Oue, Hiroshi

Cerebrovasculature is critical in maintaining brain homeostasis; its dysregulation often leads to vascular cognitive impairment and dementia (VCID) during aging. VCID is the second most prevalent cause of dementia in the elderly, after Alzheimer’s disease (AD), with frequent cooccurrence of VCID and AD. While multiple factors are involved in the pathogenesis of AD and VCID, APOE4 increases the risk for both diseases. A major apolipoprotein E (apoE) receptor, the low-density lipoprotein receptor-related protein 1 (LRP1), is abundantly expressed in vascular mural cells (pericytes and smooth muscle cells). Here, we investigated how deficiency of vascular mural cell LRP1 affects the cerebrovascular system and cognitive performance using vascular mural cell–specific Lrp1 -KO mice ( smLrp1 –/– ) in a human APOE3 or APOE4 background. We found that spatial memory was impaired in the 13- to 16-month-old APOE4 smLrp1 –/– mice but not in the APOE3 smLrp1 –/– mice, compared with their respective littermate control mice. These disruptions in the APOE4 smLrp1 –/– mice were accompanied with excess paravascular glial activation and reduced cerebrovascular collagen IV. In addition, blood-brain barrier (BBB) integrity was disrupted in the APOE4 smLrp1 –/– mice. Together, our results suggest that vascular mural cell LRP1 modulates cerebrovasculature integrity and function in an APOE genotype–dependent manner.

AbstractIntroductionCerebrovascular pathologies including cerebral amyloid angiopathy (CAA) and blood‐brain barrier (BBB) dysregulation are prominent features in the majority of Alzheimer's disease (AD) cases.MethodsWe performed neuropathologic and biochemical studies on a large, neuropathologically confirmed human AD cohort (N = 469). Amounts of endothelial tight junction proteins claudin‐5 (CLDN5) and occludin (OCLN), and major AD‐related molecules (amyloid beta [Aβ40], Aβ42, tau, p‐tau, and apolipoprotein E) in the temporal cortex were assessed by ELISA.ResultsHigher levels of soluble tau, insoluble p‐tau, and apolipoprotein E (apoE) were independently correlated with lower levels of endothelial tight junction proteins CLDN5 and OCLN in AD brains. Although high Aβ40 levels, APOE ε4, and male sex were predominantly associated with exacerbated CAA severity, those factors did not influence tight junction protein levels.DiscussionRefining the molecular mechanisms connecting tau, Aβ, and apoE with cerebrovascular pathologies is critical for greater understanding of AD pathogenesis and establishing effective therapeutic interventions for the disease.