Dataset Information

Deficiency of Neuronal p38? MAPK Attenuates Amyloid Pathology in Alzheimer Disease Mouse and Cell Models through Facilitating Lysosomal Degradation of BACE1.

ABSTRACT: Amyloid ? (A?) damages neurons and triggers microglial inflammatory activation in the Alzheimer disease (AD) brain. BACE1 is the primary enzyme in A? generation. Neuroinflammation potentially up-regulates BACE1 expression and increases A? production. In Alzheimer amyloid precursor protein-transgenic mice and SH-SY5Y cell models, we specifically knocked out or knocked down gene expression of mapk14, which encodes p38? MAPK, a kinase sensitive to inflammatory and oxidative stimuli. Using immunological and biochemical methods, we observed that reduction of p38? MAPK expression facilitated the lysosomal degradation of BACE1, decreased BACE1 protein and activity, and subsequently attenuated A? generation in the AD mouse brain. Inhibition of p38? MAPK also enhanced autophagy. Blocking autophagy by treating cells with 3-methyladenine or overexpressing dominant-negative ATG5 abolished the deficiency of the p38? MAPK-induced BACE1 protein reduction in cultured cells. Thus, our study demonstrates that p38? MAPK plays a critical role in the regulation of BACE1 degradation and A? generation in AD pathogenesis.

SUBMITTER: Schnoder L

PROVIDER: S-EPMC4732195 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Deficiency of Neuronal p38α MAPK Attenuates Amyloid Pathology in Alzheimer Disease Mouse and Cell Models through Facilitating Lysosomal Degradation of BACE1.

Schnöder Laura L Hao Wenlin W Qin Yiren Y Liu Shirong S Tomic Inge I Liu Xu X Fassbender Klaus K Liu Yang Y

The Journal of biological chemistry 20151209 5

Amyloid β (Aβ) damages neurons and triggers microglial inflammatory activation in the Alzheimer disease (AD) brain. BACE1 is the primary enzyme in Aβ generation. Neuroinflammation potentially up-regulates BACE1 expression and increases Aβ production. In Alzheimer amyloid precursor protein-transgenic mice and SH-SY5Y cell models, we specifically knocked out or knocked down gene expression of mapk14, which encodes p38α MAPK, a kinase sensitive to inflammatory and oxidative stimuli. Using immunolog ...[more]

PMID: 26663083

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Project description:Alzheimer's disease (AD) is characterized by two landmark pathologies, the overproduction of amyloid-beta peptides (Aβ), predominated by the β-amyloid protein precursor cleaving enzyme 1 (BACE1), and hyperphosphorylation of the microtubule protein, tau, because of an imbalance in a kinase/phosphatase system that involves the activation of the protein kinase A (PKA). Current evidence indicates that brain microRNAs participate in multiple aspects of AD pathology. Here, the role and underlying molecular mechanisms of microRNA-200a-3p (miR-200a-3p) in mediating neuroprotection against AD-related deficits were investigated. The expression of miR-200a-3p was measured in the hippocampus of APP/PS1 and SAMP8 mice and in an AD cell model in vitro, as well as in blood plasma extracted from AD patients. The targets of miR-200a-3p were determined using bioinformatics and dual-luciferase assay analyses. In addition, cell apoptosis was detected using flow cytometry, and related protein levels were measured using Western blot and enzyme-linked immunosorbent assay (ELISA) techniques. miR-200a-3p was confirmed to be depressed in microarray miRNA profile analysis in vitro and in vivo, suggesting that miR-200a-3p is a potential biomarker of AD. Subsequently, miR-200a-3p was demonstrated to inhibit cell apoptosis accompanied by the inactivation of the Bax/caspase-3 axis and downregulation of Aβ1-42 and tau phosphorylation levels in vitro. Further mechanistic studies revealed that miR-200a-3p reduced the production of Aβ1-42 and decreased hyperphosphorylation of tau by regulating the protein translocation of BACE1 and the protein kinase cAMP-activated catalytic subunit beta (PRKACB) associated with the three prime untranslated regions, respectively. Importantly, the function of miR-200a-3p was reversed by overexpression of BACE1 or PRKACB in cultured cells. This resulted in an elevation in cell apoptosis and increases in Aβ1-42 and tau hyperphosphorylation levels, involving the epitopes threonine 205 and serine 202, 214, 396, and 356, the favorable phosphorylated sites of PKA. In conclusion, our study suggests that miR-200a-3p is implicated in the pathology of AD, exerting neuroprotective effects against Aβ-induced toxicity by two possible mechanisms: one involving the inhibition of Aβ overproduction via suppression of the expression of BACE1 and synergistically decreasing the hyperphosphorylation of tau via attenuation of the expression of PKA.

Dataset Information

Deficiency of Neuronal p38? MAPK Attenuates Amyloid Pathology in Alzheimer Disease Mouse and Cell Models through Facilitating Lysosomal Degradation of BACE1.

Publications

Deficiency of Neuronal p38α MAPK Attenuates Amyloid Pathology in Alzheimer Disease Mouse and Cell Models through Facilitating Lysosomal Degradation of BACE1.

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