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

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.