Zhang, Weicong; (2024) Investigating Cell-type Specific Neuropathology in knock-in APP and tau Mouse Models of Alzheimer’s Disease Correlated with Cognitive Deficits and Anxiety. Doctoral thesis (Ph.D), UCL (University College London).

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Text WEICONG ZHANG Thesis final submission Jan 2025.pdf - Accepted Version Download (4MB) | Preview

Abstract

Alzheimer’s disease (AD) is a debilitating chronic neurodegenerative condition characterised by progressive cognitive deficits, neuropsychiatric symptoms (NPS), and toxic amyloid-beta accumulation, shown to be correlated with selective dysfunction of cell types. Currently, there are no disease modifying cures for cognition decline and NPS of AD, although there are drugs under clinical trials which slow down clinical decline, e.g. Donanemab (Eli Lilly); this could be related to the lack of mouse models that accurately recapitulate Aβ pathology and tauopathy as in the human condition. Therefore, the initial aim of this project was to generate a human tau and mice app gene knock-in mouse model of AD that harbours genes for microtubule-associated protein tau (MapthTau) and β-amyloid precursor protein App (AppNL-F). Using this model (App NL-F /MAPT htau/wt) in conjunction with AppNL-F KI, an age-matched wild-type control, we performed behavioural studies combined with neurochemistry and confocal microscopy to investigate the impact of MAPT tau on anxiety level and AD progression in the CA1 region of brains, which are among the first to degenerate. In conclusion, this project provides evidence that AD mouse models showed more severe cognition decline and anxiety levels compared to the age-matched wild-type mice. However, MAPT did not significantly affect the spread of the cellular hallmarks of AD: Aβ, neuroinflammation or the selective alteration of inhibitory interneurons (Calretinin, Parvalbumin, Cholecystokinin), which was previously shown to be correlated with synaptic dysfunction associated with the cognitive decline. Recent experimental data has suggested neuronal excitation-inhibition (E-I) imbalance as a critical regulator of AD pathology. GABA receptors play important roles in the balance. We found the downregulation of δ subunit of GABAA receptors(δ-GABAARs) located in discreet neuronal circuitry of the hippocampus. Our data suggested a δ-subunit selective agonist increased levels of δ-GABAAR, lowered inflammation and anxiety in AD mice, which indicated a potential target to improve the quality of life of AD patients and caregivers.

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