Novel role of β-arrestins in Tauopathy

阿尔茨海默病(AD)的主要病理特征是 淀粉样蛋白β(Aβ)和过度磷酸化的tau。多个GPCR(即β2AR、GPR3、AT2R、CXCR2、 &NMDARs)在AD发病机制中起着不可或缺的作用。然而，目前还不清楚 不同的GPCR阵列如何都对β和tau的发病机制产生积极影响 阿尔茨海默病的神经退行性变。鉴于GPCR通过β-arrestin共享共同的行动机制 作为信号复合体的支架，中心假说是β阻滞素的作用 GPCRs下游直接影响AD的发病机制。β-逮捕存在于三个不同的状态 在细胞中；1)游离的，2)gpr结合的，3)微管结合的，每一个都有不同的信号 能力。先前的研究表明，β-arrestins在AD大脑中上调，而β-- 抑制素促进A-β的发病。然而，目前尚不清楚β-arrestins是否以及如何 对阿尔茨海默病和神经退行性变的病理性影响。初步数据显示， β-arrestin寡聚体通过两种不同的机制促进转位性病变：1)与tau直接竞争 用于与微管(MT)结合，从而解除对MT动力学的调控；2)抑制tau清除 通过放松对自噬机制的管制。 通过利用分子、细胞生物学、生化、电生理、行为、病毒和 组织化学工具，这项提议将1)验证β-arrestins在活体中的作用，2) 验证β-arrestins在tau/微管动力学中的作用，以及3)研究β- P62介导的自噬和tau翻转中的拦阻蛋白。这份提案将验证β是否- 抑制素及其寡聚体状态有望成为缓解tau的治疗靶点 发病机制。

The major defining pathological hallmarks of Alzheimer’s disease (AD) are the accumulation of amyloid β (Aβ) and hyperphosphorylated tau. Multiple GPCRs (i.e, β2AR, GPR3, AT2R, CXCR2, & NMDARs) have been shown to play integral roles in AD pathogenesis. However, it is unclear as to how a diverse array of GPCRs all positively impinge on Aβ and tau pathogenesis as well as neurodegeneration in AD. Given that GPCRs share a common mechanism of action via β-arrestin scaffolding signaling complexes, the central hypothesis is that the actions of β-arrestins downstream of GPCRs directly impact AD pathogenesis. β-arrestins exist in three distinct states in cells; 1) free unbound, 2) GPCR-bound, and 3) microtubule-bound, each with different signaling capability. Previous studies have shown that β-arrestins are upregulated in AD brains and that β- arrestins promote Aβ pathogenesis. However, it is unknown whether and how β-arrestins pathogenically impinge on tauopathy and neurodegeneration in AD. Preliminary data indicate that β-arrestin oligomers promote tauopathy via 2 distinct mechanisms: 1) directly competing with tau for binding to microtubules (MT), thereby deregulating MT dynamics; 2) inhibiting tau clearance by deregulating the autophagy machinery. By utilizing molecular, cell biological, biochemical, electrophysiological, behavioral, viral, and histochemical tools, this proposal will 1) validate the role of β-arrestins in tauopathy in vivo, 2) validate the role of β-arrestins in tau/microtubule dynamics, and 3) investigate the role of β- arrestins in p62-mediated autophagy and tau turnover. This proposal will validate whether β- arrestins and their oligomeric status serve as promising therapeutic targets to mitigate tau pathogenesis.