Benitez Jimenez, Diana Pamela;
(2021)
Assessment of microglia influence in synaptic transmission and early amyloid-β plaque deposition in knock-in mouse models for Alzheimer`s disease.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Alzheimer´s disease (AD) is the most common type of dementia representing an estimated 60-80% of all cases, and no cure or successful therapy has been found. Two main hallmarks have been identified in AD histopathology: senile plaques, composed of amyloid-β protein (Aβ), and neurofibrillary tangles, composed of phosphorylated TAU protein. Additionally, genetic studies have shown that immune processes play important roles in AD. Microglial gene expression and function are closely correlated to amyloid pathology and are therefore potential targets for altering the progression of AD. Recently an Amyloid Precursor Protein knock-in line was generated, which, in contrast to transgenic AD mice shows an Aβ pathology without overexpression. This project aims to analyse if microglial cells are active modulators of Aβ plaques and synaptic changes in APP knock-in mice at the early stages of the pathology. Initial characterisation of electrophysiological phenotypes for APPNL-G-F and APPNL-F were studied. Also, dose- and time-dependent effects of the drug PLX5622, which has been shown to specifically deplete microglia, were analysed. APPNL-G-F mice exhibited unaltered synaptic transmission at 3.5 months of age regardless a clear accumulation of hippocampal Aβ plaques. APPNL-F mice showed increased glutamate release probability, unchanged spontaneous excitatory activity and little accumulation of Aβ plaques at 10 months of age. After PLX5622 treatments, surviving microglia tended to be CD68+ in both APP knock-in models. Partial microglia ablation led to aged but not young wild type animals mimicking the increased glutamate release probability and exacerbated the APP knock-in phenotype. Complete ablation was less effective in altering synaptic function, while neither treatment altered plaque load. It is suggested that alteration of surviving microglia towards a phagocytic phenotype, rather than microglial loss, drives age-dependent effects on glutamate release that become exacerbated in AD.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Assessment of microglia influence in synaptic transmission and early amyloid-β plaque deposition in knock-in mouse models for Alzheimer`s disease |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2021. 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. |
| 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 Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10138578 |
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