Dataset Information

Alcohol Dehydrogenase 1B Suppresses ?-Amyloid-Induced Neuron Apoptosis.

ABSTRACT: ?-amyloid (A?) deposition, neurofibrillary tangles induced by phosphorylation of tau protein, and neuronal apoptosis are pathological hallmarks of Alzheimer's disease (AD). The dementia rate in alcoholic abusers were found to be higher than in control people. The present study explored the potential roles of alcohol dehydrogenase 1B (ADH1B) in AD pathology by determining the ADH1B levels in AD patient sera, in the hippocampus of APP/PS-1 AD model mice, and in an AD model cell line treated with A?1-42. The results show that ADH1B levels decreased significantly both in the serum of AD patients and in the hippocampus of APP/PS-1 AD model mice. In addition, the apoptotic rate was reduced and viability was significantly increased in AD model cells transfected with ADH1B overexpression vector. The levels of the p75 neurotrophin receptor (p75NTR), an A?1-42 receptor, were down-regulated in the ADH1B overexpressing AD model cell and up-regulated in cells transfected with the shRNA vector of ADH1B. Protein levels of cleaved caspase-3 and Bax decreased significantly, whereas Bcl-2 levels increased in cells overexpressing ADH1B. The opposite trend was observed for cleaved caspase-3, Bax, and Bcl-2 levels in cells transfected with the shRNA vector of ADH1B. The levels of reactive oxygen species (ROS) were found to be reduced in ADH1B overexpressing cells and increased when cells were transfected with the shRNA vector of ADH1B. These results indicate that ADH1B might be important in the prevention of AD, especially for abusers of alcohol, and a potential new target of AD treatment.

SUBMITTER: Wang Y

PROVIDER: S-EPMC6560161 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Alcohol Dehydrogenase 1B Suppresses β-Amyloid-Induced Neuron Apoptosis.

Wang Yaqi Y Zhang Yi Y Zhang Xiaomin X Yang Tingting T Liu Chengeng C Wang Peichang P

Frontiers in aging neuroscience 20190605

β-amyloid (Aβ) deposition, neurofibrillary tangles induced by phosphorylation of tau protein, and neuronal apoptosis are pathological hallmarks of Alzheimer's disease (AD). The dementia rate in alcoholic abusers were found to be higher than in control people. The present study explored the potential roles of alcohol dehydrogenase 1B (ADH1B) in AD pathology by determining the ADH1B levels in AD patient sera, in the hippocampus of APP/PS-1 AD model mice, and in an AD model cell line treated with A ...[more]

PMID: 31231206

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Project description:The association of Alzheimer disease (AD) and Diabetes (DM) is less clear. Accumulation of beta amyloid (Aβ) and presence of hyperphosphorylated tau (p-tau) are hallmarks of AD, spreading in the region where insulin receptors are also found. Aβ exerts neuron toxicity, and could disturb insulin signaling of phosphatidylinositol 3-kinase (PI3K), glycogen synthase kinase (GSK)-3β and AMP-activated protein kinase (AMPK), but increase IRS-1-Ser307 phosphorylation which is viewed as insulin resistance marker. Previously we reported dipeptidyl peptidase-4 (DPP-4) mediate insulin resistance signals, and Abelmoschus esculentus (AE) subfractions F1 (rich in quercetin glucosides and triterpene ester) and F2 (containing large amount of polysaccharides) attenuate DPP-4-mediated apoptosis. In the present study, we aim to investigate if Aβ induce neuron death by regulating DPP-4 and insulin resistance signals, and the putative effect of F1 and F2. By MTT, microscopy, and Western blotting, we demonstrate treatment of appropriate doses of AE subfractions prevent Aβ-induced neuron apoptosis. F1 attenuate Aβ-induced caspase 3 expression especially at 25 μg/mL, while F2 attenuate caspase 3 activation even at the low dose of 1 μg/mL. Both AE subfractions decrease Aβ-enhanced DPP-4, but increase Aβ-reduced p-AMPK and p-PI3K. The activity analysis reveals that F2 is more valid than F1 to reduce DPP-4 activity. The inhibition of DPP-4 demonstrates it plays the pivotal role in Aβ-induced neuron apoptosis. Moreover, although both F1 and F2 are effective to inhibit p-IRS-1-Ser307, F2 takes advantage to reduce p-Tau while F1 is superior to enhance p-GSK-3β. This implies AE subfractions act on different targets, and could be developed respectively. In conclusion, we demonstrate AE is potential to prevent Aβ-induced neuron damage by regulating DPP-4 and the insulin resistance cascades. AE could be an adjuvant to protect neuron degenerative disease related to Aβ and insulin resistance.

Project description:BackgroundAlzheimer's disease (AD) is the most common neurodegenerative disease worldwide but has no effective treatment. Amyloid beta (Aβ) protein, a primary risk factor for AD, accumulates and aggregates in the brain of patients with AD. Paired immunoglobulin-like receptor B (PirB) has been identified as a receptor of Aβ and Aβ-PirB molecular interactions that cause synapse elimination and synaptic dysfunction. PirB deletion has been shown to suppress Aβ-induced synaptic dysfunction and behavioral deficits in AD model mice, implying that PirB mediates Aβ-induced AD pathology. Therefore, inhibiting the Aβ-PirB molecular interaction could be a successful approach for combating AD pathology. We previously showed that lateral olfactory tract usher substance (LOTUS) is an endogenous antagonist of type1 Nogo receptor and PirB and that LOTUS overexpression promotes neuronal regeneration following damage to the central nervous system, including spinal cord injury and ischemic stroke. Therefore, in this study, we investigated whether LOTUS inhibits Aβ-PirB interaction and Aβ-induced dendritic spine elimination.MethodsThe inhibitory role of LOTUS against Aβ-PirB (or leukocyte immunoglobulin-like receptor subfamily B member 2: LilrB2) binding was assessed using a ligand-receptor binding assay in Cos7 cells overexpressing PirB and/or LOTUS. We assessed whether LOTUS inhibits Aβ-induced intracellular alterations and synaptotoxicity using immunoblots and spine imaging in a primary cultured hippocampal neuron.ResultsWe found that LOTUS inhibits the binding of Aβ to PirB overexpressed in Cos7 cells. In addition, we found that Aβ-induced dephosphorylation of cofilin and Aβ-induced decrease in post-synaptic density-95 expression were suppressed in cultured hippocampal neurons from LOTUS-overexpressing transgenic (LOTUS-tg) mice compared with that in wild-type mice. Moreover, primary cultured hippocampal neurons from LOTUS-tg mice improved the Aβ-induced decrease in dendritic spine density. Finally, we studied whether human LOTUS protein inhibits Aβ binding to LilrB2, a human homolog of PirB, and found that human LOTUS inhibited the binding of Aβ to LilrB2 in a similar manner.ConclusionsThis study implied that LOTUS improved Aβ-induced synapse elimination by suppressing Aβ-PirB interaction in rodents and inhibited Aβ-LilrB2 interaction in humans. Our findings revealed that LOTUS may be a promising therapeutic agent in counteracting Aβ-induced AD pathologies.

Dataset Information

Alcohol Dehydrogenase 1B Suppresses ?-Amyloid-Induced Neuron Apoptosis.

Publications

Alcohol Dehydrogenase 1B Suppresses β-Amyloid-Induced Neuron Apoptosis.

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