ER stress induced immunopathology involving complement in CADASIL: implications for therapeutics

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic disorder caused by NOTCH3 mutations.
• It leads to severe arteriopathy, fibrotic thickening of small arteries, and subcortical ischemic strokes.
• The precise mechanisms underlying vascular smooth muscle cell (VSMC) degeneration in CADASIL remain unclear.

Purpose of the Study:

• To investigate the inflammatory and immune responses in cerebral microvessels of CADASIL patients.
• To explore the role of endoplasmic reticulum (ER) stress and complement activation in CADASIL arteriopathy.

Main Methods:

• Proteomic and immunohistochemical analyses of cerebral microvessels from CADASIL subjects and controls.
• Functional VSMC cultures with NOTCH3 mutations were used to assess inflammatory gene expression.
• Immunolocalization of complement components in cerebral vessels and cultured VSMCs.

Main Results:

• Loss of VSMCs and significant alterations in proteins related to ER stress were observed in CADASIL cerebral microvessels.
• Robust recruitment of perivascular microglia/macrophages and increased intercellular adhesion molecule-1 (ICAM-1) expression were noted.
• Evidence of alternative complement pathway activation, with complement factors present in approximately 70% of cerebral vessels and cultured VSMCs.

Conclusions:

• Endoplasmic reticulum (ER) stress and VSMC damage in CADASIL trigger localized inflammatory and immune responses.
• These findings highlight the involvement of ER stress, inflammation, and complement activation in CADASIL arteriopathy.
• The study suggests potential immunomodulatory therapeutic strategies for CADASIL.