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.

科学证据继续支持血管在认知障碍和痴呆（VCID）中的作用

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