研究揭示臨床前神經血管障礙機制

研究揭示臨床前神經血管障礙機制

作者：

小柯機器人

發布時間：2020/8/11 18:36:18

美國威爾康奈爾醫學大學Costantino Iadecola和Laibaik Park研究組合作取得新進展。他們發現Tau誘導突觸後密度95（PSD95）–神經元一氧化氮合酶（nNOS）解偶聯和神經血管障礙，而不依賴神經退行性變。這一研究成果發表在2020年8月10日的《自然-神經科學》上。

他們報告說，表達突變的tau的小鼠表現出選擇性的神經活動抑制引起的腦血流量的增加，其先於tau病理和認知障礙。這種功能障礙可歸因於腦小動脈血管舒張減少，並且可通過減少tau產生而逆轉。從機制上講，神經血管耦合的失敗涉及tau誘導的nNOS與PSD95的解離，以及在穀氨酸能突觸活動過程中有效的血管擴張劑一氧化氮的產生減少。

這些數據將穀氨酸能信號功能障礙和一氧化氮缺乏確定為tau病理生物學的尚未描述的早期表現，和神經退行性病變不同，並為在Tauopathies的臨床前階段觀察到的神經血管改變提供了一種機制。

據介紹，腦血管異常已成為阿爾茨海默氏病和額顳葉痴呆的臨床前表現，這些疾病的特徵是微管相關蛋白tau的高磷酸化形式的積累。然而，尚不清楚tau是否會不依賴神經退行性變而促成這些神經血管改變。

附：英文原文

Title: Tau induces PSD95–neuronal NOS uncoupling and neurovascular dysfunction independent of neurodegeneration

Author: Laibaik Park, Karin Hochrainer, Yorito Hattori, Sung Ji Ahn, Antoine Anfray, Gang Wang, Ken Uekawa, James Seo, Victoria Palfini, Ismary Blanco, Diana Acosta, David Eliezer, Ping Zhou, Josef Anrather, Costantino Iadecola

Issue&Volume: 2020-08-10

Abstract: Cerebrovascular abnormalities have emerged as a preclinical manifestation of Alzheimer’s disease and frontotemporal dementia, diseases characterized by the accumulation of hyperphosphorylated forms of the microtubule-associated protein tau. However, it is unclear whether tau contributes to these neurovascular alterations independent of neurodegeneration. We report that mice expressing mutated tau exhibit a selective suppression of neural activity-induced cerebral blood flow increases that precedes tau pathology and cognitive impairment. This dysfunction is attributable to a reduced vasodilatation of intracerebral arterioles and is reversible by reducing tau production. Mechanistically, the failure of neurovascular coupling involves a tau-induced dissociation of neuronal nitric oxide synthase (nNOS) from postsynaptic density 95 (PSD95) and a reduced production of the potent vasodilator nitric oxide during glutamatergic synaptic activity. These data identify glutamatergic signaling dysfunction and nitric oxide deficiency as yet-undescribed early manifestations of tau pathobiology, independent of neurodegeneration, and provide a mechanism for the neurovascular alterations observed in the preclinical stages of tauopathies.

DOI: 10.1038/s41593-020-0686-7

Source: https://www.nature.com/articles/s41593-020-0686-7