Characterization of glial & neuronal changes associated with amyloid-β pathology in alzheimer’s disease models
File(s)
Author(s)
Tang, Jiabin
Type
Thesis
Abstract
There are an estimated 47 million people worldwide with Alzheimer’s Disease (AD) according to a report by the World Health Organization. Amyloid-β (Aβ) deposition, tau pathology, glial activation and neurodegeneration are four hallmarks of AD. This project has focused on characterising the relationships between Aβ oligomers, Aβ plaques, glial activation and neurodegeneration in two human amyloid mouse models. The two models were the triple knock-in AppNL-G-F mouse which shows increased Aβ pathology without App overexpression, and the Apphu mouse which expresses the human App gene. The comparison between AppNL-G-F, Apphu and WT mouse improved our knowledge of the difference between Aβ oligomers and plaques on their relationships with a range of cellular markers.
Temporal and spatial relationships of individual pathologies were characterized with immunohistochemistry and imaging mass cytometry, using markers assessing Aβ proteins, microglial and astrocytic activation, as well as neuronal and synaptic densities. Aβ oligomers were abundant in brains of Apphu mice, but there were only low levels of Aβ plaques. The brains showed astrocyte activation but very little microglial activation. In AppNL-G-F mice, both high levels of Aβ oligomers and numerous plaques were observed and they were associated with substantial astrocytic and microglial activation.
The increase of Aβ oligomers over time correlated more closely with the extent of astrocytic activation than with microglia activation. However, in spatial analysis, microglia were more closely associated with Aβ oligomers than with Aβ plaques in AppNL-G-F mice. In terms of neurodegeneration, the initially high levels of neuronal and synaptic markers spatially associated with Aβ oligomers become significantly lower over time in AppNL-G-F mice. No sex difference in AppNL-G-F mice was observed with Aβ pathology, either Aβ oligomers or plaques, but male mice tended to show more microglia and higher synaptic density compared with female mice, potentially suggesting lower susceptibility or a more protective microenvironment.
Based on these results, Aβ oligomers appear to be more directly related to neuroinflammation and neurodegeneration, but their presence is not sufficient to evoke the microglial activation or neuronal loss without the existence of Aβ plaques.
Temporal and spatial relationships of individual pathologies were characterized with immunohistochemistry and imaging mass cytometry, using markers assessing Aβ proteins, microglial and astrocytic activation, as well as neuronal and synaptic densities. Aβ oligomers were abundant in brains of Apphu mice, but there were only low levels of Aβ plaques. The brains showed astrocyte activation but very little microglial activation. In AppNL-G-F mice, both high levels of Aβ oligomers and numerous plaques were observed and they were associated with substantial astrocytic and microglial activation.
The increase of Aβ oligomers over time correlated more closely with the extent of astrocytic activation than with microglia activation. However, in spatial analysis, microglia were more closely associated with Aβ oligomers than with Aβ plaques in AppNL-G-F mice. In terms of neurodegeneration, the initially high levels of neuronal and synaptic markers spatially associated with Aβ oligomers become significantly lower over time in AppNL-G-F mice. No sex difference in AppNL-G-F mice was observed with Aβ pathology, either Aβ oligomers or plaques, but male mice tended to show more microglia and higher synaptic density compared with female mice, potentially suggesting lower susceptibility or a more protective microenvironment.
Based on these results, Aβ oligomers appear to be more directly related to neuroinflammation and neurodegeneration, but their presence is not sufficient to evoke the microglial activation or neuronal loss without the existence of Aβ plaques.
Version
Open Access
Date Issued
2022-10-13
Date Awarded
01/01/2023
License URL
Advisor
Matthews, Paul
Gentleman, Steve
Publisher Department
Department of Brain Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)