Vitanova, Karina; (2022) Assessment of the effects of plaques and glia on synaptic transmission in App knock-in models of Alzheimer’s disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder associated with the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles, coupled to extensive synaptic denervation and gliosis. The role of microglia in disease progression has become a central focus for AD research with studies showing that they cluster around amyloid plaques and some indications that plaque-associated microglia phagocytose synapses in these regions. The present work aimed to explore if this is a protective mechanism to limit plaque-associated toxicity by examining the hippocampus of AppNL-F and AppNL-G-F using patch-clamp electrophysiology and immunohistochemistry. This work also explored AppNL-F/Trem2R47H mice to determine how a compromised microglial response affects synaptic activity. I found that AppNL-G-F mice exhibit heavier plaque pathology with age and a larger number of smaller-sized plaques, similar to what I observed in AppNL-F/Trem2R47H mice in comparison to AppNL-F mice. AppNL-G-F mice also showed increased microglial density compared to wild-types, regardless of age, and no changes in astrocyte density. In comparison, the presence of the Trem2R47H mutation in AppNL-F mice led to reduced microglial density in the SLM region, where the plaque load in these mice was the heaviest, and also reversed the increased astrocytic density which was observed in AppNL-F mice. In terms of electrophysiological changes, I found alterations in the kinetics of the postsynaptic response and changes in the failure rate in both models. Exploring electrophysiological changes in plaque-associated regions revealed that both AppNL-G- F and AppNL-F mice exhibit lower amplitudes in plaque compared to no-plaque conditions, while this effect was lost in AppNL-F/Trem2R47H mice. Furthermore, both AppNL-F and AppNL-F/Trem2R47H mice showed enhanced release probability in plaque conditions. Altogether, these results illustrate the dual effects of plaque presence around axons which are driven by the effects of soluble Aβ and microglia on the presynapse and postsynapse, respectively.

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