Amyloid-β oligomers in the nucleus accumbens decrease motivation via insertion of calcium-permeable AMPA receptors

It is essential to identify the neuronal mechanisms of Alzheimer's Disease (AD)-associated neuropsychiatric symptoms, e.g., apathy, before improving the life quality of AD patients. Here, we focused on the nucleus accumbens (NAc), a critical brain region processing motivation, also known to dis...

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Veröffentlicht in:Molecular psychiatry Jg. 27; H. 4; S. 2146 - 2157
Hauptverfasser: Guo, Changyong, Wen, Di, Zhang, Yihong, Mustaklem, Richie, Mustaklem, Basil, Zhou, Miou, Ma, Tao, Ma, Yao-Ying
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England Nature Publishing Group 01.04.2022
Schlagworte:
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Alzheimer Disease - pathology
Alzheimer's disease
Amyloid beta-Peptides - metabolism
Calcium - metabolism
Calcium permeability
Emotional behavior
Humans
Mental disorders
Motivation
Neurodegeneration
Neurodegenerative diseases
Nucleus accumbens
Nucleus Accumbens - metabolism
Oligomers
Quality of life
Receptors, AMPA - metabolism
Receptors, Calcium-Sensing
Synapses - metabolism
Synaptic transmission
α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
β-Amyloid
ISSN:1359-4184, 1476-5578, 1476-5578
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Zusammenfassung:It is essential to identify the neuronal mechanisms of Alzheimer's Disease (AD)-associated neuropsychiatric symptoms, e.g., apathy, before improving the life quality of AD patients. Here, we focused on the nucleus accumbens (NAc), a critical brain region processing motivation, also known to display AD-associated pathological changes in human cases. We found that the synaptic calcium permeable (CP)-AMPA receptors (AMPARs), which are normally absent in the NAc, can be revealed by acute exposure to Aβ oligomers (AβOs), and play a critical role in the emergence of synaptic loss and motivation deficits. Blockade of NAc CP-AMPARs can effectively prevent AβO-induced downsizing and pruning of spines and silencing of excitatory synaptic transmission. We conclude that AβO-triggered synaptic insertion of CP-AMPARs is a key mechanism mediating synaptic degeneration in AD, and preserving synaptic integrity may prevent or delay the onset of AD-associated psychiatric symptoms.
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ISSN:1359-4184
1476-5578
1476-5578
DOI:10.1038/s41380-022-01459-0