang X, Ip NY (2019) Targeting neuroinflammation as a therapeutic strategy for Alzheimer’s disease: mechanisms, drug candidates, and new opportunities. ACS Chem Neurosci 10(2):872–879. https://doi.org/10.1021/acschemneuro.8b00402. (PMID: 10.1021/acschemneuro.8b0040230221933) Ghosh A, Giese KP (2015) Calcium/calmodulin-dependent kinase II and Alzheimer’s disease. Mol Brain 8(1):78. https://doi.org/10.1186/s13041-015-0166-2. (PMID: 10.1186/s13041-015-0166-2266032844657223) Giacobini E, Cuello AC, Fisher A (2022) Reimagining cholinergic therapy for Alzheimer’s disease. Brain 145(7):2250–2275. https://doi.org/10.1093/brain/awac096. (PMID: 10.1093/brain/awac09635289363) Goodell DJ, Zaegel V, Coultrap SJ, Hell JW, Bayer KU (2017) DAPK1 mediates LTD by making CaMKII/GluN2B binding LTP specific. Cell Rep 19(11):2231–2243. https://doi.org/10.1016/j.celrep.2017.05.068. (PMID: 10.1016/j.celrep.2017.05.068286147115549467) Griffioen G (2023) Calcium dyshomeostasis drives pathophysiology and neuronal demise in age-related neurodegenerative diseases. Int J Mol Sci. https://doi.org/10.3390/ijms241713243. (PMID: 10.3390/ijms2417132433768604810487569) Griffiths J, Grant SGN (2023) Synapse pathology in Alzheimer’s disease. Semin Cell Dev Biol 139:13–23. https://doi.org/10.1016/j.semcdb.2022.05.028. (PMID: 10.1016/j.semcdb.2022.05.02835690535) Grimm HP, Schumacher V, Schäfer M et al (2023) Delivery of the Brainshuttle™ amyloid-beta antibody fusion trontinemab to non-human primate brain and projected efficacious dose regimens in humans. Mabs 15(1):2261509. https://doi.org/10.1080/19420862.2023.2261509. (PMID: 10.1080/19420862.2023.22615093782369010572082) Guan PP, Cao LL, Wang P (2021) Elevating the levels of calcium ions exacerbate Alzheimer’s disease via inducing the production and aggregation of β-amyloid protein and phosphorylated tau. Int J Mol Sci. https://doi.org/10.3390/ijms22115900. (PMID: 10.3390/ijms22115900350086448745381) Guo S, Wang H, Yin Y (2022) Microglia polarization from M1 to M2 in neurodegenerative diseases. Front Aging Neurosci 14:815347. https://doi.org/10.3389/fnagi.2022.815347. (PMID: 10.3389/fnagi.2022.815347352505438888930) Halliday MR, Rege SV, Ma Q et al (2016) Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease. J Cereb Blood Flow Metab 36(1):216–227. https://doi.org/10.1038/jcbfm.2015.44. (PMID: 10.1038/jcbfm.2015.44257577564758554) Hallschmid M (2021) Intranasal insulin for Alzheimer’s disease. CNS Drugs 35(1):21–37. https://doi.org/10.1007/s40263-020-00781-x. (PMID: 10.1007/s40263-020-00781-x335154287873098) Hampel H, Mesulam MM, Cuello AC et al (2018) The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain 141(7):1917–1933. https://doi.org/10.1093/brain/awy132. (PMID: 10.1093/brain/awy132298507776022632) Hansen DV, Hanson JE, Sheng M (2018) Microglia in Alzheimer’s disease. J Cell Biol 217(2):459–472. https://doi.org/10.1083/jcb.201709069. (PMID: 10.1083/jcb.201709069291964605800817) Hell JW (2014) CaMKII: claiming center stage in postsynaptic function and organization. Neuron 81(2):249–265. https://doi.org/10.1016/j.neuron.2013.12.024. (PMID: 10.1016/j.neuron.2013.12.024244620934570830) Henning NJ, Boike L, Spradlin JN et al (2022) Deubiquitinase-targeting chimeras for targeted protein stabilization. Nat Chem Biol 18(4):412–421. https://doi.org/10.1038/s41589-022-00971-2. (PMID: 10.1038/s41589-022-00971-23521061810125259) Hong S, Ostaszewski BL, Yang T et al (2014) Soluble Aβ oligomers are rapidly sequestered from brain ISF in vivo and bind GM1 ganglioside on cellular membranes. Neuron 82(2):308–319. https://doi.org/10.1016/j.neuron.2014.02.027. (PMID: 10.1016/j.neuron.2014.02.027246851764129520) Hosokawa T, Liu PW, Cai Q et al (2021) CaMKII activation persistently segregates postsynaptic proteins via liquid phase separation. Nat Neurosci 24(6):777–785. https://doi.org/10.1038/s41593-021-00843-3. (PMID: 10.1038/s41593-021-00843-333927400) Hu Z, Chen PH, Li W et al (2023) Targeted dephosphorylation of Tau by phosphorylation targeting chimeras (PhosTACs) as a therapeutic modality. J Am Chem Soc. https://doi.org/10.1021/jacs.2c11706. (PMID: 10.1021/jacs.2c117063815555110755699) Huang X (2023) A concise review on oxidative stress-mediated ferroptosis and cuproptosis in Alzheimer’s disease. Cells. https://doi.org/10.3390/cells12101369. (PMID: 10.3390/cells121013693820129010778542) Huang YA, Zhou B, Wernig M, Südhof TC (2017) ApoE2, ApoE3, and ApoE4 differentially stimulate APP transcription and Aβ secretion. Cell 168(3):427-441.e21. https://doi.org/10.1016/j.cell.2016.12.044. (PMID: 10.1016/j.cell.2016.12.044281110745310835) Hur JY (2022) Γ-Secretase in Alzheimer’s disease. Exp Mol Med 54(4):433–446. https://doi.org/10.1038/s12276-022-00754-8. (PMID: 10.1038/s12276-022-00754-8353965759076685) Iadecola C, Gottesman RF (2018) Cerebrovascular alterations in Alzheimer disease. Circ Res 123(4):406–408. https://doi.org/10.1161/circresaha.118.313400. (PMID: 10.1161/circresaha.118.313400303552536214471) Incontro S, Díaz-Alonso J, Iafrati J et al (2018) The CaMKII/NMDA receptor complex controls hippocampal synaptic transmission by kinase-dependent and independent mechanisms. Nat Commun 9(1):2069. https://doi.org/10.1038/s41467-018-04439-7. (PMID: 10.1038/s41467-018-04439-7298022895970233) Jackson RJ, Hyman BT, Serrano-Pozo A (2024a) Multifaceted roles of APOE in Alzheimer disease. Nat Rev Neurol 20(8):457–474. https://doi.org/10.1038/s41582-024-00988-2. (PMID: 10.1038/s41582-024-00988-23890699912185264) Jackson RJ, Keiser MS, Meltzer JC et al (2024b) APOE2 gene therapy reduces amyloid deposition and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease. Mol Ther 32(5):1373–1386. https://doi.org/10.1016/j.ymthe.2024.03.024. (PMID: 10.1016/j.ymthe.2024.03.0243850451711081918) Janota C, Lemere CA, Brito MA (2016) Dissecting the contribution of vascular alterations and aging to Alzheimer’s disease. Mol Neurobiol 53(6):3793–3811. https://doi.org/10.1007/s12035-015-9319-7. (PMID: 10.1007/s12035-015-9319-726143259) Jarome TJ, Ferrara NC, Kwapis JL, Helmstetter FJ (2016) CaMKII regulates proteasome phosphorylation and activity and promotes memory destabilization following retrieval. Neurobiol Learn Mem 128:103–109. https://doi.org/10.1016/j.nlm.2016.01.001. (PMID: 10.1016/j.nlm.2016.01.001267795884754128) Johnson JD, Mills JS (1986) Calmodulin. Med Res Rev 6(3):341–363. https://doi.org/10.1002/med.2610060304. (PMID: 10.1002/med.26100603043526053) Jorfi M, Maaser-Hecker A, Tanzi RE (2023) The neuroimmune axis of Alzheimer’s disease. Genome Med 15(1):6. https://doi.org/10.1186/s13073-023-01155-w. (PMID: 10.1186/s13073-023-01155-w367032359878767) Jucker M, Walker LC (2023) Alzheimer’s disease: from immunotherapy to immunoprevention. Cell 186(20):4260–4270. https://doi.org/10.1016/j.cell.2023.08.021. (PMID: 10.1016/j.cell.2023.08.0213772990810578497) Kang C (2024) Donanemab: first approval. Drugs 84(10):1313–1318. https://doi.org/10.1007/s40265-024-02087-4. (PMID: 10.1007/s40265-024-02087-439237715) Kang JW, Vemuganti V, Kuehn JF, Ulland TK, Rey FE, Bendlin BB (2024) Gut microbial metabolism in Alzheimer’s disease and related dementias. Neurotherapeutics. https://doi.org/10.1016/j.neurot.2024.e00470. (PMID: 10.1016/j.neurot.2024.e004703967476312014335) Kapoor B, Biswas P, Gulati M, Rani P, Gupta R (2024) Gut microbiome and Alzheimer’s disease: what we know and what remains to be explored. Ageing Res Rev. https://doi.org/10.1016/j.arr.2024.102570. (PMID: 10.1016/j.arr.2024.10257039486524) Kaushik M, Kaushik P, Parvez S (2022) Memory related molecular signatures: the pivots for memory consolidation and Alzheimer’s related memory decline. Ageing Res Rev 76:101577. https://doi.org/10.1016/j.arr.2022.101577. (PMID: 10.1016/j.arr.2022.10157735104629) Kellar D, Craft S (2020) Brain insulin resistance in Alzheimer’s disease and related disorders: mechanisms and therapeutic approaches. Lancet Neurol 19(9):758–766. https://doi.org/10.1016/s1474-4422(20)30231-3. (PMID: 10.1016/s1474-4422(20)30231-3327307669661919) Kellar D, Register T, Lockhart SN et al (2022) Intranasal insulin modulates cerebrospinal fluid markers of neuroinflammation in mild cognitive impairment and Alzheimer’s disease: a randomized trial. Sci Rep 12(1):1346. https://doi.org/10.1038/s41598-022-05165-3. (PMID: 10.1038/s41598-022-05165-3350790298789895) Khan S, Barve KH, Kumar MS (2020) Recent advancements in pathogenesis, diagnostics and treatment of Alzheimer’s disease. Curr Neuropharmacol 18(11):1106–1125. https://doi.org/10.2174/1570159x18666200528142429. (PMID: 10.2174/1570159x18666200528142429324841107709159) Kim AY, Al Jerdi S, MacDonald R, Triggle CR (2024) Alzheimer’s disease and its treatment-yesterday, today, and tomorrow. Front Pharmacol 15:1399121. https://doi.org/10.3389/fphar.2024.1399121. (PMID: 10.3389/fphar.2024.13991213886866611167451) Kim K, Saneyoshi T, Hosokawa T, Okamoto K, Hayashi Y (2016) Interplay of enzymatic and structural functions of CaMKII in long-term potentiation. J Neurochem 139(6):959–972. https://doi.org/10.1111/jnc.13672. (PMID: 10.1111/jnc.1367227207106) Kim N, Lee HJ (2021) Redox-active metal ions and amyloid-degrading enzymes in Alzheimer’s disease. Int J Mol Sci. https://doi.org/10.3390/ijms22147697. (PMID: 10.3390/ijms22147697350088838745666) Klemmensen MM, Borrowman SH, Pearce C, Pyles B, Chandra B (2024) Mitochondrial dysfunction in neurodegenerative disorders. Neurotherapeutics 21(1):e00292. https://doi.org/10.1016/j.neurot.2023.10.002. (PMID: 10.1016/j.neurot.2023.10.00238241161) Knopman DS, Amieva H, Petersen RC et al (2021) Alzheimer disease. Nat Rev Dis Primers 7(1):33. https://doi.org/10.1038/s41572-021-00269-y. (PMID: 10.1038/s41572-021-00269-y339863018574196) Kojima H, Rosendale M, Sugiyama Y et al (2019) The role of CaMKII-Tiam1 complex on learning and memory. Neurobiol Learn Mem 166:107070. https://doi.org/10.1016/j.nlm.2019.107070. (PMID: 10.1016/j.nlm.2019.10707031445077) Kolobova E, Petrushanko I, Mitkevich V, Makarov AA, Grigorova IL (2024) Β-amyloids and immune responses associated with Alzheimer’s disease. Cells. https://doi.org/10.3390/cells13191624. (PMID: 10.3390/cells131916243940438811475064) LaFerla FM (2002) Calcium dyshomeostasis and intracellular signalling in Alzheimer’s disease. Nat Rev Neurosci 3(11):862–872. https://doi.org/10.1038/nrn960. (PMID: 10.1038/nrn96012415294) Lai KO, Wong AS, Cheung MC et al (2012) TrkB phosphorylation by Cdk5 is required for activity-dependent structural plasticity and spatial memory. Nat Neurosci 15(11):1506–1515. https://doi.org/10.1038/nn.3237. (PMID: 10.1038/nn.3237230643827511999) Lee J, Chen X, Nicoll RA (2022) Synaptic memory survives molecular turnover. Proc Natl Acad Sci USA 119(42):e2211572119. https://doi.org/10.1073/pnas.2211572119. (PMID: 10.1073/pnas.2211572119362155049586278) Li YY, Qin ZH, Sheng R (2024) The multiple roles of autophagy in neural function and diseases. Neurosci Bull 40(3):363–382. https://doi.org/10.1007/s12264-023-01120-y. (PMID: 10.1007/s12264-023-01120-y37856037) Lin YT, Seo J, Gao F et al (2018) APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron 98(6):1141-1154.e7. https://doi.org/10.1016/j.neuron.2018.05.008. (PMID: 10.1016/j.neuron.2018.05.008298612876023751) Lisman J, Yasuda R, Raghavachari S (2012) Mechanisms of CaMKII action in long-term potentiation. Nat Rev Neurosci 13(3):169–182. https://doi.org/10.1038/nrn3192. (PMID: 10.1038/nrn3192223342124050655) Lisman JE (1985) A mechanism for memory storage insensitive to molecular turnover: a bistable autophosphorylating kinase. Proc Natl Acad Sci USA 82(9):3055–3057. https://doi.org/10.1073/pnas.82.9.3055. (PMID: 10.1073/pnas.82.9.30552986148397705) Lisman JE, Goldring MA (1988) Feasibility of long-term storage of graded information by the Ca2+/calmodulin-dependent protein kinase molecules of the postsynaptic density. Proc Natl Acad Sci USA 85(14):5320–5324. https://doi.org/10.1073/pnas.85.14.5320. (PMID: 10.1073/pnas.85.14.53203393540281742) Litwiniuk A, Juszczak GR, Stankiewicz AM, Urbańska K (2023) The role of glial autophagy in Alzheimer’s disease. Mol Psychiatry 28(11):4528–4539. https://doi.org/10.1038/s41380-023-02242-5. (PMID: 10.1038/s41380-023-02242-537679471) Liu E, Zhang Y, Wang JZ (2024a) Updates in Alzheimer’s disease: from basic research to diagnosis and therapies. Transl Neurodegener 13(1):45. https://doi.org/10.1186/s40035-024-00432-x. (PMID: 10.1186/s40035-024-00432-x3923284811373277) Liu X, Liu Y, Liu J et al (2024b) Correlation between the gut microbiome and neurodegenerative diseases: a review of metagenomics evidence. Neural Regen Res 19(4):833–845. https://doi.org/10.4103/1673-5374.382223. (PMID: 10.4103/1673-5374.38222337843219) Liu XL, Ouyang FB, Hu LT et al (2022) Mesenchymal stem cells improve cognitive impairment and reduce Aβ deposition via promoting AQP4 polarity and relieving neuroinflammation in rats with chronic hypertension-induced cerebral small-vessel disease. Front Aging Neurosci 14:883503. https://doi.org/10.3389/fnagi.2022.883503. (PMID: 10.3389/fnagi.2022.883503356635759160459) Long JM, Holtzman DM (2019) Alzheimer disease: an update on pathobiology and treatment strategies. Cell 179(2):312–339. https://doi.org/10.1016/j.cell.2019.09.001. (PMID: 10.1016/j.cell.2019.09.001315644566778042) Louveau A, Smirnov I, Keyes TJ et al (2015) Structural and functional features of central nervous system lymphatic vessels. Nature 523(7560):337–341. https://doi.org/10.1038/nature14432. (PMID: 10.1038/nature14432260305244506234) Lozupone M, Dibello V, Sardone R et al (2023) The development of peptide- and oligonucleotide-based drugs to prevent the formation of abnormal tau in tauopathies. Expert Opin Drug Discov 18(5):515–526. https://doi.org/10.1080/17460441.2023.2200245. (PMID: 10.1080/17460441.2023.220024537042028) Lučić I, Héluin L, Jiang PL et al (2023) CaMKII autophosphorylation can occur between holoenzymes without subunit exchange. Elife. https://doi.org/10.7554/eLife.86090. (PMID: 10.7554/eLife.860903756645510468207) Ly PT, Song W (2011) Loss of activated CaMKII at the synapse underlies Alzheimer’s disease memory loss. J Neurochem 119(4):673–675. https://doi.org/10.1111/j.1471-4159.2011.07473.x. (PMID: 10.1111/j.1471-4159.2011.07473.x21899538) Marino C, Perez-Corredor P, O’Hare M et al (2024) APOE Christchurch-mimetic therapeutic antibody reduces APOE-mediated toxicity and tau phosphorylation. Alzheimers Dement 20(2):819–836. https://doi.org/10.1002/alz.13436. (PMID: 10.1002/alz.1343637791598) Martens YA, Zhao N, Liu CC et al (2022) ApoE cascade hypothesis in the pathogenesis of Alzheimer’s disease and related dementias. Neuron 110(8):1304–1317. https://doi.org/10.1016/j.neuron.2022.03.004. (PMID: 10.1016/j.neuron.2022.03.004352989219035117) McDaid J, Mustaly-Kalimi S, Stutzmann GE (2020) Ca(2+) dyshomeostasis disrupts neuronal and synaptic function in Alzheimer’s disease. Cells. https://doi.org/10.3390/cells9122655. (PMID: 10.3390/cells9122655333218667763805) Merighi S, Nigro M, Travagli A, Gessi S (2022) Microglia and Alzheimer’s disease. Int J Mol Sci. https://doi.org/10.3390/ijms232112990. (PMID: 10.3390/ijms232112990364995129740965) Miners JS, Van Helmond Z, Chalmers K, Wilcock G, Love S, Kehoe PG (2006) Decreased expression and activity of neprilysin in Alzheimer disease are associated with cerebral amyloid angiopathy. J Neuropathol Exp Neurol 65(10):1012–1021. https://doi.org/10.1097/01.jnen.0000240463.87886.9a. (PMID: 10.1097/01.jnen.0000240463.87886.9a17021406) MohanaSundaram A, Mofatteh M, Ashraf GM, Praticò D (2024) Glymphotherapeutics for Alzheimer’s disease: time to move the needle. Ageing Res Rev 101:102478. https://doi.org/10.1016/j.arr.2024.102478. (PMID: 10.1016/j.arr.2024.10247839222666) Mohaupt P, Vialaret J, Hirtz C, Lehmann S (2023) Readthrough isoform of aquaporin-4 (AQP4) as a therapeutic target for Alzheimer’s disease and other proteinopathies. Alzheimers Res Ther 15(1):170. https://doi.org/10.1186/s13195-023-01318-2. (PMID: 10.1186/s13195-023-01318-23782196510566184) Montagne A, Nation DA, Sagare AP et al (2020) APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature 581(7806):71–76. https://doi.org/10.1038/s41586-020-2247-3. (PMID: 10.1038/s41586-020-2247-3323769547250000) Monteiro AR, Barbosa DJ, Remião F, Silva R (2023) Alzheimer’s disease: insights and new prospects in disease pathophysiology, biomarkers and disease-modifying drugs. Biochem Pharmacol 211:115522. https://doi.org/10.1016/j.bcp.2023.115522. (PMID: 10.1016/j.bcp.2023.11552236996971) Mota BC, Ashburner N, Abelleira-Hervas L et al (2022) I2-imidazoline ligand CR4056 improves memory, increases ApoE expression and reduces BBB leakage in 5xFAD mice. Int J Mol Sci. https://doi.org/10.3390/ijms23137320. (PMID: 10.3390/ijms23137320366139189820355) Murdock MH, Yang CY, Sun N et al (2024) Multisensory gamma stimulation promotes glymphatic clearance of amyloid. Nature 627(8002):149–156. https://doi.org/10.1038/s41586-024-07132-6. (PMID: 10.1038/s41586-024-07132-63841887610917684) Narasimhan S, Holtzman DM, Apostolova LG et al (2024) Apolipoprotein E in Alzheimer’s disease trajectories and the next-generation clinical care pathway. Nat Neurosci 27(7):1236–1252. https://doi.org/10.1038/s41593-024-01669-5. (PMID: 10.1038/s41593-024-01669-538898183) Nasb M, Tao W, Chen N (2024) Alzheimer’s disease puzzle: delving into pathogenesis hypotheses. Aging Dis 15(1):43–73. https://doi.org/10.14336/ad.2023.0608. (PMID: 10.14336/ad.2023.06083745093110796101) Nelson MR, Liu P, Agrawal A et al (2023) The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration and neuroinflammation. Nat Neurosci 26(12):2104–2121. https://doi.org/10.1038/s41593-023-01480-8. (PMID: 10.1038/s41593-023-01480-83795731710689245) Nicole O, Pacary E (2020) CaMKIIβ in neuronal development and plasticity: an emerging candidate in brain diseases. Int J Mol Sci. https://doi.org/10.3390/ijms21197272. (PMID: 10.3390/ijms21197272330196577582470) Nicoll RA, Schulman H (2023) Synaptic memory and CaMKII. Physiol Rev 103(4):2877–2925. https://doi.org/10.1152/physrev.00034.2022. (PMID: 10.1152/physrev.00034.202237290118) Nixon RA (2024) Autophagy-lysosomal-associated neuronal death in neurodegenerative disease. Acta Neuropathol 148(1):42. https://doi.org/10.1007/s00401-024-02799-7. (PMID: 10.1007/s00401-024-02799-73925938211418399) Nixon RA, Rubinsztein DC (2024) Mechanisms of autophagy-lysosome dysfunction in neurodegenerative diseases. Nat Rev Mol Cell Biol 25(11):926–946. https://doi.org/10.1038/s41580-024-00757-5. (PMID: 10.1038/s41580-024-00757-53910744612239022) O’Day DH (2020) Calmodulin binding proteins and Alzheimer’s disease: biomarkers, regulatory enzymes and receptors that are regulated by calmodulin. Int J Mol Sci. https://doi.org/10.3390/ijms21197344. (PMID: 10.3390/ijms21197344330279067582761) O’Day DH (2023) Protein biomarkers shared by multiple neurodegenerative diseases are calmodulin-binding proteins offering novel and potentially universal therapeutic targets. J Clin Med. https://doi.org/10.3390/jcm12227045. (PMID: 10.3390/jcm122270453800265910672630) O’Day DH, Eshak K, Myre MA (2015) Calmodulin binding proteins and Alzheimer’s disease. J Alzheimers Dis 46(3):553–569. https://doi.org/10.3233/jad-142772. (PMID: 10.3233/jad-142772258128524878311) O’Day DH, Mathavarajah S, Myre MA, Huber RJ (2020) Calmodulin-mediated events during the life cycle of the amoebozoan Dictyostelium discoideum. Biol Rev Camb Philos Soc 95(2):472–490. https://doi.org/10.1111/brv.12573. (PMID: 10.1111/brv.1257331774219) Ochalek A, Mihalik B, Avci HX et al (2017) Neurons derived from sporadic Alzheimer’s disease iPSCs reveal elevated TAU hyperphosphorylation, increased amyloid levels, and GSK3B activation. Alzheimers Res Ther 9(1):90. https://doi.org/10.1186/s13195-017-0317-z. (PMID: 10.1186/s13195-017-0317-z291912195709977) Oksanen M, Petersen AJ, Naumenko N et al (2017) PSEN1 mutant iPSC-derived model reveals severe astrocyte pathology in Alzheimer’s disease. Stem Cell Reports 9(6):1885–1897. https://doi.org/10.1016/j.stemcr.2017.10.016. (PMID: 10.1016/j.stemcr.2017.10.016291539895785689) Opazo P, Viana da Silva S, Carta M et al (2018) CaMKII metaplasticity drives Aβ oligomer-mediated synaptotoxicity. Cell Rep 23(11):3137–3145. https://doi.org/10.1016/j.celrep.2018.05.036. (PMID: 10.1016/j.celrep.2018.05.036298983866089247) Özden C, Sloutsky R, Mitsugi T et al (2022) CaMKII binds both substrates and activators at the active site. Cell Rep 40(2):111064. https://doi.org/10.1016/j.celrep.2022.111064. (PMID: 10.1016/j.celrep.2022.111064358307969336311) Palmer JE, Wilson N, Son SM et al (2024) Autophagy, aging, and age-related neurodegeneration. Neuron. https://doi.org/10.1016/j.neuron.2024.09.015. (PMID: 10.1016/j.neuron.2024.09.01539406236) Pan Q, Li YQ, Guo K et al (2021) Elderly patients with mild cognitive impairment exhibit altered gut microbiota profiles. J Immunol Res 2021:5578958. https://doi.org/10.1155/2021/5578958. (PMID: 10.1155/2021/5578958348697828635943) Park J, Jang KM, Park KK (2020) Apamin suppresses LPS-induced neuroinflammatory responses by regulating SK channels and TLR4-mediated signaling pathways. Int J Mol Sci. https://doi.org/10.3390/ijms21124319. (PMID: 10.3390/ijms21124319334192927795830) Park J, Jang KM, Park KK (2022) Effects of apamin on MPP(+)-induced calcium overload and neurotoxicity by targeting CaMKII/ERK/p65/STAT3 signaling pathways in dopaminergic neuronal cells. Int J Mol Sci. https://doi.org/10.3390/ijms232315255. (PMID: 10.3390/ijms232315255366141659821383) Parodi-Rullán RM, Javadov S, Fossati S (2021) Dissecting the crosstalk between endothelial mitochondrial damage, vascular inflammation, and neurodegeneration in cerebral amyloid angiopathy and Alzheimer’s disease. Cells. https://doi.org/10.3390/cells10112903. (PMID: 10.3390/cells10112903348311258616424) Passeri E, Elkhoury K, Morsink M et al (2022) Alzheimer’s disease: treatment strategies and their limitations. Int J Mol Sci. https://doi.org/10.3390/ijms232213954. (PMID: 10.3390/ijms232213954366136039820200) Patel S, Bansoad AV, Singh R, Khatik GL (2022) BACE1: a key regulator in Alzheimer’s disease progression and current development of its inhibitors. Curr Neuropharmacol 20(6):1174–1193. https://doi.org/10.2174/1570159x19666211201094031. (PMID: 10.2174/1570159x19666211201094031348527469886827) Phillips MCL, Deprez LM, Mortimer GMN et al (2021) Randomized crossover trial of a modified ketogenic diet in Alzheimer’s disease. Alzheimers Res Ther 13(1):51. https://doi.org/10.1186/s13195-021-00783-x. (PMID: 10.1186/s13195-021-00783-x336223927901512) Picón-Pagès P, Fanlo-Ucar H, Herrera-Fernández V et al (2022) Amyloid β-peptide causes the permanent activation of CaMKIIα through its oxidation. Int J Mol Sci. https://doi.org/10.3390/ijms232315169. (PMID: 10.3390/ijms232315169362332969570324) Poejo J, Salazar J, Mata AM, Gutierrez-Merino C (2021) The relevance of Amyloid β-calmodulin complexation in neurons and brain degeneration in Alzheimer’s disease. Int J Mol Sci. https://doi.org/10.3390/ijms22094976. (PMID: 10.3390/ijms22094976340670618125740) Popugaeva E, Pchitskaya E, Bezprozvanny I (2017) Dysregulation of neuronal calcium homeostasis in Alzheimer’s disease—A therapeutic opportunity? Biochem Biophys Res Commun 483(4):998–1004. https://doi.org/10.1016/j.bbrc.2016.09.053. (PMID: 10.1016/j.bbrc.2016.09.05327641664) Pszczołowska M, Walczak K, Miśków W, Mroziak M, Chojdak-Łukasiewicz J, Leszek J (2024) Mitochondrial disorders leading to Alzheimer’s disease-perspectives of diagnosis and treatment. Geroscience 46(3):2977–2988. https://doi.org/10.1007/s11357-024-01118-y. (PMID: 10.1007/s11357-024-01118-y3845700811009177) Quiroz YT, Aguillon D, Aguirre-Acevedo DC et al (2024) APOE3 Christchurch heterozygosity and autosomal dominant Alzheimer’s disease. N Engl J Med 390(23):2156–2164. https://doi.org/10.1056/NEJMoa2308583. (PMID: 10.1056/NEJMoa230858338899694) Rad SK, Arya A, Karimian H et al (2018) Mechanism involved in insulin resistance via accumulation of β-amyloid and neurofibrillary tangles: link between type 2 diabetes and Alzheimer’s disease. Drug des Devel Ther 12:3999–4021. https://doi.org/10.2147/dddt.S173970. (PMID: 10.2147/dddt.S173970305384276255119) Rajendran K, Krishnan UM (2024) Mechanistic insights and emerging therapeutic stratagems for Alzheimer’s disease. Ageing Res Rev 97:102309. https://doi.org/10.1016/j.arr.2024.102309. (PMID: 10.1016/j.arr.2024.10230938615895) Reese LC, Laezza F, Woltjer R, Taglialatela G (2011) Dysregulated phosphorylation of Ca(2+) /calmodulin-dependent protein kinase II-α in the hippocampus of subjects with mild cognitive impairment and Alzheimer’s disease. J Neurochem 119(4):791–804. https://doi.org/10.1111/j.1471-4159.2011.07447.x. (PMID: 10.1111/j.1471-4159.2011.07447.x218832164021864) Reyes Gaido OE, Nkashama LJ, Schole KL et al (2023) CaMKII as a therapeutic target in cardiovascular disease. Annu Rev Pharmacol Toxicol 63:249–272. https://doi.org/10.1146/annurev-pharmtox-051421-111814. (PMID: 10.1146/annurev-pharmtox-051421-11181435973713) Rhea EM, Leclerc M, Yassine HN et al (2024) State of the science on brain insulin resistance and cognitive decline due to Alzheimer’s disease. Aging Dis 15(4):1688–1725. https://doi.org/10.14336/ad.2023.0814. (PMID: 10.14336/ad.2023.08143761190711272209) Rossetti T, Banerjee S, Kim C et al (2017) Memory erasure experiments indicate a critical role of CaMKII in memory storage. Neuron 96(1):207-216.e2. https://doi.org/10.1016/j.neuron.2017.09.010. (PMID: 10.1016/j.neuron.2017.09.010289576695634137) Rostagno AA (2022) Pathogenesis of Alzheimer’s disease. Int J Mol Sci. https://doi.org/10.3390/ijms24010107. (PMID: 10.3390/ijms24010107366135449820480) Russo R, Cattaneo F, Lippiello P et al (2018) Motor coordination and synaptic plasticity deficits are associated with increased cerebellar activity of NADPH oxidase, CAMKII, and PKC at preplaque stage in the TgCRND8 mouse model of Alzheimer’s disease. Neurobiol Aging 68:123–133. https://doi.org/10.1016/j.neurobiolaging.2018.02.025. (PMID: 10.1016/j.neurobiolaging.2018.02.02529602494) Rynearson KD, Ponnusamy M, Prikhodko O et al (2021) Preclinical validation of a potent γ-secretase modulator for Alzheimer’s disease prevention. J Exp Med. https://doi.org/10.1084/jem.20202560. (PMID: 10.1084/jem.20202560336511037931646) Sacktor TC, Fenton AA (2018) What does LTP tell us about the roles of CaMKII and PKMζ in memory? Mol Brain 11(1):77. https://doi.org/10.1186/s13041-018-0420-5. (PMID: 10.1186/s13041-018-0420-5305932896309091) Saitoh T, Schwartz JH (1985) Phosphorylation-dependent subcellular translocation of a Ca2+/calmodulin-dependent protein kinase produces an autonomous enzyme in Aplysia neurons. J Cell Biol 100(3):835–842. https://doi.org/10.1083/jcb.100.3.835. (PMID: 10.1083/jcb.100.3.8352982886) Sałaciak K, Koszałka A, Żmudzka E, Pytka K (2021) The calcium/calmodulin-dependent kinases II and IV as therapeutic targets in neurodegenerative and neuropsychiatric disorders. Int J Mol Sci. https://doi.org/10.3390/ijms22094307. (PMID: 10.3390/ijms22094307339191638122486) Saneyoshi T, Matsuno H, Suzuki A et al (2019) Reciprocal activation within a kinase-effector complex underlying persistence of structural LTP. Neuron 102(6):1199-1210.e6. https://doi.org/10.1016/j.neuron.2019.04.012. (PMID: 10.1016/j.neuron.2019.04.012310783686669903) Santiago JA, Karthikeyan M, Lackey M, Villavicencio D, Potashkin JA (2023) Diabetes: a tipping point in neurodegenerative diseases. Trends Mol Med 29(12):1029–1044. https://doi.org/10.1016/j.molmed.2023.09.005. (PMID: 10.1016/j.molmed.2023.09.0053782790410844978) Sapkota D, Florian C, Doherty BM et al (2022) Aqp4 stop codon readthrough facilitates amyloid-β clearance from the brain. Brain 145(9):2982–2990. https://doi.org/10.1093/brain/awac199. (PMID: 10.1093/brain/awac1993600141410233234) Scheltens P, De Strooper B, Kivipelto M et al (2021) Alzheimer’s disease. Lancet 397(10284):1577–1590. https://doi.org/10.1016/s0140-6736(20)32205-4. (PMID: 10.1016/s0140-6736(20)32205-4336674168354300) Se Thoe E, Fauzi A, Tang YQ, Chamyuang S, Chia AYY (2021) A review on advances of treatment modalities for Alzheimer’s disease. Life Sci 276:119129. https://doi.org/10.1016/j.lfs.2021.119129. (PMID: 10.1016/j.lfs.2021.11912933515559) Sędzikowska A, Szablewski L (2021) Insulin and insulin resistance in Alzheimer’s disease. Int J Mol Sci. https://doi.org/10.3390/ijms22189987. (PMID: 10.3390/ijms22189987349483178708129) Self WK, Holtzman DM (2023) Emerging diagnostics and therapeutics for Alzheimer disease. Nat Med 29(9):2187–2199. https://doi.org/10.1038/s41591-023-02505-2. (PMID: 10.1038/s41591-023-02505-237667136) Serrano-Pozo A, Das S, Hyman BT (2021) APOE and Alzheimer’s disease: advances in genetics, pathophysiology, and therapeutic approaches. Lancet Neurol 20(1):68–80. https://doi.org/10.1016/s1474-4422(20)30412-9. (PMID: 10.1016/s1474-4422(20)30412-9333404858096522) Sharma A, Sari E, Lee Y et al (2023) Extracellular CIRP induces calpain activation in neurons via PLC-IP(3)-dependent calcium pathway. Mol Neurobiol 60(6):3311–3328. https://doi.org/10.1007/s12035-023-03273-3. (PMID: 10.1007/s12035-023-03273-33685342910506840) Shoshan-Barmatz V, Nahon-Crystal E, Shteinfer-Kuzmine A, Gupta R (2018) VDAC1, mitochondrial dysfunction, and Alzheimer’s disease. Pharmacol Res 131:87–101. https://doi.org/10.1016/j.phrs.2018.03.010. (PMID: 10.1016/j.phrs.2018.03.01029551631) Sikanyika NL, Parkington HC, Smith AI, Kuruppu S (2019) Powering amyloid beta degrading enzymes: a possible therapy for Alzheimer’s disease. Neurochem Res 44(6):1289–1296. https://doi.org/10.1007/s11064-019-02756-x. (PMID: 10.1007/s11064-019-02756-x30806879) Singer O, Marr RA, Rockenstein E et al (2005) Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model. Nat Neurosci 8(10):1343–1349. https://doi.org/10.1038/nn1531. (PMID: 10.1038/nn153116136043) Sinsky J, Pichlerova K, Hanes J (2021) Tau protein interaction partners and their roles in Alzheimer’s disease and other tauopathies. Int J Mol Sci. https://doi.org/10.3390/ijms22179207. (PMID: 10.3390/ijms22179207345021168431036) Sirkis DW, Bonham LW, Johnson TP, La Joie R, Yokoyama JS (2022) Dissecting the clinical heterogeneity of early-onset Alzheimer’s disease. Mol Psychiatry 27(6):2674–2688. https://doi.org/10.1038/s41380-022-01531-9. (PMID: 10.1038/s41380-022-01531-9353935559156414) Sloutsky R, Stratton MM (2021) Functional implications of CaMKII alternative splicing. Eur J Neurosci 54(8):6780–6794. https://doi.org/10.1111/ejn.14761. (PMID: 10.1111/ejn.1476132343011) Squitti R, Pal A, Picozza M et al (2020) Zinc therapy in early Alzheimer’s disease: safety and potential therapeutic efficacy. Biomolecules. https://doi.org/10.3390/biom10081164. (PMID: 10.3390/biom10081164327848557466035) Srivastava S, Ahmad R, Khare SK (2021) Alzheimer’s disease and its treatment by different approaches: a review. Eur J Med Chem 216:113320. https://doi.org/10.1016/j.ejmech.2021.113320. (PMID: 10.1016/j.ejmech.2021.11332033652356) Stefaniak O, Dobrzyńska M, Drzymała-Czyż S, Przysławski J (2022) Diet in the prevention of Alzheimer’s disease: current knowledge and future research requirements. Nutrients. https://doi.org/10.3390/nu14214564. (PMID: 10.3390/nu14214564363648269656789) Steward A, Biel D, Dewenter A et al (2023) ApoE4 and connectivity-mediated spreading of tau pathology at lower amyloid levels. JAMA Neurol 80(12):1295–1306. https://doi.org/10.1001/jamaneurol.2023.4038. (PMID: 10.1001/jamaneurol.2023.40383793069510628846) Sun Y, Yan C, He L et al (2023) Inhibition of ferroptosis through regulating neuronal calcium homeostasis: an emerging therapeutic target for Alzheimer’s disease. Ageing Res Rev 87:101899. https://doi.org/10.1016/j.arr.2023.101899. (PMID: 10.1016/j.arr.2023.10189936871781) Szapiro G, Vianna MR, McGaugh JL, Medina JH, Izquierdo I (2003) The role of NMDA glutamate receptors, PKA, MAPK, and CAMKII in the hippocampus in extinction of conditioned fear. Hippocampus 13(1):53–58. https://doi.org/10.1002/hipo.10043. (PMID: 10.1002/hipo.1004312625457) Tai LM, Thomas R, Marottoli FM et al (2016) The role of APOE in cerebrovascular dysfunction. Acta Neuropathol 131(5):709–723. https://doi.org/10.1007/s00401-016-1547-z. (PMID: 10.1007/s00401-016-1547-z268840684837016) Tang X, Walter E, Wohleb E, Fan Y, Wang C (2024) ATG5 (autophagy related 5) in microglia controls hippocampal neurogenesis in Alzheimer disease. Autophagy 20(4):847–862. https://doi.org/10.1080/15548627.2023.2277634. (PMID: 10.1080/15548627.2023.227763437915255) Tao W, Lee J, Chen X et al (2021) Synaptic memory requires CaMKII. Elife. https://doi.org/10.7554/eLife.60360. (PMID: 10.7554/eLife.60360349190548789279) Thiel G, Rössler OG (2023) Calmodulin regulates transient receptor potential TRPM3 and TRPM8-induced gene transcription. Int J Mol Sci. https://doi.org/10.3390/ijms24097902. (PMID: 10.3390/ijms240979023813906110743231) Tiwari S, Atluri V, Kaushik A, Yndart A, Nair M (2019) Alzheimer’s disease: pathogenesis, diagnostics, and therapeutics. Int J Nanomed 14:5541–5554. https://doi.org/10.2147/ijn.S200490. (PMID: 10.2147/ijn.S200490) Tolar M, Hey J, Power A, Abushakra S (2021) Neurotoxic soluble amyloid oligomers drive Alzheimer’s pathogenesis and represent a clinically validated target for slowing disease progression. Int J Mol Sci. https://doi.org/10.3390/ijms22126355. (PMID: 10.3390/ijms22126355341985828231952) Tong BC, Wu AJ, Li M, Cheung KH (2018) Calcium signaling in Alzheimer’s disease & therapies. Biochim Biophys Acta Mol Cell Res 1865(11 Pt B):1745–1760. https://doi.org/10.1016/j.bbamcr.2018.07.018. (PMID: 10.1016/j.bbamcr.2018.07.01830059692) Tsujioka S, Sumino A, Nagasawa Y et al (2023) Imaging single CaMKII holoenzymes at work by high-speed atomic force microscopy. Sci Adv 9(26):eadh1069. https://doi.org/10.1126/sciadv.adh1069. (PMID: 10.1126/sciadv.adh10693739021310313165) Tsvetkov P, Coy S, Petrova B et al (2022) Copper induces cell death by targeting lipoylated TCA cycle proteins. Science 375(6586):1254–1261. https://doi.org/10.1126/science.abf0529. (PMID: 10.1126/science.abf0529352982639273333) Twarowski B, Herbet M (2023) Inflammatory processes in Alzheimer’s disease-pathomechanism, diagnosis and treatment: a review. Int J Mol Sci. https://doi.org/10.3390/ijms24076518. (PMID: 10.3390/ijms240765183704749210095343) van Dyck CH, Swanson CJ, Aisen P et al (2023) Lecanemab in early Alzheimer’s disease. N Engl J Med 388(1):9–21. https://doi.org/10.1056/NEJMoa2212948. (PMID: 10.1056/NEJMoa221294836449413) Vaz M, Silvestre S (2020) Alzheimer’s disease: recent treatment strategies. Eur J Pharmacol 887:173554. https://doi.org/10.1016/j.ejphar.2020.173554. (PMID: 10.1016/j.ejphar.2020.17355432941929) Vigil FA, Giese KP (2018) Calcium/calmodulin-dependent kinase II and memory destabilization: a new role in memory maintenance. J Neurochem 147(1):12–23. https://doi.org/10.1111/jnc.14454. (PMID: 10.1111/jnc.14454297044306221169) Villalobo A (2023) Regulation of ErbB receptors by the Ca(2+) sensor protein calmodulin in cancer. Biomedicines. https://doi.org/10.3390/biomedicines11030661. (PMID: 10.3390/biomedicines110306613697963910045772) Villalobo A, González-Muñoz M, Berchtold MW (2019) Proteins with calmodulin-like domains: structures and functional roles. Cell Mol Life Sci 76(12):2299–2328. https://doi.org/10.1007/s00018-019-03062-z. (PMID: 10.1007/s00018-019-03062-z3087733411105222) Vydra Bousova K, Zouharova M, Jiraskova K, Vetyskova V (2023) Interaction of calmodulin with TRPM: an initiator of channel modulation. Int J Mol Sci. https://doi.org/10.3390/ijms242015162. (PMID: 10.3390/ijms2420151623789484210607381) Wang DM, Yang YJ, Zhang L, Zhang X, Guan FF, Zhang LF (2013) Naringin enhances CaMKII activity and improves long-term memory in a mouse model of Alzheimer’s disease. Int J Mol Sci 14(3):5576–5586. https://doi.org/10.3390/ijms14035576. (PMID: 10.3390/ijms14035576234784343634479) Wang JZ, Grundke-Iqbal I, Iqbal K (2007) Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurosci 25(1):59–68. https://doi.org/10.1111/j.1460-9568.2006.05226.x. (PMID: 10.1111/j.1460-9568.2006.05226.x172412673191918) Wang L, Yin YL, Liu XZ et al (2020) Current understanding of metal ions in the pathogenesis of Alzheimer’s disease. Transl Neurodegener 9:10. https://doi.org/10.1186/s40035-020-00189-z. (PMID: 10.1186/s40035-020-00189-z322660637119290) Wang M, Yan C, Li X et al (2024) Non-invasive modulation of meningeal lymphatics ameliorates ageing and Alzheimer’s disease-associated pathology and cognition in mice. Nat Commun 15(1):1453. https://doi.org/10.1038/s41467-024-45656-7. (PMID: 10.1038/s41467-024-45656-73836574010873306) Wang R, Reddy PH (2017) Role of glutamate and NMDA receptors in Alzheimer’s disease. J Alzheimers Dis 57(4):1041–1048. https://doi.org/10.3233/jad-160763. (PMID: 10.3233/jad-160763276623225791143) Wang W, Zhou Q, Jiang T et al (2021) A novel small-molecule PROTAC selectively promotes tau clearance to improve cognitive functions in Alzheimer-like models. Theranostics 11(11):5279–5295. https://doi.org/10.7150/thno.55680. (PMID: 10.7150/thno.55680338597478039949) Wang WA, Agellon LB, Michalak M (2019a) Organellar calcium handling in the cellular reticular network. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a038265. (PMID: 10.1101/cshperspect.a038265314515136886452) Wang X, Kastanenka KV, Arbel-Ornath M et al (2018) An acute functional screen identifies an effective antibody targeting amyloid-β oligomers based on calcium imaging. Sci Rep 8(1):4634. https://doi.org/10.1038/s41598-018-22979-2. (PMID: 10.1038/s41598-018-22979-2295455795854710) Wang X, Su B, Lee HG et al (2009) Impaired balance of mitochondrial fission and fusion in Alzheimer’s disease. J Neurosci 29(28):9090–9103. https://doi.org/10.1523/jneurosci.1357-09.2009. (PMID: 10.1523/jneurosci.1357-09.2009196056462735241) Wang X, Sun G, Feng T et al (2019b) Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Cell Res 29(10):787–803. https://doi.org/10.1038/s41422-019-0216-x. (PMID: 10.1038/s41422-019-0216-x314888826796854) Wang Y, Cai M, Lou Y, Zhang S, Liu X (2023a) ZBTB20-AS1 promoted Alzheimer’s disease progression through ZBTB20/GSK-3β/Tau pathway. Biochem Biophys Res Commun 640:88–96. https://doi.org/10.1016/j.bbrc.2022.11.107. (PMID: 10.1016/j.bbrc.2022.11.10736502636) Wang YJ, Sun YR, Pei YH et al (2023b) The lymphatic drainage systems in the brain: a novel target for ischemic stroke? Neural Regen Res 18(3):485–491. https://doi.org/10.4103/1673-5374.346484. (PMID: 10.4103/1673-5374.34648436018151) Webber EK, Fivaz M, Stutzmann GE, Griffioen G (2023) Cytosolic calcium: judge, jury and executioner of neurodegeneration in Alzheimer’s disease and beyond. Alzheimers Dement 19(8):3701–3717. https://doi.org/10.1002/alz.13065. (PMID: 10.1002/alz.1306537132525) Wegmann S, Biernat J, Mandelkow E (2021) A current view on Tau protein phosphorylation in Alzheimer’s disease. Curr Opin Neurobiol 69:131–138. https://doi.org/10.1016/j.conb.2021.03.003. (PMID: 10.1016/j.conb.2021.03.00333892381) Wei Y, Han C, Wang Y et al (2015) Ribosylation triggering Alzheimer’s disease-like Tau hyperphosphorylation via activation of CaMKII. Aging Cell 14(5):754–763. https://doi.org/10.1111/acel.12355. (PMID: 10.1111/acel.12355260953504568963) Wei Y, Liu M, Wang D (2022) The propagation mechanisms of extracellular tau in Alzheimer’s disease. J Neurol 269(3):1164–1181. https://doi.org/10.1007/s00415-021-10573-y. (PMID: 10.1007/s00415-021-10573-y33913022) Windham IA, Cohen S (2024) The cell biology of APOE in the brain. Trends Cell Biol 34(4):338–348. https://doi.org/10.1016/j.tcb.2023.09.004. (PMID: 10.1016/j.tcb.2023.09.00437805344) AsACH W, Khachaturian ZS (2017) Calcium hypothesis of Alzheimer’s disease and brain aging: a framework for integrating new evidence into a comprehensive theory of pathogenesis. Alzheimers Dement 13(2):178-182.e17. https://doi.org/10.1016/j.jalz.2016.12.006. (PMID: 10.1016/j.jalz.2016.12.006) Wu C, Yang L, Feng S et al (2022) Therapeutic non-invasive brain treatments in Alzheimer’s disease: recent advances and challenges. Inflamm Regen 42(1):31. https://doi.org/10.1186/s41232-022-00216-8. (PMID: 10.1186/s41232-022-00216-8361846239527145) Xi Y, Chen Y, Jin Y et al (2022) Versatile nanomaterials for Alzheimer’s disease: pathogenesis inspired disease-modifying therapy. J Control Release 345:38–61. https://doi.org/10.1016/j.jconrel.2022.02.034. (PMID: 10.1016/j.jconrel.2022.02.03435257810) Xiao S, Chan P, Wang T et al (2021) A 36-week multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial of sodium oligomannate for mild-to-moderate Alzheimer’s dementia. Alzheimers Res Ther 13(1):62. https://doi.org/10.1186/s13195-021-00795-7. (PMID: 10.1186/s13195-021-00795-7337312097967962) Xie A, Cheng G, Wu J et al (2025) Highly BBB-permeable nanomedicine reverses neuroapoptosis and neuroinflammation to treat Alzheimer’s disease. Biomaterials 312:122749. https://doi.org/10.1016/j.biomaterials.2024.122749. (PMID: 10.1016/j.biomaterials.2024.12274939121725) Yamagata Y, Kobayashi S, Umeda T et al (2009) Kinase-dead knock-in mouse reveals an essential role of kinase activity of Ca2+/calmodulin-dependent protein kinase IIalpha in dendritic spine enlargement, long-term potentiation, and learning. J Neurosci 29(23):7607–7618. https://doi.org/10.1523/jneurosci.0707-09.2009. (PMID: 10.1523/jneurosci.0707-09.2009195159296665418) Yan T, Chen J, Wang Y, Wang Y, Zhang Y, Zhao Y (2023) Deficiency of aldehyde dehydrogenase 2 aggravates ethanol-induced cytotoxicity in N2a cells via CaMKII/Drp1-mediated mitophagy. Food Chem Toxicol 182:114129. https://doi.org/10.1016/j.fct.2023.114129. (PMID: 10.1016/j.fct.2023.11412937967785) Yan T, Zhao Y (2020) Acetaldehyde induces phosphorylation of dynamin-related protein 1 and mitochondrial dysfunction via elevating intracellular ROS and Ca(2+) levels. Redox Biol 28:101381. https://doi.org/10.1016/j.redox.2019.101381. (PMID: 10.1016/j.redox.2019.10138131756635) Yang J, Liang J, Hu N et al (2024) The gut microbiota modulates neuroinflammation in Alzheimer’s disease: elucidating crucial factors and mechanistic underpinnings. CNS Neurosci Ther 30(10):e70091. https://doi.org/10.1111/cns.70091. (PMID: 10.1111/cns.700913946053811512114) Yang L, Liu W, Shi L et al (2023a) NMDA receptor-Arc signaling is required for memory updating and is disrupted in Alzheimer’s disease. Biol Psychiatry 94(9):706–720. https://doi.org/10.1016/j.biopsych.2023.02.008. (PMID: 10.1016/j.biopsych.2023.02.0083679660010423741) Yang LG, March ZM, Stephenson RA, Narayan PS (2023b) Apolipoprotein E in lipid metabolism and neurodegenerative disease. Trends Endocrinol Metab 34(8):430–445. https://doi.org/10.1016/j.tem.2023.05.002. (PMID: 10.1016/j.tem.2023.05.0023735710010365028) Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brinton RD (2009) Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 106(34):14670–14675. https://doi.org/10.1073/pnas.0903563106. (PMID: 10.1073/pnas.0903563106196671962732886) Yasuda R, Hayashi Y, Hell JW (2022) CaMKII: a central molecular organizer of synaptic plasticity, learning and memory. Nat Rev Neurosci 23(11):666–682. https://doi.org/10.1038/s41583-022-00624-2. (PMID: 10.1038/s41583-022-00624-236056211) Yi J, Wang HL, Lu G et al (2024) Spautin-1 promotes PINK1-PRKN-dependent mitophagy and improves associative learning capability in an Alzheimer disease animal model. Autophagy 20(12):2655–2676. https://doi.org/10.1080/15548627.2024.2383145. (PMID: 10.1080/15548627.2024.23831453905147311587853) Yu TW, Lane HY, Lin CH (2021) Novel therapeutic approaches for Alzheimer’s disease: an updated review. Int J Mol Sci. https://doi.org/10.3390/ijms22158208. (PMID: 10.3390/ijms22158208350087858745213) Zeng Y, Zhao D, Xie CW (2010) Neurotrophins enhance CaMKII activity and rescue amyloid-β-induced deficits in hippocampal synaptic plasticity. J Alzheimers Dis 21(3):823–831. https://doi.org/10.3233/jad-2010-100264. (PMID: 10.3233/jad-2010-100264206345863125154) Zhang J, Zhang Y, Wang J, Xia Y, Zhang J, Chen L (2024) Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies. Signal Transduct Target Ther 9(1):211. https://doi.org/10.1038/s41392-024-01911-3. (PMID: 10.1038/s41392-024-01911-33917453511344989) Zhang X, Connelly J, Levitan ES, Sun D, Wang JQ (2021a) Calcium/Calmodulin-dependent protein kinase II in cerebrovascular diseases. Transl Stroke Res 12(4):513–529. https://doi.org/10.1007/s12975-021-00901-9. (PMID: 10.1007/s12975-021-00901-9337130308213567) Zhang Y, Gao H, Zheng W, Xu H (2022a) Current understanding of the interactions between metal ions and apolipoprotein E in Alzheimer’s disease. Neurobiol Dis 172:105824. https://doi.org/10.1016/j.nbd.2022.105824. (PMID: 10.1016/j.nbd.2022.10582435878744) Zhang Y, Gao X, Bai X, Yao S, Chang YZ, Gao G (2022b) The emerging role of furin in neurodegenerative and neuropsychiatric diseases. Transl Neurodegener 11(1):39. https://doi.org/10.1186/s40035-022-00313-1. (PMID: 10.1186/s40035-022-00313-1359961949395820) Zhang Z, Yang X, Song YQ, Tu J (2021b) Autophagy in Alzheimer’s disease pathogenesis: therapeutic potential and future perspectives. Ageing Res Rev 72:101464. https://doi.org/10.1016/j.arr.2021.101464. (PMID: 10.1016/j.arr.2021.10146434551326) Zhang ZH, Peng JY, Chen YB, Wang C, Chen C, Song GL (2023) Different effects and mechanisms of selenium compounds in improving pathology in Alzheimer’s disease. Antioxidants. https://doi.org/10.3390/antiox12030702. (PMID: 10.3390/antiox120307023827563110812535) Zheng J, Tian N, Liu F et al (2021) A novel dephosphorylation targeting chimera selectively promoting tau removal in tauopathies. Signal Transduct Target Ther 6(1):269. https://doi.org/10.1038/s41392-021-00669-2. (PMID: 10.1038/s41392-021-00669-2342620148280143) Zhou X, Shi Q, Zhang X et al (2023) ApoE4-mediated blood-brain barrier damage in Alzheimer’s disease: progress and prospects. Brain Res Bull 199:110670. https://doi.org/10.1016/j.brainresbull.2023.110670. (PMID: 10.1016/j.brainresbull.2023.11067037224887) Zott B, Konnerth A (2023) Impairments of glutamatergic synaptic transmission in Alzheimer’s disease. Semin Cell Dev Biol 139:24–34. https://doi.org/10.1016/j.semcdb.2022.03.013. (PMID: 10.1016/j.semcdb.2022.03.01335337739) |
| Grant Information: | 32271160 Natural Science Foundation of China; 2021M693914 China Postdoctoral Science Foundation; 2022JH2/20200069 Scientific Research Project of Liaoning Province; xtcx2019-11 Medical Electrophysiological Key Lab Foundation of Sichuan Province; KeyME-2019-07 Key Laboratory Foundation of Medical Electrophysiology of Ministry of Education |
| Contributed Indexing: | Keywords: Alzheimer’s disease; Ca2⁺/CaM-CaMKII; Calcium dyshomeostasis; Learning and memory function; Synaptic plasticity |
| Substance Nomenclature: | EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2) 0 (Amyloid beta-Peptides) SY7Q814VUP (Calcium) 0 (tau Proteins) |
| Entry Date(s): | Date Created: 20250901 Date Completed: 20251017 Latest Revision: 20251017 |
| Update Code: | 20251017 |
| DOI: | 10.1007/s00204-025-04160-7 |
| PMID: | 40888949 |
| Datenbank: | MEDLINE |
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Nájsť tento článok vo Web of Science | Abstract: | Competing Interests: Declarations. Conflict of interests: The authors report no declarations of interest.<br />Alzheimer's disease (AD), a neurodegenerative "memory killer" demanding urgent global intervention, has long been shrouded in mystery regarding its core pathological mechanisms. Although the traditional amyloid-β (Aβ) hypothesis remains dominant, recent groundbreaking research has revealed that early activation of aberrant calcium (Ca <sup>2</sup> ⁺) signaling pathways serves as the "initiating trigger" of AD pathogenesis-preceding even the formation of classical Aβ plaques-a discovery that fundamentally overturns the existing cognitive framework. This study systematically deconstructs, for the first time, the cascading regulatory network of the Ca <sup>2</sup> ⁺/CaM-CaMKII signaling axis in AD pathology, elucidating its potential links with core AD mechanisms, including the Aβ hypothesis, tau hyperphosphorylation, Ca <sup>2</sup> ⁺ dyshomeostasis, synaptic dysfunction, and neuronal loss. Furthermore, this pathway not only triggers neurotoxic cascades through spatiotemporally specific regulation of synaptic Ca <sup>2</sup> ⁺ overload but also directly disrupts neuroplasticity-the physical basis of memory encoding-by reshaping the dynamic equilibrium between long-term potentiation (LTP) and long-term depression (LTD).Crucially, the research uncovers the dual role of CaMKII as a "molecular switch": while physiologically maintaining memory consolidation via Thr286 autophosphorylation, its pathological overactivation due to Ca <sup>2</sup> ⁺ dyshomeostasis leads to a "memory solidification-toxicity cycle." These findings establish a theoretical foundation for developing innovative therapies based on precise calcium signaling modulation-including Ca <sup>2</sup> ⁺ homeostasis intervention and CaMKII allosteric modulators-offering a potential breakthrough in overcoming the long-standing limitation of "symptom relief without targeting root causes" in AD treatment.<br /> (© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.) |
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| ISSN: | 1432-0738 |
| DOI: | 10.1007/s00204-025-04160-7 |