Sunday, May 18, 2025
5/18/2025
Epitranscriptomic Mechanism in pathogenesis of Alzheimer’s disease - Contact PD/PI: Jiang, Lulu Epitranscriptomic Mechanism in Pathogenesis of Alzheimer's disease PROJECT SUMMARY The accumulation of microtubule-associated protein tau (tau) aggregates intricately parallels cognitive decline in Alzheimer's disease and related disorders (ADRD), underscoring its paramount importance in maintaining neuronal health. Yet, despite this association, the precise cascade through which tau aggregation induces neuronal toxicity remains elusive, representing a significant gap in our understanding of ADRD pathology. Recent proteomic and transcriptomic analyses of post-mortem AD brains consistently highlight dysregulation in RNA metabolism and protein translation, hinting at complex molecular underpinnings. Emerging evidence suggests that tau pathology instigates translational inhibition, dampening protein synthesis and triggering neuronal dysfunction. However, the elusive molecular mechanism governing tau-mediated regulation of protein translation remains a central enigma, underscoring the need for further investigation. In particular, our recent findings in the interaction of RNA modification with tau aggregation unveil novel insights into tauopathy pathogenesis. We have uncovered a striking elevation of cytoplasmic RNA methylation in human AD cases, shedding light on a new avenue for exploring disease mechanisms and developing disease-modifying strategies. The project aims to elucidate the role of RNA modification in ADRD by focusing on deciphering the dynamics of N6-methyladenosine (m6A) RNA modification in AD progression, by determining the impact of RNA methylation on AD pathogenesis, and assessing the treatment effect of inhibiting excessive RNA methylation in a mouse model of AD. The premise of the study is based on the identification of elevated m6A levels in post-mortem brain tissue of AD patients, particularly in neurons affected by tau aggregation. Our study revealed that oligomeric tau sequesters m6A-modified RNA, leading to translational inhibition and neuronal dysfunction. I hypothesize that dysregulated RNA modification and protein translational inhibition induced by tau aggregation mediate the pathogenesis of AD and related tauopathies. In Aim 1 of the current research, we seek to decode the epitranscriptomic profiles impacted by tau pathology using m6A DART-seq, aiming to improve understanding of AD pathogenesis on an epitranscriptomic level. In Aim 2, we will determine the role of RNA methylation in AD pathogenesis using 3D neuron-glial brain assembloids, targeting m6A methyltransferase and demethylase. Preliminary data indicates a protective effect of the Mettl3 inhibitor, STM2457, in delaying disease progression. In Aim 3, we aim to evaluate the therapeutic impact of inhibiting excessive RNA methylation in a humanized tau and APP double transgenic mouse model of AD. We will investigate treatment protocols targeting the m6A 'writer,' Mettl3, and the 'eraser,' ALKBH5, as this model recapitulates crucial aspects of AD pathology. Overall, the project aims to provide new insight into brain m6A as a novel layer of complexity in gene expression regulation in AD and related tauopathies. It will shed light on the molecular mechanisms of neurodegenerative diseases at the epitranscriptomic level, potentially leading to new therapeutic strategies.
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