The role of cell cycle and excitotoxicity in Alzheimer’s disease pathogenesis
Creators: name: Deng, Yuanyuan
Publisher: name: Macquarie University
Year: 2024
Subjects: classificationCode: 399999
subject: Other education not elsewhere classified

description: Alzheimer’s disease (AD) is the most prevalent form of neurodegenerative diseases. The prevalence of AD is increasing globally with an ever-aging population, imposing severe burdens upon society and the economy. The disease is characterised by extracellular Aβ plaques and intracellular tau tangles. Debates surrounding whether Aβ or tau drives the disease or whether their depositions are secondary events mediated by other underlying causes have swirled over the past decade. Several hypotheses have been proposed to explain the AD pathogenesis, including pathological roles of key proteins like Aβ and tau, or toxic processes involving excitotoxicity, cell cycle, inflammation, and/or mitochondrial dysfunction. However, therapeutic candidates developed based on these only show limited efficacies in AD patients, and none provides a unifying insight into the diverse early events. These knowledge gaps are particularly obvious when examining the role of cell cycle and GABA interneuron-related excitotoxicity in AD. This thesis considers two potential disease pathways which have not been addressed in detail before. Firstly, cell cycle regulator proteins have been increasingly detected in neurons of human AD and AD mouse brains with unclear mechanisms. By taking advantage of the evolution of technologies and tools in biology research, we applied the fluorescent ubiquitination-based cell cycle indicator (FUCCI) to monitor cell cycle in live neurons and explore the role of cell cycle in AD models. Transient cell cycle re-entry activity was observed in naïve neurons. Further, primary hippocampal neurons showed rapid activation of the cell cycle process under oligomericamyloid-β (oAβ) challenge. Surprisingly, this cell cycle re-entry activity protected neurons from Aβ-induced cell death. Accordingly, increased numbers of neurons with high FUCCI reporter activity and high numbers of endogenous cell cycle control protein geminin-stained neurons were detected in the brains of human mutant Aβ precursor protein transgenic (APP23) mice at ages before overt cell loss. Furthermore, human AD brains also showed high numbers of cell cycle-positive neurons. Next, considering the hyperexcitation of neuronal networks in AD, the second part of the thesis focused on applying the innovative Collaborative Cross (CC) forward genetics mouse platform to identify novel modifier genes of neuronal hyperexcitation. We identified <i>Lamp5 </i>as a novel modifier gene of neuronal hyperexcitation and investigated its function in the context of AD using a range of different AD mouse models. We found a markedly decrease of LAMP5 expression in AD and Frontotemporal lobar degeneration (FTLD-tau) brains, as well as in APP23, APP/PS1 and TAU58 mouse models. Genetic reduction of <i>LAMP5 </i>led to the degeneration of LAMP5 interneurons in cortex and dentate gyrus in 3 months old Lamp5-deficient (Lamp5Δ/Δ) mice. Moreover, LAMP5 reduction augmented functional deficits and neuronal network hypersynchronisity in Aβ- or tau-driven AD mouse models. In conclusion, we suggest that there are crucial roles of cell cycle re-entry and neuronal hyperexcitation in AD. Moreover, we bring the following new insights into specific underlying mechanisms. Neurons dynamically leave cell cycle arrest and re-enter cell cycle rather than in a permanently postmitotic state. Cells susceptible to initiate cell cycle are more resilient to Aβ toxicity, challenging the typical notion that cell cycle re-entry is a prerequisite for neuronal death in AD. Furthermore, by defining the specific function of LAMP5 interneurons in neuronal network hyperexcitation in AD, we expanded the excitotoxicity hypothesis previously centered around the glutamatergic and cholinergic systems in abnormal neuronal networks. Altogether, our work enhances the current understanding of both the cell cycle and excitotoxicity hypothesis in the pathogenesis of AD and may thereby shed light on the identification of new therapeutic targets for AD treatment.