Taddei, Raquel N;
(2024)
Understanding the role of glia and oligomeric tau in the
early synapse loss of Alzheimer disease dementia.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Synapse loss is the strongest correlate of dementia in AD. Yet, the underlying causes of synaptic derangement remain largely unknown. Emerging evidence suggests that glial cells play a central role in synapse elimination and recent studies have shown that microglia internalize more synapses in demented than in control brains. Additionally, amyloid-β and tau oligomers are significantly higher in the synapses of demented brains. The present study included 60 human brains of demented and resilient individuals at intermediate stages of tau pathology (Braak III-IV) and cognitively unimpaired controls (Braak 0-II). The temporal cortex, a Braak III-IV region with incipient neurofibrillary tangles (NFTs), and the visual cortex, a Braak VI region without NFTs were evaluated. Glial cell phenotypic changes were quantified with immunohistochemistry and artificial intelligence-supported analyses, and synaptic elements with expansion microscopy and Imaris analyses, complemented with western blotting. Demented brains showed higher inflammatory and lower homeostatic but no change in total glial cell numbers compared with resilient and controls. Notably, these glial cell changes occurred irrespectively of amyloid-β and NFTs (temporal cortex) and ahead of NFT development (visual cortex). Moreover, a significant synapse loss was present in the NFT-free visual cortex of demented brains and showed a strong association with cognitive scores, especially with visual memory tasks. Synapses extracted from the visual cortex of demented brains contained more oligomeric and hyperphosphorylated tau compared with resilient but no change in tau truncation or detectable seeding activity. Importantly, microglia and astrocytes of demented brains harboured significantly more internalized synaptic elements and particularly high tau oligomer-positive synapses. A primary glial cell dysfunction may determine the early synapse loss driving AD dementia irrespectively of AD-typical lesions, and this may be promoted and perpetuated by oligomeric tau contained in synapses, leading to chronic synapse elimination and the development and progression of AD dementia.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Understanding the role of glia and oligomeric tau in the early synapse loss of Alzheimer disease dementia |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2024. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| Keywords: | Alzheimer Disease, Synapse loss, Neuroinflammation |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10190350 |
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