Amylin exacerbates tau pathology in the visual cortex of diabetic mice by impairing lysosomal activity

IF 6.9 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Daniel Moreira-Silva , Melike Yuksel , Moorthi Ponnusamy , Mitchell T. Hansen , Joseph D. McMillan , Sneha Geethakrishnan , Shuai Wang , Lisa A. Collier , Gopal Thinakaran
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Abstract

The aggregation of the peptide hormone amylin in the pancreas is a pathological hallmark of type-2 diabetes. Additionally, amylin can form aggregates in the brain, promoting β-amyloid deposition and tau phosphorylation in Alzheimer's disease. The cross-seeding between amylin and tau exacerbates tau pathology spread and synaptic loss, leading to neurodegeneration and cognitive deficits. Given the link between lysosomal dysfunction and tauopathy in the brain and amylin aggregation in the pancreas, we hypothesized that amylin could potentially worsen tau pathology in diabetic mice. We administered streptozotocin and/or amylin peripherally to the PS19 model of tauopathy at 3 months and characterized them at 6 months of age. We found that streptozotocin diminished body weight gain, increased blood glucose levels, worsened motor performance, and improved fear-conditioned memory in PS19 mice. Both amylin and streptozotocin administration prompted the emergence of tau pathology in the pancreas, which coincided with a decrease in the number of lysosomes in pancreatic islets. Mice treated with amylin and streptozotocin also developed robust tau pathology concomitant with lowering lysosomal cathepsin D levels in the visual cortex. These findings suggest that in diabetic mice, amylin administration diminished pancreatic lysosomes, possibly increasing the number of amylin aggregates that reached the brain and contributing to the worsening of tau pathology due to lysosomal impairment in the visual cortex. The outcome of our research enhances the understanding of the cellular pathways by which amylin may serve as a link between the pancreas-brain axis during diabetes, influencing the risk of developing tau pathology.
胰淀素通过损害溶酶体活性加剧了糖尿病小鼠视觉皮层的tau病理
胰腺中肽激素胰淀素的聚集是2型糖尿病的病理标志。此外,胰淀素可以在大脑中形成聚集体,促进阿尔茨海默病中β-淀粉样蛋白沉积和tau蛋白磷酸化。胰淀素和tau之间的交叉播种加剧了tau病理扩散和突触丧失,导致神经变性和认知缺陷。鉴于溶酶体功能障碍与脑tau病变和胰腺胰淀素聚集之间的联系,我们假设胰淀素可能潜在地恶化糖尿病小鼠的tau病理。我们在3个月大的PS19牛头病模型周围给予链脲佐菌素和/或胰淀素,并在6个月大时对其进行表征。我们发现链脲佐菌素减少了PS19小鼠的体重增加,升高了血糖水平,恶化了运动表现,改善了恐惧条件记忆。胰淀素和链脲佐菌素均引起胰腺出现tau病理,与此同时胰岛溶酶体数量减少。用胰淀素和链脲佐菌素治疗的小鼠也出现了强大的tau病理,同时视觉皮层溶酶体组织蛋白酶D水平降低。这些发现表明,在糖尿病小鼠中,给药胰淀素减少了胰腺溶酶体,可能增加了到达大脑的胰淀素聚集体的数量,并导致视觉皮层溶酶体损伤导致tau病理恶化。我们的研究结果增强了对细胞通路的理解,在糖尿病期间,胰肽可能作为胰腺-脑轴之间的联系,影响tau病理发展的风险。
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来源期刊
Genes & Diseases
Genes & Diseases Multiple-
CiteScore
7.30
自引率
0.00%
发文量
347
审稿时长
49 days
期刊介绍: Genes & Diseases is an international journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch. Aims and Scopes Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis will be placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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