Brain mural cell loss in the parietal cortex in Alzheimer’s disease correlates with cognitive decline and TDP‐43 pathology

Abstract

AimsBrain mural cells (BMC), smooth muscle cells and pericytes, interact closely with endothelial cells and modulate numerous cerebrovascular functions. A loss of BMC function is suspected to play a role in the pathophysiology of Alzheimer’s Disease (AD).MethodsBMC markers, namely smooth muscle alpha actin (α‐SMA) for smooth muscle cells, as well as platelet‐derived growth factor receptor β (PDGFRβ) and aminopeptidase N (ANPEP or CD13) for pericytes, were assessed by Western immunoblotting in microvessel extracts from the parietal cortex of 60 participants of the Religious Orders study, with ages at death ranging from 75 to 98 years old.ResultsParticipants clinically diagnosed with AD had lower vascular levels of α‐SMA, PDGFRβ and CD13. These reductions were correlated with lower cognitive scores for global cognition, episodic and semantic memory, perceptual speed and visuospatial ability. In addition, α‐SMA, PDGFRβ and CD13 were negatively correlated with vascular Aβ40 concentrations. Vascular levels of BMC markers were also inversely correlated with insoluble cleaved phosphorylated transactive response DNA binding protein 43 (TDP‐43) (25 kDa) and positively correlated with soluble cleaved phosphorylated TDP‐43 (35 kDa) in cortical homogenates, suggesting strong association between BMC loss and cleaved phosphorylated TDP‐43 aggregation.ConclusionsThe results of this study highlight a loss of BMC in AD. The associations between α‐SMA, PDGFRβ and CD13 vascular levels with cognitive scores, TDP‐43 aggregation and cerebrovascular accumulation of Aβ in the parietal cortex suggest that BMC loss contributes to both AD symptoms and pathology, further strengthening the link between cerebrovascular defects and dementia.

Potential Role of Venular Amyloid in Alzheimer’s Disease Pathogenesis

“…In the context of AD-like pathology, it is possible that this effect is further exacerbated by arterial and venular Aβ [34,51], since Aβ40 is directly toxic to pericytes in vitro [84][85][86]. Loss of venular mural cells, which are primarily pericytes, has been well demonstrated in AD rodent models [18,45], and mural cell loss associates with cognitive decline in AD patients [87,88].…”

“…Additionally, tortuosity, a common cerebrovascular structural abnormality common in leukoaraiosis and AD, creates cavities in the surrounding brain parenchyma [16], potentially contributing to enlarged perivascular spaces. In the TgCRND8 mouse model of AD, arterial tortuosity occurs as a direct result of arterial Aβ deposition [57], and venular tortuosity occurs from pharmacological depletion of mural cells, which are lost in AD patients [45,87,88]. Therefore, vascular amyloid accumulation contributes to the enlargement of perivascular spaces, and through impaired Aβ clearance, enlarged perivascular spaces likely enhance vascular Aβ deposition.…”

The Alzheimer risk factor CD2AP causes dysfunction of the brain vascular network

“…Interestingly, when participants were classified based on clinical diagnosis, the levels of vascular CD2AP were reduced by ~30% in the brain of AD subjects when compared with NCI volunteers ( Figure 1H and I and Extended data Figure 1B). There was no change in the levels of the endothelial cell marker CD31 (Extended Figure 1C and 41 ), suggesting that the reduction in CD2AP is not associated with endothelial cell death. Remarkably, the lower levels of CD2AP in the brain vascular fraction correlated with cognitive dysfunction, as indicated by several cognitive parameters including the last MMSE score and global cognitive score ( Figure 1J and Extended data Table 2).…”

“…To gain insights into the role of CD2AP in AD pathogenesis, we first analyzed the levels of CD2AP in homogenates containing detergent-soluble proteins isolated from parietal neocortices of subjects from the Religious Order Study, a thoroughly characterized longitudinal clinicalpathologic study of aging and dementia 39,40 . Sex, cognitive performance and neuropathology for all participants are available in Extended data Table 1 and were previously published 15,41 . No difference was found for the levels of CD2AP in cortical extracts containing all brain cells when participants were classified according to their neuropathological scores (Extended data Figure 1A) or clinical diagnosis ( Figure 1A-B).…”

“…Mural cells are involved in the regulation of CBF 87 and maintenance of BBB 88 , and their dysfunction is related to AD pathogenesis (see refs 8,12,41,89 by our group and others). Here, we found that CD2AP and ApoER2 concentrations in vascular extracts were lower in subjects with low levels of the mural cell markers Platelet-derived growth factor receptor beta (PDGFRb) ( Figure 4G and 4H) and alpha-smooth muscle actin (a-SMA) ( Figure 4I and 4J), that were both reported to be decreased in the brain of AD volunteers 41 . Cerebral amyloid angiopathy (CAA) and cortical infarcts are also frequently observed in AD 90,91 .…”