The Role of Synaptopathy in Alzheimer's Disease: A Review of Key Transgenic Mouse Models

Abstract

Introduction: Long-term potentiation (LTP) and its counterpart, long-term depression (LTD), are considered the cellular basis underpinning learning and memory. Impairments in these processes are associated with neurodegenerative diseases such as Alzheimer’s disease (AD). These impairments are emergent during the onset of AD, suggesting a critical role in the pathophysiology of AD. Popular transgenic AD models, such as 5xFAD, 3xTg, Tau MAPT P301L, and APPswe/PSEN1dE9 demonstrate changes in synaptic plasticity early during their lifespan. This systematic review aims to investigate localization and onset of synaptopathy associated with AD. Methods: A comprehensive literature search was conducted using PubMed (Medline) to identify common features across models associated with synaptic plasticity. Papers were screened through two stages. The first stage involved establishing a set of criteria, including search terms. The second stage centered on ensuring chosen studies focused on synaptopathy and utilized the models selected. Results: Eight studies were selected across the four transgenic mouse models that established onset and localization of synaptopathy in AD pathophysiology. In the majority of studies, impairments in synaptic plasticity were first found in the CA1 region of the hippocampus. Moreover, onset of these impairments developed prior to onset of neuropathology and behavioral or cognitive deficits. Impairments in synaptic plasticity included inhibition of glutamate release, decreased cell excitability, dendritic atrophy and impaired receptor signaling. Discussion: The results of this review suggest localization of synaptic plasticity impairments to the CA1 region preceding development of neuropathologies such as amyloid or tau aggregation and cognitive deficits. This indicates an early and critical role of synaptopathy at the CA1 region, implicating it as a potential causal factor in the pathophysiology of AD. Conclusion: While the FAD models evaluated in this review implicate changes in synaptic plasticity within AD, they are not representative of late onset AD (LOAD), the prevalent form of the disease in the population. Currently research using LOAD models is limited, causing reliance on FAD models for the study of AD. As prevalence of AD increases in the population, it is essential that new models of LOAD are developed and studied to further current understandings of AD pathophysiology.