Transgenic autoinhibition of p21-activated kinase exacerbates synaptic impairments and fronto-dependent behavioral deficits in an animal model of Alzheimer’s disease

Bories, Cyril; Arsenault, Daniel; Lemire, Myriam; Tremblay, Cyntia

doi:10.18632/aging.101239

Cited by 19 publications

(13 citation statements)

References 99 publications

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“…Alzheimer’s disease (AD) is a neurodegenerative disease that occurs in the elderly [ 1 , 2 ]. Its clinical manifestation includes progressive cognitive dysfunction and memory impairment [ 1 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

Abnormal gut microbiota composition contributes to cognitive dysfunction in SAMP8 mice

Zhan

Yang

et al. 2018

Aging

145

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Alzheimer’s disease is characterized by cognitive dysfunction and aging is an important predisposing factor; however, the pathological and therapeutic mechanisms are not fully understood. Recently, the role of gut microbiota in Alzheimer’s disease has received increasing attention. The cognitive function in senescence-accelerated mouse prone 8 (SAMP8) mice was significantly decreased and the Chao 1 and Shannon indices, principal coordinates analysis, and principal component analysis results were notably abnormal compared with that of those in senescence-accelerated mouse resistant 1 (SAMR1) mice. Moreover, 27 gut bacteria at six phylogenetic levels differed between SAMP8 and SAMR1 mice. In a separate study, we transplanted fecal bacteria from SAMP8 or SAMR1 mice into pseudo germ-free mice. Interestingly, the pseudo germ-free mice had significantly lower cognitive function prior to transplant. Pseudo germ-free mice that received fecal bacteria transplants from SAMR1 mice but not from SAMP8 mice showed improvements in behavior and in α-diversity and β-diversity indices. In total, 14 bacteria at six phylogenetic levels were significantly altered by the gut microbiota transplant. These results suggest that cognitive dysfunction in SAMP8 mice is associated with abnormal composition of the gut microbiota. Thus, improving abnormal gut microbiota may provide an alternative treatment for cognitive dysfunction and Alzheimer’s disease.

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Section: Introductionmentioning

confidence: 99%

Abnormal gut microbiota composition contributes to cognitive dysfunction in SAMP8 mice

Zhan

Yang

et al. 2018

Aging

145

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“…3 and Supplementary Table 7 ). P21-activated kinase 1, encoded by the PAK1 gene, has been implicated in AD (Zhao et al ., 2006), and recent studies have revealed that inactivation of PAK1 obliterated social recognition without changing amyloid beta (Aβ)/tau pathology, and also exacerbated synaptic impairment and behavioral deficits in mouse models of AD (Arsenault et al ., 2013, Bories et al ., 2017).…”

Section: Resultsmentioning

confidence: 99%

Network-based Translation of GWAS Findings to Pathobiology and Drug Repurposing for Alzheimer’s Disease

Fang

Zhang

Wang

et al. 2020

Preprint

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Genome-wide association studies (GWAS) have identified numerous susceptibility loci for Alzheimer's disease (AD). However, utilizing GWAS to identify high-confidence AD risk genes (ARGs) that can guide development of new therapeutics for patients suffering from AD has heretofore not been successful. To address this critical problem in the field, we have developed a genotype-informed, network-based methodology that interrogates pathogenesis to identify new therapeutics. When applied to AD, this approach integrates GWAS findings, multi-omics data from brain samples of AD patients and preclinical AD models, drug-target networks, and the human protein-protein interactome, along with large-scale patient database validation and in vitro mechanistic observations in human microglia cells. Through this approach, we identified 103 ARGs validated by various levels of pathobiological evidence in AD. Via network-based prediction and population-based validation, we then showed that pioglitazone usage is significantly associated with decreased risk of AD (hazard ratio (HR) = 0.895, 95% confidence interval [CI] 0.841-0.951, P = 3.97 x 10-4) in a retrospective case-control validation. Pioglitazone is a peroxisome proliferator-activated receptor agonist used to treat type 2 diabetes, and propensity score matching cohort studies confirmed its association with reduced risk of AD in comparison to glipizide (HR =0.921, 95% CI 0.861-0.983, P = 0.0146), an insulin secretagogue that is also used to treat type 2 diabetes. In vitro experiments showed that pioglitazone downregulated glycogen synthase kinase 3 beta (GSK3β) and cyclin-dependent kinase (CDK5) in human microglia cells, supporting a possible mechanism-of-action for its beneficial effect in AD. In summary, we present an integrated, network-based methodology to rapidly translate GWAS findings and multi-omics data to genotype-informed therapeutic discovery in AD.

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“…AD is associated with changes in synaptic proteins [35,43,[70][71][72][73][74][75], which could have a significant impact at the cellular level. To find if sexes influenced synaptic function at the molecular level in AD, we quantified several proteins in the parietotemporal cortex by Western blot.…”

Section: Transgenic Expression Induced Synaptic Protein Impairmentsmentioning

confidence: 99%

Sex-dependent alterations in the physiology of entorhinal cortex neurons in old heterozygous 3xTg-AD mice

2020

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While the higher prevalence of Alzheimer’s disease (AD) in women is clear, studies suggest that biological sex may also influence AD pathogenesis. However, mechanisms behind these differences are not clear. To investigate physiological differences between sexes at the cellular level in the brain, we investigated the intrinsic and synaptic properties of entorhinal cortex neurons in heterozygous 3xTg-AD mice of both sexes at the age of 20 months. This brain region was selected because of its early association with AD symptoms. First, we found physiological differences between male and female non-transgenic mice, providing indirect evidence of axonal alterations in old females. Second, we observed a transgene-dependent elevation of the firing activity, post-burst afterhyperpolarization (AHP), and spontaneous excitatory postsynaptic current (EPSC) activity, without any effect of sex. Third, the passive properties and the hyperpolarization-activated current (Ih) were altered by transgene expression only in female mice, whereas the paired-pulse ratio (PPR) of evoked EPSC was changed only in males. Fourth, both sex and transgene expression were associated with changes in action potential properties. Consistent with previous work, higher levels of Aβ neuropathology were detected in 3xTg-AD females, whereas tau deposition was similar. In summary, our results support the idea that aging and AD neuropathology differentially alter the physiology of entorhinal cortex neurons in males and females.

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Transgenic autoinhibition of p21-activated kinase exacerbates synaptic impairments and fronto-dependent behavioral deficits in an animal model of Alzheimer’s disease

Cited by 19 publications

References 99 publications

Abnormal gut microbiota composition contributes to cognitive dysfunction in SAMP8 mice

Abnormal gut microbiota composition contributes to cognitive dysfunction in SAMP8 mice

Network-based Translation of GWAS Findings to Pathobiology and Drug Repurposing for Alzheimer’s Disease

Sex-dependent alterations in the physiology of entorhinal cortex neurons in old heterozygous 3xTg-AD mice

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