Vascular smooth muscle cell dysfunction contribute to neuroinflammation and Tau hyperphosphorylation in Alzheimer disease

Abstract

Summary Despite the emerging evidence implying early vascular contributions to neurodegenerative syndromes, the role of vascular smooth muscle cells (VSMCs) in the pathogenesis of Alzheimer disease (AD) is still not well understood. Herein, we show that VSMCs in brains of patients with AD and animal models of the disease are deficient in multiple VSMC contractile markers which correlated with Tau accumulation in brain arterioles. Ex vivo and in vitro experiments demonstrated that VSMCs undergo dramatic phenotypic transitions under AD-like conditions, adopting pro-inflammatory phenotypes. Notably, these changes coincided with Tau hyperphosphorylation at residues Y18, T205, and S262. We also observed that VSMC dysfunction occurred in an age-dependent manner and that expression of Sm22α protein was inversely correlated with CD68 and Tau expression in brain arterioles of the 3xTg-AD and 5xFAD mice. Together, these findings further support the contribution of dysfunctional VSMCs in AD pathogenesis and nominate VSMCs as a potential therapeutic target in AD.

In Silico Analysis of Metabolites from Peruvian Native Plants as Potential Therapeutics against Alzheimer’s Disease

“…Multiple studies have recently demonstrated a strong relationship between the pathogenesis of AD and some vascular-associated diseases, including atherosclerosis and hypertension [ 57 , 58 ]. Moreover, Aguilar et al, 2021, have shown that vascular smooth muscle cells contribute to the neuroinflammation and tau hyperphosphorylation in the early and late stages of the disease [ 6 ]. These findings identify the vascular tissue as a novel therapeutic target for the development of drugs to reduce the impact of vascular dysfunction on the initiation and progression of AD.…”

“…These clinical manifestations are consequences of the formation of neurofibrillary tangles, senile plaques, glial cell activation, and cerebrovascular dysregulation [ 4 ]. The importance of understanding the mechanisms of cerebrovascular alterations and their relation to AD has gained more attention, since cerebrovascular dysfunction can cause the degenerative processes of smooth muscle cells, astrocytes, pericytes, and endothelial cells [ 5 , 6 , 7 , 8 ]. Furthermore, several studies have demonstrated the reduced resting cerebral blood flow, low vasoreactivity, and neurovascular coupling dysregulation in AD patients [ 9 , 10 , 11 ], and that more than 50% of AD-diagnosed patients also have a cerebrovascular lesion.…”

Protocol to assess the effects of dysfunctional human vascular smooth muscle cells on other brain cells using in vitro models of Alzheimer’s disease

“…We have shown that dysfunctional VSMCs can play a detrimental role on AD pathogenesis ( Aguilar-Pineda et al., 2021 ). The protocol below details the steps to establish functional assays that can be used to evaluate the effect of dysfunctional VSMCs on other brain cells using in vitro systems to mimic AD-like conditions for the screening of new drug treatments.…”

“…Our approach can be applied to assess the effects of dysfunctional VSMCs on other cerebral cell lines including pericytes, astrocytes, and neurons under AD-like conditions in vitro . For complete details on the use and execution of this protocol, please refer to Aguilar-Pineda et al. (2021) .…”

“…For complete details on the use and execution of this protocol, please refer to Aguilar-Pineda et al. (2021) .…”