Abstract
Synapse loss is the strongest correlate for cognitive decline in Alzheimer's disease. The mechanisms underlying synapse loss have been extensively investigated using mouse models expressing genes with human familial Alzheimer's disease mutations. In this review, we summarize how multiphoton in vivo imaging has improved our understanding of synapse loss mechanisms associated with excessive amyloid in the living animal brain. We also discuss evidence obtained from these imaging studies for the role of cell-intrinsic calcium dyshomeostasis and cell-extrinsic activities of microglia, which are the immune cells of the brain, in mediating synapse loss.
Highlights
Immunohistochemistry of postmortem brain from Alzheimer’s disease (AD) patients revealed that synapse loss is the strongest correlate for the cognitive deficit (Terry et al, 1991; DeKosky et al, 1996; Scheff and Price, 2006; Scheff et al, 2007; de Wilde et al, 2016)
Mouse models that express familial AD-associated mutations in genes coding for amyloid precursor protein and presenilin that increase amyloid levels in the brain or that express mutated Tau leading to neurofibrillary tangles provide an entry point to study mechanisms of synapse loss associated with prominent AD related pathologies, such as amyloid plaques and neurofibrillary tangles (Jankowsky and Zheng, 2017)
We focus on how in vivo imaging using two-photon microscopy has revealed the properties and mechanisms of synapse loss in mouse models of AD, emphasizing mouse models of amyloidosis
Summary
Immunohistochemistry of postmortem brain from Alzheimer’s disease (AD) patients revealed that synapse loss is the strongest correlate for the cognitive deficit (Terry et al, 1991; DeKosky et al, 1996; Scheff and Price, 2006; Scheff et al, 2007; de Wilde et al, 2016). BACE-1 levels are increased in dystrophic neurites in cultured neurons and brain sections of AD patients, and 5XFAD amyloid mouse model (Zhang et al, 2009; Kandalepas et al, 2013; Sadleir et al, 2016), and dystrophic neurites can contribute to plaque growth. Consistent with this idea, inhibition of BACE1 decreased the growth rate of plaques (Peters et al, 2018), which, in turn, reduced the formation of dystrophic neurites associated with plaque (Peters et al, 2018). Since neurite dystrophy is Frontiers in Cellular Neuroscience | www.frontiersin.org
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