病理性血管生成与阿尔茨海默病中的脑血管病变和神经退行性变相关。

Pathological angiogenesis was associated with cerebrovascular lesion and neurodegeneration in Alzheimer's disease.

作者信息

Gao Feng, Zhan Yaxi, Wang Qiong, Zhang Mengguo, Dai Linbin, Shen Yong

机构信息

Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.

Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.

出版信息

Alzheimers Dement. 2025 Feb;21(2):e14521. doi: 10.1002/alz.14521. Epub 2025 Jan 8.

DOI:10.1002/alz.14521

PMID:39777972

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11848169/

Abstract

INTRODUCTION

We investigated the specific factors driving abnormal angiogenesis in Alzheimer's disease (AD) and its role in cerebrovascular lesions and neurodegeneration.

METHODS

We assessed cerebrovascular pathologies, amyloid-beta (Aβ), and tau pathologies in post mortem human brains and detected 12 angiogenic factors in cerebrospinal fluid (CSF) from the China Aging and Neurodegenerative Disease Initiative (CANDI) cohort.

RESULTS

We observed severe blood-brain barrier damage and elevated levels of the vascular marker CD31 in human AD brains, which had a stronger correlation with tau pathology than Aβ pathology. Consistently, only CSF pTau181 showed positive associations with CSF angiogenesis factors (soluble vascular endothelial growth factor receptor 2 [sVEGFR2], VEGF-C, VEGF-D, placental growth factor [PLGF], Angiopoietin2, and Serpin E1), but not CSF Aβ42/40. Additionally, higher levels of CSF sVEGFR1, soluble Tyrosine-protein kinase receptor 2 [sTIE2], PLGF, and interleukin 8 [IL8], as well as lower levels of CSF urokinase-type plasminogen activator [uPA], were associated with worsen cerebrovascular pathologies and neurodegeneration.

DISCUSSION

Our findings indicate that tau pathology may play a critical role in pathological angiogenesis, contributing to cerebrovascular lesions and neurodegeneration in AD.

HIGHLIGHTS

BBB damage and elevated vascular marker CD31 in human AD brains had a stronger correlation with tau pathology than Aβ pathology. CSF pTau181 mediated the effect of CSF Aβ42/40 on CSF sVEGFR1 and sTIE2. Only CSF pTau181 showed positive associations with sVEGFR2, VEGF-C, VEGF-D, PLGF, Angiopoietin2, and Serpin E1. Higher sVEGFR1, sTIE2, PLGF, and IL8, and lower uPA in CSF, were associated with cerebrovascular pathologies and neurodegeneration.

摘要

引言

我们研究了驱动阿尔茨海默病（AD）异常血管生成的具体因素及其在脑血管病变和神经退行性变中的作用。

方法

我们评估了死后人类大脑中的脑血管病变、淀粉样β蛋白（Aβ）和tau病变，并检测了来自中国衰老与神经退行性疾病倡议（CANDI）队列的脑脊液（CSF）中的12种血管生成因子。

结果

我们观察到人类AD大脑中存在严重的血脑屏障损伤和血管标志物CD31水平升高，其与tau病变的相关性强于Aβ病变。一致地，只有脑脊液pTau181与脑脊液血管生成因子（可溶性血管内皮生长因子受体2 [sVEGFR2]、血管内皮生长因子C [VEGF-C]、血管内皮生长因子D [VEGF-D]、胎盘生长因子 [PLGF]、血管生成素2和丝氨酸蛋白酶抑制剂E1）呈正相关，而与脑脊液Aβ42/40无相关性。此外，脑脊液sVEGFR1、可溶性酪氨酸蛋白激酶受体2 [sTIE2]、PLGF和白细胞介素8 [IL8]水平较高，以及脑脊液尿激酶型纤溶酶原激活剂 [uPA]水平较低，与更严重的脑血管病变和神经退行性变相关。

讨论

我们的研究结果表明，tau病变可能在病理性血管生成中起关键作用，导致AD中的脑血管病变和神经退行性变。

要点

人类AD大脑中的血脑屏障损伤和血管标志物CD31水平升高与tau病变的相关性强于Aβ病变。脑脊液pTau181介导了脑脊液Aβ42/40对脑脊液sVEGFR1和sTIE2的影响。只有脑脊液pTau181与sVEGFR2、VEGF-C、VEGF-D、PLGF、血管生成素-2和丝氨酸蛋白酶抑制剂E1呈正相关。脑脊液中较高的sVEGFR1、sTIE2、PLGF和IL8以及较低的uPA与脑血管病变和神经退行性变相关。