Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice

Ou, Zhanhui; Kong, Xuejian; Sun, Xiangdong; He, Xiaosong; Zhang, Le; Gong, Zhuo; Huang, Jingyi; Xu, Biao; Long, Dahong; Li, Jianhua; Li, Qingqing; Xu, Liping; Xuan, Aiguo

doi:10.1016/j.bbi.2017.12.009

Cited by 249 publications

(151 citation statements)

References 71 publications

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“…These results are consistent with previous studies describing that chronic oral metformin administration has neuroprotective effects on HFD-induced decline in hippocampal neurogenesis and neurological disorders including dementia in animals and humans [10,12,14,15,[55][56][57][58]. Similarly, in animal disease models, chronic or acute IP injection of metformin improves neurodegeneration, cognitive decline, and neuroinflammation [45,49,57]. These findings suggest that metformin exerts direct beneficial effects on brain functions, although its hypoglycemic effect is predominantly mediated via the gut [15].…”

Section: Discussionsupporting

confidence: 92%

“…To gain insight into the mechanism behind the improvement in adult neurogenesis and spatial memory in metformin-treated DIO mice with reduced plasma levels of insulin and FFA, we examined the levels of protein and phosphorylation of metformin-related signaling pathways such as the AMPK-mTOR/aPKC f/k pathway and IR-IRS1 signaling in the hippocampus of middle-aged DIO mice with or without chronic treatment with metformin [23,24,[44][45][46][47][48]. IP injection of metformin for 1 or 14 days increased the phosphorylation level of AMPK in the hippocampus or the whole brain of disease model animals [45,49]. Similarly, in our studies, chronic metformin administration in drinking water augmented the phosphorylation level of AMPK in middle-aged DIO mice, whereas the phosphorylation level of mTOR was unchanged in those mice (Fig.…”

Section: Chronic Metformin Treatment Increases the Phosphorylation Ofmentioning

confidence: 99%

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Metformin treatment ameliorates diabetes‐associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1

et al. 2018

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Age‐related reduction in adult hippocampal neurogenesis is correlated with cognitive impairment. Diabetes is a chronic systemic disease that negatively affects adult neural stem cells and memory functions in the hippocampus. Despite growing concern regarding the potential role of diabetic drugs in neural abnormalities, their effects on progressive deterioration of neurogenesis and cognitive functions remain unknown. Here, we show that the combination of aging and diabetes in mice causes a marked decrease in hippocampal neurogenesis along with memory impairment and elevated neuroinflammation. Prolonged treatment with metformin, a biguanide antidiabetic medication, promotes cell proliferation and neuronal differentiation and inhibits aging‐ and diabetes‐associated microglial activation, which is related to homeostatic neurogenesis, leading to enhanced hippocampal neurogenesis in middle‐aged diabetic mice. Although chronic therapy with metformin fails to achieve recovery from hyperglycemia, a key feature of diabetes in middle‐aged diabetic mice, it improves hippocampal‐dependent spatial memory functions accompanied by increased phosphorylation of adenosine monophosphate‐activated protein kinase ( AMPK ), atypical protein kinase C ζ ( aPKC ζ), and insulin receptor substrate 1 ( IRS 1) at selective serine residues in the hippocampus. Our findings suggest that signaling networks acting through long‐term metformin‐stimulated phosphorylation of AMPK , aPKC ζ/λ, and IRS 1 serine sites contribute to neuroprotective effects on hippocampal neurogenesis and cognitive function independent of a hypoglycemic effect.

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Section: Discussionsupporting

confidence: 92%

Section: Chronic Metformin Treatment Increases the Phosphorylation Ofmentioning

confidence: 99%

Metformin treatment ameliorates diabetes‐associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1

et al. 2018

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“…Oral antidiabetic agents have yielded promising results when tested in disease models. The gluconeogenesis inhibitor molecule metformin extends lifespan in mice, lowers hyperphosphorylated τ in a diabetes mouse model, and reverses AD features in APP/PS1 mice (Chen et al, ; Martin‐Montalvo et al, ; Ou et al, ). Glucagon‐like peptide 1 (GLP1) receptor agonists act as an insulin sensitizing hormone and show neuroprotective effects (Li et al, ; Li et al, ).…”

Section: Treatment Strategies Targeting Mitochondria: Novel Approachementioning

confidence: 99%

“…Oral antidiabetic agents have yielded promising results when tested in disease models. The gluconeogenesis inhibitor molecule metformin extends lifespan in mice, lowers hyperphosphorylated τ in a diabetes mouse model, and reverses AD features in APP/PS1 mice (Chen et al, 2019;Martin-Montalvo et al, 2013;Ou et al, 2018).…”

Section: Ad Drug Development Pipeline: Bioenergetics Beyond Mitochomentioning

confidence: 99%

Mitochondrial dysfunction in Alzheimer's disease: Role in pathogenesis and novel therapeutic opportunities

Ortiz

Swerdlow

2019

British J Pharmacology

290

149

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Dysfunction of cell bioenergetics is a common feature of neurodegenerative diseases, the most common of which is Alzheimer's disease (AD). Disrupted energy utilization implicates mitochondria at its nexus. This review summarizes some of the evidence that points to faulty mitochondrial function in AD and highlights past and current therapeutic development efforts. Classical neuropathological hallmarks of disease (β‐amyloid and τ) and sporadic AD risk genes (APOE) may trigger mitochondrial disturbance, yet mitochondrial dysfunction may incite pathology. Preclinical and clinical efforts have overwhelmingly centred on the amyloid pathway, but clinical trials have yet to reveal clear‐cut benefits. AD therapies aimed at mitochondrial dysfunction are few and concentrate on reversing oxidative stress and cell death pathways. Novel research efforts aimed at boosting mitochondrial and bioenergetic function offer an alternative treatment strategy. Enhancing cell bioenergetics in preclinical models may yield widespread favourable effects that could benefit persons with AD. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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“…Dulbecco's modified Eagle's medium (DMEM) was obtained from Solarbio Science & Technology Co., Ltd. Foetal bovine serum (FBS) and dimethyl sulphoxide (DMSO) were from Dingguo Changsheng Biotechnology Co., Ltd. The purity of 1, 1-Dimethylbiguanide hydrochloride (Metformin) is over 98.0%, purchased from Yuanye Co., Ltd. Aβ [25][26][27][28][29][30][31][32][33][34][35] was synthesized by ChinaPeptides Co., Ltd., and 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) was obtained from Amresco. FITC Annexin V Apoptosis Detection Kit was purchased from Beyotime Co., Ltd. l-Glutamic acid (Glu) with a purity ≥99% was obtained from Genview Scientific Inc, and γ-Amino butyric acid (GABA) with a purity ≥99.0% was obtained from Sigma-Aldrich.…”

Section: Chemicalsmentioning

confidence: 99%

Metformin inhibits Aβ_25‐35‐induced apoptotic cell death in SH‐SY5Y cells

Liu

Jiang

et al. 2019

Basic Clin Pharma Tox

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Metformin, a first-line drug for type-2 diabetes, plays a potentially protective role in preventing Alzheimer's disease (AD), but its underlying mechanism is unclear. In this study, Aβ 25-35 -treated SH-SY5Y cells were used as a cell model of AD to investigate the neuroprotective effect of metformin, as well as its underlying mechanisms.We found that metformin decreased the cell apoptosis rate and death, ratio of Bcl-2/ Bax, and expression of NR2A and NR2B, and increased the expression of LC3 in Aβ 25-35 -treated SH-SY5Y cells. Metformin also reduced intracellular and extracellular Glu concentrations, as well as the intracellular concentration of Ca 2+ and ROS in Aβ 25-35 -treated SH-SY5Y cells. These findings suggest that metformin inhibits Aβ 25-35 -treated SH-SY5Y cell death by inhibiting apoptosis, decreasing intracellular Ca 2+ and ROS by reducing neurotoxicity of excitatory amino acids, and by possibly reversing autophagy disorder via regulating autophagy process. K E Y W O R D S apoptosis, Aβ 25-35 , metformin, neuroprotection, toxicity of excitatory amino acids How to cite this article: Li L-X, Liu M-Y, Jiang X, et al. Metformin inhibits Aβ 25-35 -induced apoptotic cell death in SH-SY5Y cells.

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Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice

Cited by 249 publications

References 71 publications

Metformin treatment ameliorates diabetes‐associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1

Metformin treatment ameliorates diabetes‐associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1

Mitochondrial dysfunction in Alzheimer's disease: Role in pathogenesis and novel therapeutic opportunities

Metformin inhibits Aβ_25‐35‐induced apoptotic cell death in SH‐SY5Y cells

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Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice

Cited by 249 publications

References 71 publications

Metformin treatment ameliorates diabetes‐associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1

Metformin treatment ameliorates diabetes‐associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1

Mitochondrial dysfunction in Alzheimer's disease: Role in pathogenesis and novel therapeutic opportunities

Metformin inhibits Aβ25‐35‐induced apoptotic cell death in SH‐SY5Y cells

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Metformin inhibits Aβ_25‐35‐induced apoptotic cell death in SH‐SY5Y cells