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Metformin Ameliorates A? Pathology by Insulin-Degrading Enzyme in a Transgenic Mouse Model of Alzheimer's Disease.

ABSTRACT: Alzheimer's disease (AD) is the most common neurodegenerative disease. The accumulation of amyloid beta (A?) is the main pathology of AD. Metformin, a well-known antidiabetic drug, has been reported to have AD-protective effect. However, the mechanism is still unclear. In this study, we tried to figure out whether metformin could activate insulin-degrading enzyme (IDE) to ameliorate A?-induced pathology. Morris water maze and Y-maze results indicated that metformin could improve the learning and memory ability in APPswe/PS1dE9 (APP/PS1) transgenic mice. 18F-FDG PET-CT result showed that metformin could ameliorate the neural dysfunction in APP/PS1 transgenic mice. PCR analysis showed that metformin could effectively improve the mRNA expression level of nerve and synapse-related genes (Syp, Ngf, and Bdnf) in the brain. Metformin decreased oxidative stress (malondialdehyde and superoxide dismutase) and neuroinflammation (IL-1? and IL-6) in APP/PS1 mice. In addition, metformin obviously reduced the A? level in the brain of APP/PS1 mice. Metformin did not affect the enzyme activities and mRNA expression levels of A?-related secretases (ADAM10, BACE1, and PS1). Meanwhile, metformin also did not affect the mRNA expression levels of A?-related transporters (LRP1 and RAGE). Metformin increased the protein levels of p-AMPK and IDE in the brain of APP/PS1 mice, which might be the key mechanism of metformin on AD. In conclusion, the well-known antidiabetic drug, metformin, could be a promising drug for AD treatment.

SUBMITTER: Lu XY

PROVIDER: S-EPMC7191377 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Metformin Ameliorates Aβ Pathology by Insulin-Degrading Enzyme in a Transgenic Mouse Model of Alzheimer's Disease.

Lu Xin-Yi XY Huang Shun S Chen Qu-Bo QB Zhang Dapeng D Li Wanyan W Ao Ran R Leung Feona Chung-Yin FC Zhang Zhimin Z Huang Jisheng J Tang Ying Y Zhang Shi-Jie SJ

Oxidative medicine and cellular longevity 20200419

Alzheimer's disease (AD) is the most common neurodegenerative disease. The accumulation of amyloid beta (Aβ) is the main pathology of AD. Metformin, a well-known antidiabetic drug, has been reported to have AD-protective effect. However, the mechanism is still unclear. In this study, we tried to figure out whether metformin could activate insulin-degrading enzyme (IDE) to ameliorate Aβ-induced pathology. Morris water maze and Y-maze results indicated that metformin could improve th ...[more]

PMID: 32377293

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Project description:Alzheimer's disease (AD) is a progressive neurodegenerative disease manifested by cognitive impairment. As a unique approach to open the blood-brain barrier (BBB) noninvasively and temporarily, a growing number of studies showed that low-intensity focused ultrasound in combination with microbubbles (FUS/MB), in the absence of therapeutic agents, is capable of ameliorating amyloid or tau pathology, concurrent with improving memory deficits of AD animal models. However, the effects of FUS/MB on both the two pathologies simultaneously, as well as the memory behaviors, have not been reported so far. Methods: In this study, female triple transgenic AD (3×Tg-AD) mice at eight months of age with both amyloid-? (A?) deposits and tau phosphorylation were treated by repeated FUS/MB in the unilateral hippocampus twice per week for six weeks. The memory behaviors were investigated by the Y maze, the Morris water maze and the step-down passive avoidance test following repeated FUS/MB treatments. Afterwards, the involvement of A? and tau pathology were assessed by immunohistochemical analysis. Neuronal health and phagocytosis of A? deposits by microglia in the hippocampus were examined by confocal microscopy. Further, hippocampal proteomic alterations were analyzed by employing two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) combined with mass spectrometry. Results: The three independent memory tasks were indicative of evident learning and memory impairments in eight-month-old 3×Tg-AD mice, which developed intraneuronal A?, extracellular diffuse A? deposits and phosphorylated tau in the hippocampus and amygdala. Following repeated FUS/MB treatments, significant improvement in learning and memory ability of the 3×Tg-AD mice was achieved. Amelioration in both A? deposits and phosphorylated tau in the sonicated hemisphere was induced in FUS/MB-treated 3×Tg-AD mice. Albeit without increase in neuron density, enhancement in axonal neurofilaments emerged from the FUS/MB treatment. Confocal microscopy revealed activated microglia engulfing A? deposits in the FUS/MB-treated hippocampus. Further, proteomic analysis revealed 20 differentially expressed proteins, associated with glycolysis, neuron projection, mitochondrial pathways, metabolic process and ubiquitin binding etc., in the hippocampus between FUS/MB-treated and sham-treated 3×Tg-AD mice. Conclusions: Our findings reinforce the positive therapeutic effects on AD models with both A? and tau pathology induced by FUS/MB-mediated BBB opening, further supporting the potential of this treatment regime for clinical applications.

Dataset Information

Metformin Ameliorates A? Pathology by Insulin-Degrading Enzyme in a Transgenic Mouse Model of Alzheimer's Disease.

Publications

Metformin Ameliorates A<i>β</i> Pathology by Insulin-Degrading Enzyme in a Transgenic Mouse Model of Alzheimer's Disease.

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