Profiling the molecular signatures of astrocytes in synucleinopathy and therapeutic targeting in aging

Aging is generally considered an irreversible process predisposing the brain to neurodegenerative diseases, such as Parkinson’s disease (PD), Alzheimer’s disease (AD) and Huntington’s disease (HD). Over the past two decades, both clinical and experimental studies have provided compelling evidence on the crucial roles of reactive gliosis in aging and neurodegenerative diseases. The main theme of this thesis is to examine the detailed molecular changes that underlie reactive gliosis in aging and PD in animal models.The misfolding and pathological aggregation of specific proteins, such as α- synuclein (SNCA) and Lewy body in PD, is proposed to be one of the key factors that link reactive gliosis, neuroinflammatory responses and neurodegeneration. However, the detailed transcriptomic and functional changes of astrocytes in synucleinopathyassociated PD remain to be elucidated. In the first chapter, I report the molecular characteristics of a newly identified reactive astrocytes phenotype, the synucleinopathy-associated astrocytes (SAAs), in a human A53T-SNCA knockin (Huα- Syn(A53T)) mouse model of PD. Further studies attempted to investigate the in vivo and in vitro induction of SAAs and their interactions with other glial cells. These results revealed that SAAs may play a significant functional role in PD associated with synucleinopathy, and the therapeutic implications of SAAs in PD await further investigations.Pharmacological reversal of brain aging is a long-sought yet challenging strategy for the prevention and treatment of age-related neurodegeneration, due to the diverse cell types and complex cellular pathways impacted by the aging process. Glucagon-like peptide-1 receptor (GLP-1R) is a receptor protein expressed by subsets of neurons and glial cells in the brain. In the second chapter, I report the genome-wide reversal of transcriptomic aging signatures in multiple major brain cell types, including glial and mural cells, by treatment with exenatide, an GLP-1R agonist (GLP-1RA). The agerelated expression changes reversed by GLP-1RA encompass both shared and cell typespecific functional pathways that are implicated in aging and neurodegeneration. Concomitantly, Alzheimer’s disease (AD)-associated transcriptomic signature in microglia that arises from aging is reduced. These results show the feasibility of reversing brain aging by pharmacological means, provide mechanistic insights into the neurological benefits of GLP-1RAs in diabetic patients, and imply that GLP-1R agonism may be a generally applicable pharmacological intervention for patients at risk of age-related neurodegeneration.衆所周知，衰老與帕金森氏病，阿爾茨海默氏病和亨廷頓氏病等神經退行性疾病都具有不可逆轉等相同的病理特徵。有證據表明，反應型星形膠質細胞在衰老和神經退行性疾病中起關鍵作用。本論文的主題是研究動物模型中衰老和帕金森氏病引起的反應性膠質增生的詳細分子變化。家族性帕金森氏病患者中某些特定蛋白質的錯誤折疊和病理性聚集被認為是將神經炎性反應和神經變性聯繫起來的關鍵機制之一，例如α 突觸核蛋白及其所形成的路易小體。然而，在對於突觸核蛋白病相關的帕金森氏病的研究中，星形膠質細胞在轉錄水平和功能水平的變化尚待闡明。在本論文的第一章中，在敲入人A53T 突變型SNCA 基因的帕金森氏病小鼠模型中，我們研究了與突觸核蛋白相關的星形膠質細胞的特徵及其機制。在體和體外誘導形成突觸核蛋白相關的星形膠質細胞等進一步的研究證明不同膠質細胞與該特殊類型星形膠質細胞之間的相互作用，以及其在與突觸核蛋白相關的帕金森氏病中的潛在治療意義。這些結果表明，與突觸核蛋白病相關的星形膠質細胞可能在帕金森氏病的α 突觸核蛋白突變和路易體形成中發揮神經保護作用，這表明對神經退行性疾病具有潛在的治療作用。腦衰老的藥理學逆轉是預防和治療與年齡有關的神經退行性疾病的長期尋求但具有挑戰性的策略，這是由於衰老過程影響了多種細胞類型和所涉及的復雜的信號通路。胰高血糖素樣肽1 受體是主要分佈于腦内神經元上的受體蛋白。在本文第二章中，我們研究了通過胰高血糖素樣肽1 受體激動劑處理的多種腦細胞類型中轉錄組衰老特徵的全基因組逆轉。研究表明，由胰高血糖素樣肽1 受體激動劑逆轉的年齡相關的表達變化，同時涵蓋了與衰老和神經變性相關的各個細胞類型及其特異性功能途徑。另外，在衰老過程中，小膠質細胞中與阿爾茨海默氏病相關的轉錄組升高，而在經胰高血糖素樣肽1 受體激動劑處理后，其與阿爾茨海默氏病相關的轉錄組水平有所下降。這些結果證明了通過藥理學方法逆轉腦衰老的可行性，為糖尿病患者中胰高血糖素樣肽1 受體激動劑的神經學益處提供了機械學見解，並且暗示了胰高血糖素樣肽1 受體激動劑可能是適用於有年齡相關風險的患者用於治療神經變性病的普適藥物。Chen, Xinyi.Ph.D. Chinese University of Hong Kong 2021.Includes bibliographical references (leaves ).Abstracts also in Chinese.Title from PDF title page (viewed on …)