Targeting IDOL-ApoE receptor pathway in Alzheimer's disease

载脂蛋白E（APOE）基因型长期以来一直被认为强烈影响风险， 阿尔茨海默病（AD）的发病，但确切的机制仍然存在 不完全定义。越来越多的证据表明，ApoE的功能组合 及其受体共同作用，以改变AD的风险，靶向脑ApoE受体， 最近出现了一个有前途的治疗策略，以打击AD。但缺乏 关于调节脑ApoE受体的内源性途径的知识是 将ApoE受体作为AD的治疗靶点。 以前，我们已经确定了低密度脂蛋白受体（IDOL）的诱导降解剂，E3泛素 连接酶是三种脑ApoE受体的主要翻译后调节因子：低密度 脂蛋白受体（LDLR）、极低密度脂蛋白受体（VLDLR）和ApoE受体 2（ApoER 2）。这三种ApoE受体中的每一种都在调节ApoE作用中起关键作用， 影响AD发病机制。我们的研究表明，遗传缺失或药理学 抑制脑中的IDOL显著增加ApoE受体的蛋白水平， 改善淀粉样蛋白-β（Aβ）病理学，并改善AD小鼠模型的认知功能， 这表明抑制脑IDOL活性可以作为一种有前途的治疗策略， AD.对于机制和治疗意义，我们建议进一步研究 IDOL-ApoE受体通路在调节细胞凋亡中的多因素作用及其分子机制 ApoE作用和影响AD病理学。目的1是表征小胶质细胞的内在作用， Aβ病理学中的IDOL。目的2是阐明IDOL减少如何促进 小胶质细胞对Aβ病理学的反应。目的3是确定神经元IDOL-ApoER 2的作用， 在AD中，ApoE 4通路在预防ApoE 4诱导的突触功能障碍和认知缺陷中的作用。

Apolipoprotein E (APOE) genotype has long been known to strongly influence the risk and the onset of Alzheimer’s disease(AD), yet the exact mechanisms underlying remain incompletely defined. Accumulating evidence suggested that the functional combination of ApoE and its receptors act together to modify the risk for AD, and targeting brain ApoE receptors has recently emerged as a promising therapeutic strategy to combat AD. However, the lack of knowledge on the endogenous pathways regulating brain ApoE receptors is a major hurdle to advance ApoE receptors as accessible therapeutic targets in AD. Previously, we have identified the inducible degrader of the LDLR (IDOL), an E3 ubiquitin ligase, is a major post-translational regulator of three brain ApoE receptors: low-density lipoprotein receptor (LDLR), very low-density lipoprotein receptor (VLDLR), and ApoE Receptor 2 (ApoER2). Each of these three ApoE receptor plays key role in modulating ApoE actions and impacting AD pathogenesis. Our studies showed the genetic deletion or pharmacological inhibition of IDOL in the brain significantly increase the protein levels of ApoE receptors, ameliorate amyloid-β (Aβ) pathology, and improve cognitive functions in an AD mouse model, suggesting inhibition of brain IDOL activity may serve as a promising therapeutic strategy for AD. For the mechanistic and therapeutic implications, we propose to further investigate the multifactorial role and molecular mechanisms of IDOL-ApoE receptors pathway in modulating ApoE actions and impacting AD pathology. Aim 1 is to characterize the microglia-intrinsic role of IDOL in Aβ pathology. Aim 2 is to elucidate the mechanisms on how IDOL reduction facilitates microglia response to Aβ pathology. Aim 3 is to define the role of neuronal IDOL-ApoER2 pathway in protecting against ApoE4-induced synaptic dysfunction and cognitive deficit in AD.