Understanding the role of glia and oligomeric tau in the \nearly synapse loss of Alzheimer disease dementia
Year: 2024
Type: dissertation
Study design: Observational Study
Abstract: Synapse loss is the strongest correlate of dementia in AD. Yet, the underlying causes of synaptic \nderangement remain largely unknown. Emerging evidence suggests that glial cells play a central role \nin synapse elimination and recent studies have shown that microglia internalize more synapses in \ndemented than in control brains. Additionally, amyloid-β and tau oligomers are significantly higher in \nthe synapses of demented brains. The present study included 60 human brains of demented and \nresilient individuals at intermediate stages of tau pathology (Braak III-IV) and cognitively unimpaired \ncontrols (Braak 0-II). The temporal cortex, a Braak III-IV region with incipient neurofibrillary tangles \n(NFTs), and the visual cortex, a Braak VI region without NFTs were evaluated. Glial cell phenotypic \nchanges were quantified with immunohistochemistry and artificial intelligence-supported analyses, \nand synaptic elements with expansion microscopy and Imaris analyses, complemented with western \nblotting. Demented brains showed higher inflammatory and lower homeostatic but no change in \ntotal glial cell numbers compared with resilient and controls. Notably, these glial cell changes \noccurred irrespectively of amyloid-β and NFTs (temporal cortex) and ahead of NFT development \n(visual cortex). Moreover, a significant synapse loss was present in the NFT-free visual cortex of \ndemented brains and showed a strong association with cognitive scores, especially with visual \nmemory tasks. Synapses extracted from the visual cortex of demented brains contained more \noligomeric and hyperphosphorylated tau compared with resilient but no change in tau truncation or \ndetectable seeding activity. Importantly, microglia and astrocytes of demented brains harboured \nsignificantly more internalized synaptic elements and particularly high tau oligomer-positive \nsynapses. A primary glial cell dysfunction may determine the early synapse loss driving AD dementia \nirrespectively of AD-typical lesions, and this may be promoted and perpetuated by oligomeric tau \ncontained in synapses, leading to chronic synapse elimination and the development and progression \nof AD dementia.
Author: Taddei, Raquel N
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7053209104