Exenatide alleviates mitochondrial dysfunction and cognitive impairment in the 5×FAD mouse model of Alzheimer’s disease

An, Jie; Zhou, Yu; Zhang, Mengjun; Xie, Yunzhen; Ke, Sujie; Liu, Libin; Pan, Xiaodong; Zhou, Chen

doi:10.1016/j.bbr.2019.111932

Cited by 49 publications

(38 citation statements)

References 43 publications

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“…Because GLP-1R is expressed in lung, adipose tissue, islet cells, liver, and brain, GLP-1R agonists can elicit a variety of actions [40]. Specifically, GLP-1R agonists can cross the BBB and may serve as neuroprotective agents for Parkinson's disease and AD [10,41,42]. In this regard, we compared GLP-1 expression in both the pancreas and hippocampus of ND-fed and ExA-treated HFD/STZ mice.…”

Section: Discussionmentioning

confidence: 99%

Long-Lasting Exendin-4 Fusion Protein Improves Memory Deficits in High-Fat Diet/Streptozotocin-Induced Diabetic Mice

et al. 2020

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Glucagon-like peptide 1 (GLP-1) mimetics have been approved as an adjunct therapy for glycemic control in type 2 diabetic patients for the increased insulin secretion under hyperglycemic conditions. Recently, it is reported that such agents elicit neuroprotective effects against diabetes-associated cognitive decline. However, there is an issue of poor compliance by multiple daily subcutaneous injections for sufficient glycemic control due to their short duration, and neuroprotective actions were not fully studied, yet. In this study, using the prepared exendin-4 fusion protein agent, we investigated the pharmacokinetic profile and the role of this GLP-1 mimetics on memory deficits in a high-fat diet (HFD)/streptozotocin (STZ) mouse model of type 2 diabetic mellitus. After induction of diabetes, mice were administered weekly by intraperitoneal injection of GLP-1 mimetics for 6 weeks. This treatment reversed HFD/STZ-induced metabolic symptoms of increased body weight, hyperglycemia, and hepatic steatosis. Furthermore, the impaired cognitive performance of diabetic mice was significantly reversed by GLP-1 mimetics. GLP-1 mimetic treatment also reversed decreases in GLP-1/GLP-1 receptor expression levels in both the pancreas and hippocampus of diabetic mice; increases in hippocampal inflammation, mitochondrial fission, and calcium-binding protein levels were also reversed. These findings suggest that GLP-1 mimetics are promising agents for both diabetes and neurodegenerative diseases that are associated with increased GLP-1 expression in the brain.

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Section: Discussionmentioning

confidence: 99%

Long-Lasting Exendin-4 Fusion Protein Improves Memory Deficits in High-Fat Diet/Streptozotocin-Induced Diabetic Mice

et al. 2020

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“…And exenatide could improve cognitive decline through inhibiting apoptosis and promoting the BDNF-TrkB neurotrophic axis in adult wild-type mice( Bomba et al, 2018 ). Exenatide was reported to improve cognitive impairment by reducing Aβ 1-42 deposition, alleviating synaptic degradation, and improving hippocampal mitochondrial morphology and dynamics in the mouse model of AD( An et al, 2019 ). However, another study suggested that exenatide could enhance BDNF signaling and reduce inflammation in AD mouse model, but it failed to promote changes in cognitive function( Bomba et al, 2019 ).…”

Section: Repurposing Of Anti-diabetic Agents As a Potential Treatment Targeting Cognitive Function In Ad And Schizophreniamentioning

confidence: 99%

Repurposing of Anti-Diabetic Agents as a New Opportunity to Alleviate Cognitive Impairment in Neurodegenerative and Neuropsychiatric Disorders

Chen

Cao

et al. 2021

Front. Pharmacol.

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Cognitive impairment is a shared abnormality between type 2 diabetes mellitus (T2DM) and many neurodegenerative and neuropsychiatric disorders, such as Alzheimer’s disease (AD) and schizophrenia. Emerging evidence suggests that brain insulin resistance plays a significant role in cognitive deficits, which provides the possibility of anti-diabetic agents repositioning to alleviate cognitive deficits. Both preclinical and clinical studies have evaluated the potential cognitive enhancement effects of anti-diabetic agents targeting the insulin pathway. Repurposing of anti-diabetic agents is considered to be promising for cognitive deficits prevention or control in these neurodegenerative and neuropsychiatric disorders. This article reviewed the possible relationship between brain insulin resistance and cognitive deficits. In addition, promising therapeutic interventions, especially current advances in anti-diabetic agents targeting the insulin pathway to alleviate cognitive impairment in AD and schizophrenia were also summarized.

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“…5XFAD mice were divided into two experimental groups (treatment vs. vehicle group) using the block randomization method. Similar to previous studies [26,27], the treatment group was treated with NJK14047 at 2.5 mg/kg every other day from the age of 6 to 9 months by intraperitoneal injection. The vehicle group and its littermate wild-type mice were treated with the same volume of vehicle by intraperitoneal injection.…”

Section: Animals and Treatmentmentioning

confidence: 99%

A selective p38α/β MAPK inhibitor alleviates neuropathology and cognitive impairment, and modulates microglia function in 5XFAD mouse

et al. 2020

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Background: Chronic neuroinflammation, aggressive amyloid beta (Aβ) deposition, neuronal cell loss, and cognitive impairment are pathological presentations of Alzheimer's disease (AD). Therefore, resolution of neuroinflammation and inhibition of Aβ-driven pathology have been suggested to be important strategies for AD therapy. Previous efforts to prevent AD progression have identified p38 mitogen-activated protein kinases (MAPKs) as a promising target for AD therapy. Recent studies showed pharmacological inhibition of p38α MAPK improved memory impairment in AD mouse models. Methods: In this study, we used an AD mouse model, 5XFAD, to explore the therapeutic potential of NJK14047 which is a novel, selective p38α/β MAPK inhibitor. The mice were injected with 2.5 mg/kg NJK14047 or vehicle every other day for 3 months. Morris water maze task and histological imaging analysis were performed. Protein and mRNA expression levels were measured using immunoblotting and qRT-PCR, respectively. In vitro studies were conducted to measure the cytotoxicity of microglia-and astrocyte-conditioned medium on primary neurons using the MTT assay and TUNEL assay. Results: NJK14047 treatment downregulated phospho-p38 MAPK levels, decreased the amount of Aβ deposits, and reduced spatial learning memory loss in 9-month-old 5XFAD mice. While the pro-inflammatory conditions were decreased, the expression of alternatively activated microglial markers and microglial phagocytic receptors was increased. Furthermore, NJK14047 treatment reduced the number of degenerating neurons labeled with Fluoro-Jade B in the brains of 5XFAD mice. The neuroprotective effect of NJK14047 was further confirmed by in vitro studies.

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Exenatide alleviates mitochondrial dysfunction and cognitive impairment in the 5×FAD mouse model of Alzheimer’s disease

Cited by 49 publications

References 43 publications

Long-Lasting Exendin-4 Fusion Protein Improves Memory Deficits in High-Fat Diet/Streptozotocin-Induced Diabetic Mice

Long-Lasting Exendin-4 Fusion Protein Improves Memory Deficits in High-Fat Diet/Streptozotocin-Induced Diabetic Mice

Repurposing of Anti-Diabetic Agents as a New Opportunity to Alleviate Cognitive Impairment in Neurodegenerative and Neuropsychiatric Disorders

A selective p38α/β MAPK inhibitor alleviates neuropathology and cognitive impairment, and modulates microglia function in 5XFAD mouse

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