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

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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Insulin degrading enzyme contributes to the pathology in a mixed model of Type 2 diabetes and Alzheimer’s disease: possible mechanisms of IDE in T2D and AD

Bioscience Reports ◽

10.1042/bsr20170862 ◽

2018 ◽

Vol 38 (1) ◽

Cited By ~ 15

Author(s):

Huajie Li ◽

Jian Wu ◽

Linfeng Zhu ◽

Luolin Sha ◽

Song Yang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Type 2 Diabetes ◽

Alzheimer's Disease ◽

Glucose Tolerance ◽

Spatial Learning ◽

Expression Level ◽

Insulin Degrading Enzyme ◽

Degrading Enzyme ◽

Expression Levels

Insulin degrading enzyme (IDE) is believed to act as a junction point of Type 2 diabetes (T2D) and Alzheimer's disease (AD); however, the underlying mechanism was not completely clear yet. Transgenic APPSwe/PS1 mice were used as the AD model and were treated with streptozocin/streptozotocin (STZ) to develop a mixed mice model presenting both AD and T2D. Morris Water Maze (MWM) and recognition task were performed to trace the cognitive function. The detection of fasting plasma glucose (FPG) and plasma insulin concentration, and oral glucose tolerance test (OGTT) were used to trace the metabolism evolution. Aβ40 and Aβ42 were quantified by colorimetric ELISA kits. The mRNA or protein expression levels were determined by quantitative real-time RT-PCR and Western blotting analysis respectively. T2D contributes to the AD progress by accelerating and worsening spatial learning and recognition impairments. Metabolic parameters and glucose tolerance were significantly changed in the presence of the AD and T2D. The expression levels of IDE, PPARγ, and AMPK were down-regulated in mice with AD and T2D. PPARγ activator rosiglitazone (RSZ) or AMPK activator AICAR increased the expression level of IDE and decreased Aβ levels in mice with AD and T2D. RSZ or AICAR treatment also alleviated the spatial learning and recognition impairments in AD and T2D mice. Our results found that, in the mice with T2D and AD, the activators of PPARγ/AMPK signaling pathway significantly increased the expression level of IDE, and decreased the accumulation of Aβ40 and Aβ42, as well as alleviated the spatial learning and recognition impairments.

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O2-06-06: Higher Peripheral Trem2 Mrna Expression Levels are Related to Cognitive Deficits and Hippocampal Atrophy in Alzheimer's Disease and Amnestic MCI

Alzheimer s & Dementia ◽

10.1016/j.jalz.2016.06.429 ◽

2016 ◽

Vol 12 ◽

pp. P241-P241 ◽

Cited By ~ 1

Author(s):

Yi Jayne Tan ◽

Adeline Su Lyn Ng ◽

Joseph K.W. Lim ◽

Russell J. Chander ◽

Ji Fang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mrna Expression ◽

Cognitive Deficits ◽

Hippocampal Atrophy ◽

Expression Levels ◽

Amnestic Mci ◽

Mrna Expression Levels

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Tooth Loss Induces Memory Impairment and Gliosis in App Knock-In Mouse Models of Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-201055 ◽

2021 ◽

Vol 80 (4) ◽

pp. 1687-1704

Author(s):

Ferdous Taslima ◽

Cha-Gyun Jung ◽

Chunyu Zhou ◽

Mona Abdelhamid ◽

Mohammad Abdullah ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mrna Expression ◽

Neuronal Activity ◽

Memory Impairment ◽

Tooth Loss ◽

Amyloid Β ◽

Glial Activation ◽

Expression Levels ◽

Mrna Expression Levels

Background: Epidemiological studies have shown that tooth loss is associated with Alzheimer’s disease (AD) and dementia. However, the molecular and cellular mechanisms by which tooth loss causes AD remain unclear. Objective: We investigated the effects of tooth loss on memory impairment and AD pathogenesis in AppNL-G-F mice. Methods: Maxillary molar teeth on both sides were extracted from 2-month-old AppNL-G-F mice, and the mice were reared for 2 months. The short- and long-term memory functions were evaluated using a novel object recognition test and a passive avoidance test. Amyloid plaques, amyloid-β (Aβ) levels, glial activity, and neuronal activity were evaluated by immunohistochemistry, Aβ ELISA, immunofluorescence staining, and western blotting. The mRNA expression levels of neuroinflammatory cytokines were determined by qRT-PCR analysis. Results: Tooth loss induced memory impairment via an amyloid-cascade-independent pathway, and decreased the neuronal activity, presynaptic and postsynaptic protein levels in both the cortex and hippocampus. Interestingly, we found that tooth loss induced glial activation, which in turn leads to the upregulation of the mRNA expression levels of the neuroinflammation cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β in the hippocampus. We also found that tooth loss activated a stress-activated protein kinase, c-Jun N-terminal kinase (JNK), and increased heat shock protein 90 (HSP90) levels in the hippocampus, which may lead to a glial activation. Conclusion: Our findings suggest that taking care of teeth is very important to preserve a healthy oral environment, which may reduce the risk of cognitive dysfunction.

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MicroRNA 7 Impairs Insulin Signaling and Regulates Aβ Levels through Posttranscriptional Regulation of the Insulin Receptor Substrate 2, Insulin Receptor, Insulin-Degrading Enzyme, and Liver X Receptor Pathway

Molecular and Cellular Biology ◽

10.1128/mcb.00170-19 ◽

2019 ◽

Vol 39 (22) ◽

Cited By ~ 6

Author(s):

Mario Fernández-de Frutos ◽

Inmaculada Galán-Chilet ◽

Leigh Goedeke ◽

Byungwook Kim ◽

Virginia Pardo-Marqués ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Insulin Receptor ◽

Posttranscriptional Regulation ◽

Insulin Action ◽

Liver X Receptor ◽

Insulin Receptor Substrate ◽

Insulin Degrading Enzyme ◽

Degrading Enzyme ◽

The Brain

ABSTRACT Brain insulin resistance is a key pathological feature contributing to obesity, diabetes, and neurodegenerative disorders, including Alzheimer’s disease (AD). Besides the classic transcriptional mechanism mediated by hormones, posttranscriptional regulation has recently been shown to regulate a number of signaling pathways that could lead to metabolic diseases. Here, we show that microRNA 7 (miR-7), an abundant microRNA in the brain, targets insulin receptor (INSR), insulin receptor substrate 2 (IRS-2), and insulin-degrading enzyme (IDE), key regulators of insulin homeostatic functions in the central nervous system (CNS) and the pathology of AD. In this study, we found that insulin and liver X receptor (LXR) activators promote the expression of the intronic miR-7-1 in vitro and in vivo, along with its host heterogeneous nuclear ribonucleoprotein K (HNRNPK) gene, encoding an RNA binding protein (RBP) that is involved in insulin action at the posttranscriptional level. Our data show that miR-7 expression is altered in the brains of diet-induced obese mice. Moreover, we found that the levels of miR-7 are also elevated in brains of AD patients; this inversely correlates with the expression of its target genes IRS-2 and IDE. Furthermore, overexpression of miR-7 increased the levels of extracellular Aβ in neuronal cells and impaired the clearance of extracellular Aβ by microglial cells. Taken together, these results represent a novel branch of insulin action through the HNRNPK–miR-7 axis and highlight the possible implication of these posttranscriptional regulators in a range of diseases underlying metabolic dysregulation in the brain, from diabetes to Alzheimer’s disease.

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Effect of Bee Venom on an Experimental Cellular Model of Alzheimer’s Disease

The American Journal of Chinese Medicine ◽

10.1142/s0192415x20500901 ◽

2020 ◽

Vol 48 (08) ◽

pp. 1803-1819

Author(s):

Yong Ho Ku ◽

Jae Hui Kang ◽

Hyun Lee

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mrna Expression ◽

Caspase 3 ◽

Bee Venom ◽

Control Group ◽

Cellular Model ◽

Expression Levels ◽

Cox 2 ◽

Mrna Expression Levels

Alzheimer’s disease (AD) is a neurodegenerative disease and is characterized by the deposition of the [Formula: see text]-Amyloid peptide ([Formula: see text]A), which causes the inflammation of neurons. Bee venom (BV) elicits a strong anti-inflammatory response, and therefore we conducted an in vitro experiment to study the efficacy of BV in an AD cellular model. To mimic AD, the U87MG cell line was incubated for 168 hours with 2.5 [Formula: see text]M [Formula: see text]A. Changes were confirmed by microscopy, and peptides were measured under stain-free conditions using homo-tomography. Sulforhodamine B analysis was performed to analyze the cell viability. Real-Time quantitative polymerase chain reaction (qPCR) analysis was conducted to analyze mRNA expression levels of pro-inflammatory cytokines (NF-[Formula: see text]B, COX-2, TNF-[Formula: see text], IL-1), and Western blot was performed to measure the Caspase-3 protein levels. BV showed no cytotoxicity at concentrations below 10 [Formula: see text]g/mL. The NF-[Formula: see text]B mRNA levels were not significantly different between the BV group and the control group. The amount of [Formula: see text]A accumulation in the BV group decreased significantly. The mRNA expression levels of COX-2, TNF-[Formula: see text], and IL-1 were significantly reduced using 10 [Formula: see text]g/mL of BV compared to those in the control group. Additionally, Caspase-3 levels were also reduced compared to those of the control group when BV was used at a concentration of 10 [Formula: see text]g/mL. BV could inhibit apoptosis and inflammatory responses in an AD cellular model. In addition, it prevented cell accumulation of [Formula: see text]A, an important pathogenic mechanism in AD.

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MiR-335-5p Inhibits β-Amyloid (Aβ) Accumulation to Attenuate Cognitive Deficits Through Targeting c-jun-N-terminal Kinase 3 in Alzheimer’s Disease

Current Neurovascular Research ◽

10.2174/1567202617666200128141938 ◽

2020 ◽

Vol 17 (1) ◽

pp. 93-101 ◽

Cited By ~ 3

Author(s):

Dan Wang ◽

Zhifu Fei ◽

Song Luo ◽

Hai Wang

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transgenic Mice ◽

Western Blot ◽

Mrna Expression ◽

Cognitive Deficits ◽

Protein Levels ◽

Amyloid Aβ ◽

Β Amyloid ◽

The Relationship

Objectives: Alzheimer's disease (AD), also known as senile dementia, is a common neurodegenerative disease characterized by progressive cognitive impairment and personality changes. Numerous evidences have suggested that microRNAs (miRNAs) are involved in the pathogenesis and development of AD. However, the exact role of miR-335-5p in the progression of AD is still not clearly clarified. Methods: The protein and mRNA levels were measured by western blot and RNA extraction and quantitative real-time PCR (qRT-PCR), respectively. The relationship between miR-335-5p and c-jun-N-terminal kinase 3 (JNK3) was confirmed by dual-luciferase reporter assay. SH-SY5Y cells were transfected with APP mutant gene to establish the in vitro AD cell model. Flow cytometry and western blot were performed to evaluate cell apoptosis. The APP/PS1 transgenic mice were used as an in vivo AD model. Morris water maze test was performed to assess the effect of miR- 335-5p on the cognitive deficits in APP/PS1 transgenic mice. Results: The JNK3 mRNA expression and protein levels of JNK3 and β-Amyloid (Aβ) were significantly up-regulated, and the mRNA expression of miR-335-5p was down-regulated in the brain tissues of AD patients. The expression levels of miR-335-5p and JNK3 were significantly inversely correlated. Further, the dual Luciferase assay verified the relationship between miR-335- 5p and JNK3. Overexpression of miR-335-5p significantly decreased the protein levels of JNK3 and Aβ and inhibited apoptosis in SH-SY5Y/APPswe cells, whereas the inhibition of miR-335-5p obtained the opposite results. Moreover, the overexpression of miR-335-5p remarkably improved the cognitive abilities of APP/PS1 mice. Conclusion: The results revealed that the increased JNK3 expression, negatively regulated by miR-335-5p, may be a potential mechanism that contributes to Aβ accumulation and AD progression, indicating a novel approach for AD treatment.

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Characteristics of Insulin-degrading Enzyme in Alzheimer's Disease: A Meta-Analysis

Current Alzheimer Research ◽

10.2174/1567205015666180119105446 ◽

2018 ◽

Vol 15 (7) ◽

pp. 610-617 ◽

Cited By ~ 4

Author(s):

Huifeng Zhang ◽

Dan Liu ◽

Huanhuan Huang ◽

Yujia Zhao ◽

Hui Zhou

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Enzyme Activity ◽

Protein Level ◽

Senile Plaque ◽

Meta Analysis ◽

Cochrane Library ◽

Insulin Degrading Enzyme ◽

Degrading Enzyme ◽

Significant Difference

Background: β-amyloid (Aβ) accumulates abnormally to senile plaque which is the initiator of Alzheimer's disease (AD). As one of the Aβ-degrading enzymes, Insulin-degrading enzyme (IDE) remains controversial for its protein level and activity in Alzheimer's brain. Methods: The electronic databases PubMed, EMBASE, The Cochrane Library, OVID and Sinomed were systemically searched up to Sep. 20th, 2017. And the published case-control or cohort studies were retrieved to perform the meta-analysis. Results: Seven studies for IDE protein level (AD cases = 293; controls = 126), three for mRNA level (AD cases = 138; controls = 81), and three for enzyme activity (AD cases = 123; controls = 75) were pooling together. The IDE protein level was significantly lower in AD cases than in controls (SMD = - 0.47, 95% CI [-0.69, -0.24], p < 0.001), but IDE mRNA and enzyme activity had no significant difference (SMD = 0.02, 95% CI [-0.40, 0.43] and SMD = 0.06, 95% CI [-0.41, 0.53] respectively). Subgroup analyses found that IDE protein level was decreased in both cortex and hippocampus of AD cases (SMD = -0.43, 95% CI [-0.71, -0.16], p = 0.002 and SMD = -0.53, 95% CI [-0.91, -0.15], p = 0.006 respectively). However, IDE mRNA was higher in cortex of AD cases (SMD = 0.71, 95% CI [0.14, 1.29], p = 0.01), not in hippocampus (SMD = -0.26, 95% CI [-0.58, 0.06]). Conclusions: Our results indicate that AD patients may have lower IDE protease level. Further relevant studies are still needed to verify whether IDE is one of the factors affecting Aβ abnormal accumulation and throw new insights for AD detection or therapy.

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