Novel role of β-arrestins in Tauopathy

阿尔茨海默病（AD）的主要病理学标志是 淀粉样蛋白β（Aβ）和过度磷酸化的tau蛋白。多个GPCR（即β2AR、GPR 3、AT 2 R、CXCR 2、 和NMDAR）在AD发病机制中起重要作用。但目前尚不清楚 关于各种GPCR如何对Aβ和tau发病机制产生积极影响， AD中的神经变性。鉴于GPCR通过β-抑制蛋白具有共同的作用机制， 支架信号复合物，中心假设是β-抑制蛋白的作用， GPCR的下游直接影响AD的发病机制。β-抑制蛋白存在三种不同的状态 在细胞中; 1）游离的未结合的，2）GPCR结合的，和3）微管结合的，各自具有不同的信号传导 能力。先前的研究表明，β-arrestins在AD脑中上调，β-arrestins在AD脑中上调。 抑制蛋白促进Aβ发病。然而，β-arrestins是否以及如何与 在AD中的tau蛋白病和神经变性的病理学上起作用。初步数据表明 β-抑制蛋白寡聚体通过2种不同的机制促进tau蛋白病：1）直接与tau蛋白竞争 用于结合微管（MT），从而解除MT动力学的调节; 2）抑制tau清除 通过解除自噬机制的调节。 通过利用分子、细胞生物学、生物化学、电生理学、行为学、病毒和 组织化学工具，该提议将1）验证β-抑制蛋白在体内tau蛋白病中的作用，2） 验证β-arrestins在tau/微管动力学中的作用，以及3）研究β-arrestins在tau/微管动力学中的作用。 抑制蛋白在p62介导的自噬和tau蛋白转换中的作用。该提案将验证β- 抑制蛋白和它们的寡聚状态作为有希望的治疗靶点来减轻tau蛋白 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.