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?-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3?/tau cascade.

ABSTRACT: The brain noradrenergic system is critical for normal cognition and is affected at early stages in Alzheimer's disease (AD). Here, we reveal a previously unappreciated direct role of norepinephrine signaling in connecting ?-amyloid (A?) and tau, two key pathological components of AD pathogenesis. Our results show that A? oligomers bind to an allosteric site on ?_2A adrenergic receptor (?_2AAR) to redirect norepinephrine-elicited signaling to glycogen synthase kinase 3? (GSK3?) activation and tau hyperphosphorylation. This norepinephrine-dependent mechanism sensitizes pathological GSK3?/tau activation in response to nanomolar accumulations of extracellular A?, which is 50- to 100-fold lower than the amount required to activate GSK3? by A? alone. The significance of our findings is supported by in vivo evidence in two mouse models, human tissue sample analysis, and longitudinal clinical data. Our study provides translational insights into mechanisms underlying A? proteotoxicity, which might have strong implications for the interpretation of A? clearance trial results and future drug design and for understanding the selective vulnerability of noradrenergic neurons in AD.

SUBMITTER: Zhang F

PROVIDER: S-EPMC7891768 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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β-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade.

Zhang Fang F Gannon Mary M Chen Yunjia Y Yan Shun S Zhang Sixue S Feng Wendy W Tao Jiahui J Sha Bingdong B Liu Zhenghui Z Saito Takashi T Saido Takaomi T Keene C Dirk CD Jiao Kai K Roberson Erik D ED Xu Huaxi H Wang Qin Q

Science translational medicine 20200101 526

The brain noradrenergic system is critical for normal cognition and is affected at early stages in Alzheimer's disease (AD). Here, we reveal a previously unappreciated direct role of norepinephrine signaling in connecting β-amyloid (Aβ) and tau, two key pathological components of AD pathogenesis. Our results show that Aβ oligomers bind to an allosteric site on α<sub>2A</sub> adrenergic receptor (α<sub>2A</sub>AR) to redirect norepinephrine-elicited signaling to glycogen synthase kinase 3β (GSK3β ...[more]

PMID: 31941827

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Project description:Introduction and aimsAlzheimer's disease (AD) is characterized by the abnormal accumulation of hyperphosphorylated tau proteins and amyloid-beta (Aβ) peptides. Recent studies have shown that many microRNAs (miRNAs) are dysregulated in AD, and modulation of these miRNAs can influence the development of tau and Aβ pathology. The brain-specific miRNA miR-128, encoded by MIR128-1 and MIR128-2, is important for brain development and dysregulated in AD. In this study, the role of miR-128 in tau and Aβ pathology as well as the regulatory mechanism underlying its dysregulation were investigated.MethodsThe effect of miR-128 on tau phosphorylation and Aβ accumulation was examined in AD cellular models through miR-128 overexpression and inhibition. The therapeutic potential of miR-128 in AD mouse model was assessed by comparing phenotypes of 5XFAD mice administered with miR-128-expressing AAVs with 5XFAD mice administered with control AAVs. Phenotypes examined included behavior, plaque load, and protein expression. The regulatory factor of miR-128 transcription was identified through luciferase reporter assay and validated by siRNA knockdown and ChIP analysis.ResultsBoth gain-of-function and loss-of-function studies in AD cellular models reveal that miR-128 represses tau phosphorylation and Aβ secretion. Subsequent investigations show that miR-128 directly inhibits the expression of tau phosphorylation kinase GSK3β and Aβ modulators APPBP2 and mTOR. Upregulation of miR-128 in the hippocampus of 5XFAD mice ameliorates learning and memory impairments, decreases plaque deposition, and enhances autophagic flux. We further demonstrated that C/EBPα transactivates MIR128-1 transcription, while both C/EBPα and miR-128 expression are inhibited by Aβ.ConclusionOur findings suggest that miR-128 suppresses AD pathogenesis, and could be a promising therapeutic target for AD. We also find a possible mechanism underlying the dysregulation of miR-128 in AD, in which Aβ reduces miR-128 expression by inhibiting C/EBPα.

Dataset Information

?-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3?/tau cascade.

Publications

β-amyloid redirects norepinephrine signaling to activate the pathogenic GSK3β/tau cascade.

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