Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Sci Transl Med. 2021 Jun 2;13(596). doi: 10.1126/scitranslmed.aaz7615.
Compelling evidence supports vascular contributions to cognitive impairment and dementia (VCID) including Alzheimer's disease (AD), but the underlying pathogenic mechanisms and treatments are not fully understood. Cis P-tau is an early driver of neurodegeneration resulting from traumatic brain injury, but its role in VCID remains unclear. Here, we found robust cis P-tau despite no tau tangles in patients with VCID and in mice modeling key aspects of clinical VCID, likely because of the inhibition of its isomerase Pin1 by DAPK1. Elimination of cis P-tau in VCID mice using cis-targeted immunotherapy, brain-specific Pin1 overexpression, or DAPK1 knockout effectively rescues VCID-like neurodegeneration and cognitive impairment in executive function. Cis mAb also prevents and ameliorates progression of AD-like neurodegeneration and memory loss in mice. Furthermore, single-cell RNA sequencing revealed that young VCID mice display diverse cortical cell type-specific transcriptomic changes resembling old patients with AD, and the vast majority of these global changes were recovered by cis-targeted immunotherapy. Moreover, purified soluble cis P-tau was sufficient to induce progressive neurodegeneration and brain dysfunction by causing axonopathy and conserved transcriptomic signature found in VCID mice and patients with AD with early pathology. Thus, cis P-tau might play a major role in mediating VCID and AD, and antibody targeting it may be useful for early diagnosis, prevention, and treatment of cognitive impairment and dementia after neurovascular insults and in AD.
有强有力的证据表明血管因素与认知障碍和痴呆（VCID）有关，包括阿尔茨海默病（AD），但潜在的发病机制和治疗方法尚未完全阐明。cis P-tau 是创伤性脑损伤导致神经退行性变的早期驱动因素，但它在 VCID 中的作用尚不清楚。在这里，我们发现即使在 VCID 患者和模拟临床 VCID 关键方面的小鼠中没有 tau 缠结，也存在强烈的 cis P-tau，这可能是由于 DAPK1 抑制其异构酶 Pin1 所致。使用 cis 靶向免疫疗法、大脑特异性 Pin1 过表达或 DAPK1 敲除消除 VCID 小鼠中的 cis P-tau，可有效挽救执行功能的类似 VCID 的神经退行性变和认知障碍。cis mAb 还可预防和改善 AD 样神经退行性变和记忆丧失在小鼠中的进展。此外，单细胞 RNA 测序显示，年轻的 VCID 小鼠表现出类似于 AD 老年患者的皮质细胞类型特异性转录组变化，而 cis 靶向免疫疗法可恢复绝大多数这些全局变化。此外，纯化的可溶性 cis P-tau 通过引起轴突病变和在 VCID 小鼠和早期病理 AD 患者中发现的保守转录组特征，足以诱导进行性神经退行性变和脑功能障碍。因此，cis P-tau 可能在介导 VCID 和 AD 中起主要作用，针对它的抗体可能有助于在神经血管损伤后和 AD 中进行认知障碍和痴呆的早期诊断、预防和治疗。
