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.

► Alzheimer’s disease is the result of synaptic dysfunction and neuronal loss.
► Mouse models of AD recapitulate the synaptic dysfunction phenotype.
► Memory deficits are associated with the loss of dendritic spine numbers/morphology.
► Aβ targets and destroys dendritic spines by hijacking cytoskeletal signaling pathways.
► Dendritic spine pathologies in mouse models are reversible by a variety of treatments.