Role of Tau Conformations in Vascular Contribution to Cognitive Impairment and Dementia

Tau 构象在血管对认知障碍和痴呆的影响中的作用

• 批准号: 10176320
• 负责人: Eng H. Lo
• 金额: $ 68.62万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176320
• 关键词: Address; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Antibody Therapy; Axon; Biochemical; Blocking Antibodies; Blood Vessels; Brain; Cell Death; Cells; Clinical; Data; Dementia; Development; Disease; Endothelial Cells; Head; Human; Hypertension; Hypoxia; Impaired cognition; In Vitro; Infarction; Ischemic Stroke; Knock-out; Knockout Mice; Lead; Lesion; Mediating; Modeling; Molecular; Molecular Conformation; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neurologic Deficit; Neurons; Oligodendroglia; Oxidative Stress; Pathogenicity; Pathologic Processes; Pathology; Patients; Peptidylprolyl Isomerase; Pilot Projects; Process; Property; Rattus; Role; Serum; Stress; Testing; Traumatic Brain Injury; Vascular Dementia; Vascular Endothelial Cell; aged; base; brain dysfunction; brain endothelial cell; cerebral hypoperfusion; efficacy evaluation; gray matter; hyperphosphorylated tau; in vivo; mouse model; multidisciplinary; neurofibrillary tangle formation; neurovascular; neurovascular injury; neurovascular unit; novel; novel therapeutic intervention; oxidation; prevent; spatiotemporal; targeted treatment; tau Proteins; tau conformation; tau-1; vascular cognitive impairment and dementia; vascular contributions; vascular factor; white matter

Scientific evidence continues to support vascular contributions to cognitive impairment and dementia (VCID) such as Alzheimer's disease (AD). In fact, ~50% of dementia patients have mixed vascular and AD pathologies in their brains. Among many potential clinical triggers, multi-embolic infarcts and cerebral hypoperfusion, especially in the presence of aging and hypertension, are major vascular factors in VCID, referred as vascular dementia (VaD), but underlying mechanisms remain elusive. Notably, neurofibrillary tangles composed of hyperphosphorylated tau are a neuropathological hallmark of AD, but pure VaD human brains do not have obvious tau tangle pathology so that little is known about the role of tau pathology in the development of VaD. Recently, we have identified a unique prolyl isomerase, Pin1 that prevents accumulation of the phosphorylated Thr231-Pro motif in tau (P-tau) in the pathogenic cis conformation, but is inactivated in AD by aging, oxidation and others. Cis P-tau is a previously unknown precursor of tau pathology that instigates and propagates neurodegeneration and dementia associated with AD and traumatic brain injury (TBI), but can be blocked by cis mAb. In our pilot studies, we found robust cis P-tau in neurovascular unit cells without tau tangle pathology in pure VaD human brains and mouse models after multi-embolic infarcts or cerebral hypoperfusion. Furthermore, purified cis P-tau was toxic both to neurons and brain microvascular endothelial cells and also caused brain dysfunction in mice, both of which were effectively blocked by cis mAb. Moreover, cis mAb blocked hypoxia or serum depletion from inducing cis P-tau and cell death in vascular endothelial cells and neurons in vitro and restored white and gray matter lesions and neurologic deficits after repetitive TBI in mice. In this proposal, we have assembled a team with all the requisite expertise to test our novel hypothesis that during aging, vascular insults lead to oxidative stress that inactivates Pin1, resulting in accumulation of cis P-tau that damages the neurovascular unit, thereby serving as an early and druggable driver of VaD. We will first assess Pin1 inhibition and cis P-tau induction in different neurovascular unit cells, and their relationships with vascular pathology and white matter lesions in VaD human brains and after multi-embolic infarcts or cerebral hypoperfusion in young and old mice with or without hypertension or Pin1 knockout. We will then purify cis P-tau proteins from VaD human brains and VaD mouse brains to characterize their biochemical property and ability to damage neurovascular unit cells in vitro and in vivo to induce white matter lesions and neurologic deficits relevant to VaD. Finally, we will evaluate the efficacy of cis mAb in inhibiting neurovascular unit damage in vitro and restoring white matter lesions, delayed neurodegeneration and neurologic deficits after multi-embolic infarcts or cerebral hypoperfusion in aged hypertensive or Pin1 knockout mice. These studies should help us identify cis P-tau as an early disease driver of VCID, uncover a common molecular mechanism underlying vascular and AD pathologies, and pursue targeted therapy for these major diseases.

科学证据继续支持对认知障碍和痴呆（VCID）的血管贡献（VCID） 例如阿尔茨海默氏病（AD）。实际上，约有50％的痴呆症患者患有混合血管和AD病理 在他们的大脑中。在许多潜在的临床触发器中 特别是在衰老和高血压的情况下，是VCID的主要血管因素，称为血管 痴呆症（VAD），但潜在的机制仍然难以捉摸。值得注意的是，由 高磷酸化的tau是AD的神经病理学标志，但纯Vad人的大脑没有 显而易见的Tau Tangle病理学，因此对Tau病理在VAD发展中的作用知之甚少。 最近，我们确定了一个独特的丙酸异构酶，PIN1可防止 致病性顺式构象中的tau（p-tau）中磷酸化的Thr231-Pro基序，但在AD中被灭活 衰老，氧化等。顺式p-tau是启动和 传播与AD和创伤性脑损伤相关的神经变性和痴呆症（TBI），但可以是 被顺式mab阻塞。在我们的初步研究中，我们发现神经血管单位细胞中有强大的顺式p-tau，而没有tau缠结 多物质梗死或脑灌注不足后，纯VAD人的大脑和小鼠模型中的病理。 此外，纯化的顺式p-tau对神经元和脑微血管内皮细胞都有毒性 引起小鼠的脑功能障碍，两者都被顺式mAb有效地阻断。此外，顺式mab 血管内皮细胞中诱导顺式P-TAU和细胞死亡的缺氧或血清耗尽阻塞 小鼠重复性TBI后，神经元在体外并恢复了白质病变以及神经系统缺陷。 在此提案中，我们组建了一个拥有所有必要专业知识的团队，以检验我们的新假设 在衰老期间，血管侮辱会导致氧化应激，使PIN1失活，导致顺式积累 损害神经血管单元的p-tau，从而成为VAD的早期且可吸毒的驾驶员。我们将 首先评估不同神经血管单位细胞中的PIN1抑制和顺式P-TAU诱导，它们的关系 人类大脑中的血管病理和白质病变以及多物质梗塞或之后 患有或没有高血压或P​​IN1敲除的年轻小鼠和老鼠的脑灌注不足。然后我们会 从VAD人的大脑和VAD小鼠大脑中纯化顺式P-TAU蛋白，以表征其生化 在体外和体内损害神经血管单位细胞的特性和能力，以诱导白质病变和 与VAD相关的神经系统缺陷。最后，我们将评估顺式mAb抑制神经血管的功效 在体外损害单位损伤并恢复白质病变，延迟神经退行性和神经系统缺陷 在多胚胎梗塞或老年高血压或P​​IN1基因敲除小鼠的多胚胎梗塞或脑灌注不足之后。这些 研究应帮助我们识别顺式P-TAU为VCID的早期疾病驱动力，发现一个常见的分子 血管和AD病理学的机制，并为这些主要疾病寻求靶向疗法。

项目成果

Histone Deacetylase 3 Inhibition Decreases Cerebral Edema and Protects the Blood-Brain Barrier After Stroke.

• DOI: 10.1007/s12035-022-03083-z
• 发表时间: 2023-01
• 期刊: MOLECULAR NEUROBIOLOGY
• 影响因子: 5.1
• 作者: Lu, Hui;Ashiqueali, Ryan;Lin, Chin, I;Walchale, Aashlesha;Clendaniel, Victoria;Matheson, Rudy;Fisher, Marc;Lo, Eng H.;Selim, Magdy;Shehadah, Amjad
• 通讯作者: Shehadah, Amjad

Sepsis-associated brain injury: underlying mechanisms and potential therapeutic strategies for acute and long-term cognitive impairments.

• DOI: 10.1186/s12974-022-02464-4
• 发表时间: 2022-04-29
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3

Inhibition of death-associated protein kinase 1 attenuates cis P-tau and neurodegeneration in traumatic brain injury.

• DOI: 10.1016/j.pneurobio.2021.102072
• 发表时间: 2021-08
• 期刊: Progress in neurobiology
• 影响因子: 6.7
• 作者: Kim N;Wang B;Koikawa K;Nezu Y;Qiu C;Lee TH;Zhou XZ
• 通讯作者: Zhou XZ