Abstract
Cerebral hypoperfusion and blood-brain barrier (BBB) leakiness are pathological features of Alzheimer's disease (AD). To understand their relationship to the distribution and progression of Alzheimer's disease neuropathologic change (ADNC), we analysed associations between biochemical markers and mediators of cerebral hypoperfusion and BBB leakiness, and amyloid-β (Aβ) and hyperphosphorylated tau, in multiple brain regions at different Braak tangle stages (BS). We studied the frontal, temporal, parietal, entorhinal, calcarine and cingulate cortex, putamen and trigonal white matter from eight controls with low pathology (BS0-II), 17 brains with early-stage/intermediate AD pathology (BSIII-IV) and 11 late-stage AD cases (BSV-VI), from the South West Dementia Brain Bank and the London Neurodegenerative Diseases Brain Bank. We excluded cases with widespread moderate-severe arteriolosclerosis, macroscopic infarcts or foci of haemorrhage, Lewy body pathology or other neurodegenerative pathology. ELISAs were used to measure the myelin-associated glycoprotein:proteolipid protein-1 ratio (MAG:PLP1), an index of ante-mortem cerebral perfusion, and fibrinogen levels, to assess BBB leakiness. Also by ELISA, we measured vascular endothelial growth factor-A (VEGF-A), upregulated in cerebral ischaemia; endothelin-1 (EDN1), a mediator of vasoconstriction; CD31, an endothelial marker; platelet-derived growth factor-β (PDGFRβ), a pericyte marker; and Aβ1-40, Aβ1-42 and ptau-231 concentrations. In the temporal cortex from a subset of cases, 55 angiogenesis-related proteins were assayed using a multiplex profiler assay. MAG:PLP1 was lower in BSIII-IV than BS0-II in all brain regions. VEGF-A, EDN1 and CD31 concentrations were highest in BSIII-IV in most regions and correlated inversely with MAG:PLP1. EDN1 level correlated strongly with Aβ1-42 concentration in low-pathology controls. Angiogenesis-related protein assays showed elevated levels of endoglin (CD105), a marker of neoangiogenesis, in BSIII-IV, coinciding with altered expression of several angiogenic mediators. The PDGFRβ:CD31 ratio, a marker of pericyte content adjusted for vessel density, was lower in BSIII-IV than BS0-II and correlated positively with MAG:PLP1 and inversely with Aβ1-42. BBB leakiness, evidenced by elevated fibrinogen in brain tissue homogenates, was highest in BSV-VI in most brain regions and correlated with VEGF-A, CD31 and ptau-231 concentrations. The present data provide evidence of widespread cerebral hypoperfusion associated with pathogenic angiogenesis and vascular remodelling in AD. The study highlights a complex and dynamic temporal relationship, beginning in early-stage AD, between mediators of cerebrovascular dysfunction and the regional spread of Aβ and tau pathology. The study also identifies several therapeutic targets, including EDN1 and VEGF-A signalling, with the potential to limit cerebrovascular damage in early AD.