Synaptic changes in Alzheimer's disease and its models.
Alzheimer's disease (AD) is a highly prevalent neurodegenerative disorder characterized by a progressive loss of cognition and the presence of two hallmark lesions, senile plaques (SP) and neurofibrillary tangles (NFT), which result from the accumulation and deposition of the β-amyloid peptide (Aβ) and the aggregation of hyperphosphorylated tau protein, respectively. Initially, it was thought that Aβ fibrils, which make up SP, were the root cause of the massive neurodegeneration usual found in AD brains. Over time, the longstanding emphasis on fibrillar Aβ deposits and neuronal death slowly gave way to a new paradigm involving soluble oligomeric forms of Aβ, which play a prominent role in triggering the cognitive deficits by specifically targeting synapses and disrupting synaptic signaling pathways. While this paradigm is widely accepted today in the AD field, the molecular details have not been fully elucidated. In this review, we address some of the important evidence, which has led to the Aβ oligomer-centric hypothesis as well as some of the key findings concerning the effects of Aβ oligomers on synapses at a morphological and functional level. Understanding how Aβ oligomers target synapses provides an important framework for ongoing AD research, which can lead to the development of successful therapeutic strategies designed to alter or perhaps reverse the course of the disease.
Taub Institute for Research on Alzheimer's Disease and the Aging Brain and Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, United States.
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J
Pozueta
R
R
Lefort
M L
ML
Shelanski
D000544:Alzheimer Disease / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D049229:Dendritic Spines / Q000473:pathology* / Q000502:physiology; D004195:Disease Models, Animal; D051379:Mice; D009473:Neuronal Plasticity; D013569:Synapses / Q000473:pathology* / Q000502:physiology
D016229:Amyloid beta-Peptides