Bar Sudipta, Wilson Kenneth A, Hilsabeck Tyler A U, Alderfer Sydney, Dammer Eric B, Burton Jordan B, Shah Samah, Holtz Anja, Carrera Enrique M, Beck Jennifer N, Chen Jackson H, Kauwe Grant, Tracy Tara E, Seyfried Nicholas T, Schilling Birgit, Ellerby Lisa M, Kapahi Pankaj
Buck Institute for Research on Aging, Novato, CA 94947, USA.
Emory Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA 30322, USA.
Res Sq. 2023 Nov 8:rs.3.rs-3526342. doi: 10.21203/rs.3.rs-3526342/v1.
Tauopathies encompass a range of neurodegenerative disorders, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). Unfortunately, current treatment approaches for tauopathies have yielded limited success, underscoring the pressing need for novel therapeutic strategies. We observed distinct signatures of impaired glycogen metabolism in the brain of the tauopathy model and the brain of AD patients, indicating a link between tauopathies and glycogen metabolism. We demonstrate that the breakdown of neuronal glycogen by activating glycogen phosphorylase (GlyP) ameliorates the tauopathy phenotypes in flies and induced pluripotent stem cell (iPSC) derived neurons from FTD patients. We observed that glycogen breakdown redirects the glucose flux to the pentose phosphate pathway to alleviate oxidative stress. Our findings uncover a critical role for increased GlyP activity in mediating the neuroprotection benefit of dietary restriction (DR) through the cAMP-mediated protein kinase A (PKA) activation. Our studies identify impaired glycogen metabolism as a key hallmark for tauopathies and offer a promising therapeutic target in tauopathy treatment.
tau蛋白病包括一系列神经退行性疾病，如阿尔茨海默病（AD）和额颞叶痴呆（FTD）。不幸的是，目前针对tau蛋白病的治疗方法成效有限，这凸显了对新型治疗策略的迫切需求。我们在tau蛋白病模型的大脑以及AD患者的大脑中观察到糖原代谢受损的明显特征，表明tau蛋白病与糖原代谢之间存在联系。我们证明，通过激活糖原磷酸化酶（GlyP）来分解神经元糖原，可改善果蝇以及来自FTD患者的诱导多能干细胞（iPSC）衍生神经元中的tau蛋白病表型。我们观察到糖原分解将葡萄糖通量重定向至磷酸戊糖途径以减轻氧化应激。我们的研究结果揭示了增加的GlyP活性在通过cAMP介导的蛋白激酶A（PKA）激活来介导饮食限制（DR）的神经保护益处方面的关键作用。我们的研究确定糖原代谢受损是tau蛋白病的一个关键标志，并为tau蛋白病治疗提供了一个有前景的治疗靶点。
