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P2–413: AMP‐activated protein kinase activation ameliorates mitochondrial abnormalities and neurodegenerative changes in cellular and rat models of diabetes‐related Alzheimer's disease
Author(s) -
Du LaiLing,
Cheng XiangShu,
Xie JiaZhao,
Zhou XinWen
Publication year - 2013
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2013.05.1063
Subject(s) - ampk , streptozotocin , endocrinology , medicine , activator (genetics) , diabetes mellitus , protein kinase a , mitochondrion , chemistry , amp activated protein kinase , phosphorylation , biochemistry , receptor
Background: Collecting evidence suggests that type 2 diabetes increases the risk of developing sporadic Alzheimer’ s disease (AD), and the energy metabolic dysfunction is thought to be the convergent point of diabetes and AD, but the underlying mechanisms still remain unclear. AMPK, a crucial cellular fuel sensor for energymetabolism,may be focus to link between diabetes and AD. In current study, we investigate the role of AMPK on diabetes-related AD-like pathologic features in models of high glucose cell and intracerebroventricular-streptozotocin (ICV-STZ) animals. Methods: The activity level of AMPK and the level of tau phosphorylation were examined using Western blot in vivo and in vitro. Mitochondrial membrane potential (DJm) and ROS production were assayed using JC-1 or DCFH-DA in N2a cells. The learning ability was examined using Morris water maze in ICVSTZ rats. Results: We found that the level of p-AMPK (active type of AMPK) was decreased and tau phosphorylation was increased in both models.Mitochondria from N2a cells treated with high glucose (HG) displayed a decrease in ATP content and membrane potential, and these changes can be rescued by AMPK activator AICAR. Meanwhile, high glucose enhanced and AMPK activator AICAR can attenuate high glucose induced increase of ROS production, but there was in converse effects of AMPK inhibitor Compound C (CC) in the process. Rats injected streptozotocin (STZ) via intracerebroventricular (3mg/kg, once) were simultaneously administrated with AICAR (AMPK activator) or vehicle via intracerebroventricular injection 30-minutes after ICV-STZ injection.The learning ability was lower in STZ than control group, whereas ICV-STZ rats treated with AICAR almost completely rescued the ICV-STZ induced cognitive impairment and tau hyperphosphorylation. Conclusions: Taken all together, these results suggested that AMPK activation mitigated impaired mitochondrial functions and diabetes-related AD-like pathologic features, and that AMPK could serve as a potential therapeutic target for diabetes-related AD.