Basic Science and Pathogenesis

Background: Hypertension is a leading risk factor for the development of Alzheimer's disease and Alzheimer's disease-related dementia (AD/ADRD), which is closely linked with cerebral vascular inflammation and dysfunction. We previously found that high-salt-treated Dahl Salt-Sensitive (SS) rats displayed blood-brain barrier (BBB) leakage, astrocyte activation, neurodegeneration, and cognitive impairments. CD14 functions in the Toll-like receptor 4 (TLR4) complex to initiate proinflammatory signaling events in response to LPS. CD14 levels were elevated in the brains of human and animal AD/ADRD models. This study aims to explore the vascular contribution of CD14 to AD/ADRD.

Method: The expression of Cd14 was assessed through RT-PCR in primary cerebral vascular smooth muscle cells (VSMCs) isolated from TgF344-AD rats, and the results were compared to cells from control rats. The myogenic response of the middle cerebral artery (MCA) was compared between SS (SS^CD14+/+), SS^CD14-/-, and SD rats with and without the induction of hypertension with 4% NaCl diets. BBB function was detected by the leakage of injected Evans blue and fibrinogen. Brain cytokine levels were detected with Bio-Plex Rat Cytokine 23-Plex Assay.

Result: Cd14 emerged as one of the significantly upregulated top genes in high-salt-fed SS^CD14+/+ rats, with a subsequent three-fold increase observed specifically in cerebral VSMCs of AD compared with control rats. Hypertensive SS^CD14+/+ rats exhibited an impaired myogenic response of the MCA compared to normotensive SS^CD14+/+ rats and SD rats fed with both high- and low-salt diets. Notably, the deletion of CD14 demonstrated a remarkable trend in enhancing the myogenic response of the MCA in female SS^CD14-/- rats. Furthermore, high salt-fed 24-week SS^CD14+/+ rats displayed BBB dysfunction. An augmented pan-cytokine panel was observed in low salt-fed 12-week SS^CD14+/+ rats, and this effect was magnified in high salt-fed 24-week SS^CD14+/+ rats.

Conclusion: These results collectively point to the potential role of CD14 in influencing vascular and immune responses, suggesting a link between CD14, hypertension, and cerebrovascular pathologies, particularly in the context of AD. Additional investigations are warranted to delve into the underlying mechanisms and ascertain whether CD14 exhibits a sex-specific role in AD/ADRD.