Abstract
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by initial memory impairments that progress to dementia. In this sense, synaptic dysfunction and loss have been established as the pathological features that best correlate with the typical early cognitive decline in this disease. At the histopathological level, post mortem AD brains typically exhibit intraneuronal neurofibrillary tangles (NFTs) along with the accumulation of amyloid-beta (Abeta) peptides in the form of extracellular deposits. Specifically, the oligomeric soluble forms of Abeta are considered the most synaptotoxic species. In addition, neuritic plaques are Abeta deposits surrounded by activated microglia and astroglia cells together with abnormal swellings of neuronal processes named dystrophic neurites. These periplaque aberrant neurites are mostly presynaptic elements and represent the first pathological indicator of synaptic dysfunction. In terms of losing synaptic proteins, the hippocampus is one of the brain regions most affected in AD patients. In this work, we report an early decline in spatial memory, along with hippocampal synaptic changes, in an amyloidogenic APP/PS1 transgenic model. Quantitative electron microscopy revealed a spatial synaptotoxic pattern around neuritic plaques with significant loss of periplaque synaptic terminals, showing rising synapse loss close to the border, especially in larger plaques. Moreover, dystrophic presynapses were filled with autophagic vesicles in detriment of the presynaptic vesicular density, probably interfering with synaptic function at very early synaptopathological disease stages. Electron immunogold labeling showed that the periphery of amyloid plaques, and the associated dystrophic neurites, was enriched in Abeta oligomers supporting an extracellular location of the synaptotoxins. Finally, the incubation of primary neurons with soluble fractions derived from 6-month-old APP/PS1 hippocampus induced significant loss of synaptic proteins, but not neuronal death. Indeed, this preclinical transgenic model could serve to investigate therapies targeted at initial stages of synaptic dysfunction relevant to the prodromal and early AD.
Highlights
Alzheimer’s disease (AD) is the most common type of dementia, characterized by an initial and gradual memory impairment that eventually affects to other cognitive functions
Given that Aβ oligomeric species have been recognized as synaptotoxic agents, we intended to investigate their location
The role of amyloid plaques in AD synaptopathology has been a subject of deep controversy
Summary
Alzheimer’s disease (AD) is the most common type of dementia, characterized by an initial and gradual memory impairment that eventually affects to other cognitive functions. Synaptic loss and dysfunction have been considered the best pathological correlation with early cognitive decline (DeKosky and Scheff, 1990; Terry et al, 1991; Selkoe, 2002; Scheff et al, 2007; Arendt, 2009; Shankar and Walsh, 2009; John and Reddy, 2021). Dystrophic neurites are swollen axons and presynaptic terminals that surround amyloid plaques These dysfunctional processes are a common AD phenomenon within brain regions related to learning and memory (Su et al, 1993, 1998; Dickson et al, 1999; Dickson and Vickers, 2001), and represent the first event of disease development that might compromise neuronal integrity and synaptic function at the very early stages of AD
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