Metformin Improves Learning and Memory in the SAMP8 Mouse Model of Alzheimer’s Disease

Farr, Susan A.; Roesler, Elizabeth C.; Niehoff, Michael L.; Roby, Deborah A.; McKee, Alexis M.; Morley, John E.

doi:10.3233/jad-181240

Cited by 120 publications

(64 citation statements)

References 54 publications

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“…We did the preliminary experiments: different dosages of metformin (25,50, 100, and 200 mg/kg/day) were given to APP/PS1 mice. Morris water maze test results indicated that metformin (200 mg/kg/day) was the best dosage (data not shown), which was consistent with previous studies [23,24]. Behavioral studies (Morris water maze and Y-maze) con-firmed that metformin could significantly improve learning and memory in APP/PS1 mice, which was consistent with previous studies.…”

Section: Oxidative Medicine and Cellular Longevitysupporting

confidence: 90%

“…The animal management was approved by the Institutional Animal Care and Use Committee of Guangzhou Medical University (SCXK2019-0013). All mice were randomly divided into three groups: wild type (WT, n = 15), APP/PS1 (n = 15), and APP/PS1 +metformin (200 mg/kg/day, n = 15) [23,24]. After oral drug administration for 8 weeks, mice were performed behavioral tests and subsequently sacrificed for the collection of brains.…”

Section: Animals Andmentioning

confidence: 99%

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

Huang

Chen

et al. 2020

Oxidative Medicine and Cellular Longevity

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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 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-1β and IL-6) in APP/PS1 mice. In addition, metformin obviously reduced the Aβ level in the brain of APP/PS1 mice. Metformin did not affect the enzyme activities and mRNA expression levels of Aβ-related secretases (ADAM10, BACE1, and PS1). Meanwhile, metformin also did not affect the mRNA expression levels of Aβ-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.

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Section: Oxidative Medicine and Cellular Longevitysupporting

confidence: 90%

Section: Animals Andmentioning

confidence: 99%

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

Huang

Chen

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…Furthermore, improvements in language and cognitive behaviors were observed in a small sample size of Met-treated FXS patients [ 8 , 9 , 10 ]. In some Alzheimer’s disease (AD) mice models, Met attenuated amyloid plaque deposition and improved learning and memory [ 11 , 12 , 13 , 14 ]. Met also showed neuroprotective effects on dopaminergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-modeled mice of Parkinson’s disease (PD) [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Metformin Enhances Excitatory Synaptic Transmission onto Hippocampal CA1 Pyramidal Neurons

Chen

Liu

et al. 2020

Brain Sciences

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Metformin (Met) is a first-line drug for type 2 diabetes mellitus (T2DM). Numerous studies have shown that Met exerts beneficial effects on a variety of neurological disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD). However, it is still largely unclear how Met acts on neurons. Here, by treating acute hippocampal slices with Met (1 μM and 10 μM) and recording synaptic transmission as well as neuronal excitability of CA1 pyramidal neurons, we found that Met treatments significantly increased the frequency of miniature excitatory postsynaptic currents (mEPSCs), but not amplitude. Neither frequency nor amplitude of miniature inhibitory postsynaptic currents (mIPSCs) were changed with Met treatments. Analysis of paired-pulse ratios (PPR) demonstrates that enhanced presynaptic glutamate release from terminals innervating CA1 hippocampal pyramidal neurons, while excitability of CA1 pyramidal neurons was not altered. Our results suggest that Met preferentially increases glutamatergic rather than GABAergic transmission in hippocampal CA1, providing a new insight on how Met acts on neurons.

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“…Retrospective cohort studies of the associations between use of selected medications and occurrence of probable AD have been conducted using large claims databases to examine associations between medications that may impact positively with lower risk of dementia and possible AD. These classes of medications include angiotensinconverting enzyme inhibitor (ACEI) [1,2], simvastatin [3,4], beta blockers [5], and metformin [6,7]. Currently, there is no effective treatment to prevent or slow the progression of AD.…”

Section: Introductionmentioning

confidence: 99%

“…The choices of our medications are based on previously published studies on these medication classes related to AD therapeutics and with the consideration of the sample sizes of our databases. For example, possible benefit of ACEI [2], beta blockers [5], and metformin [7] for AD patients has been explored. Statins with higher blood-brain barrier (BBB) penetration capacity (e.g., lipophilic statins) may have more influence on AD progression [4].…”

Section: Introductionmentioning

confidence: 99%

Beneficial association of angiotensin-converting enzyme inhibitors and statins on the occurrence of possible Alzheimer’s disease after traumatic brain injury

Reisman

Morris-Eppolito

et al. 2020

Alz Res Therapy

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Background: Pathological analysis of brain tissue from animals and humans with a history of traumatic brain injury (TBI) suggests that TBI could be one of the risk factors facilitating onset of dementia with possible Alzheimer's disease (AD), but medications to prevent or delay AD onset are not yet available. Methods: This study explores four medication classes (angiotensin-converting enzyme inhibitors (ACEI), beta blockers, metformin, and statins) approved by the Food and Drug Administration (FDA) for other indications and evaluates their influence when used in combination on the risk of possible AD development for patients with a history of TBI. We identified patients with history of TBI from an existing Department of Veterans Affairs (VA) national database. Among 1, 660,151 veterans who used VA services between the ages of 50 to 89 years old, we analyzed 733,920 patients, including 15,450 patients with a history of TBI and 718,470 non-TBI patients. The TBI patients were followed for up to 18.5 years, with an average of 7.7 ± 4.7 years, and onset of dementia with possible AD was recorded based on International Statistical Classification of Diseases (ICD) 9 or 10 codes. The effect of TBI on possible AD development was evaluated by multivariable logistic regression models adjusted by age, gender, race, and other comorbidities. The association of ACEI, beta blockers, metformin, statins, and combinations of these agents over time from the first occurrence of TBI to possible AD onset was assessed using Cox proportional hazard models adjusted for demographics and comorbidities. Results: Veterans with at least two TBI occurrences by claims data were 25% (odds ratio (OR) = 1.25, 95% confidence intervals (CI) (1.13, 1.37)) more likely to develop dementia with possible AD, compared to those with no record of TBI. In multivariable logistic regression models (propensity score weighted or adjusted), veterans taking a combination of ACEI and statins had reduced risk in developing possible AD after suffering TBI, and use of this medication class combination was associated with a longer period between TBI occurring and dementia with possible AD onset, compared to patients who took statins alone or did not take any of the four target drugs after TBI.

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Metformin Improves Learning and Memory in the SAMP8 Mouse Model of Alzheimer’s Disease

Cited by 120 publications

References 54 publications

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

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

Metformin Enhances Excitatory Synaptic Transmission onto Hippocampal CA1 Pyramidal Neurons

Beneficial association of angiotensin-converting enzyme inhibitors and statins on the occurrence of possible Alzheimer’s disease after traumatic brain injury

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