Loss of endothelial CD2AP causes sex-dependent cerebrovascular dysfunction

Area of Science:

• Neuroscience
• Vascular Biology
• Genetics

Background:

• Polymorphisms in CD2-associated protein (CD2AP) are linked to increased risk of Alzheimer's disease (AD).
• The precise mechanisms by which CD2AP influences AD pathogenesis, particularly in the cerebrovasculature, are not fully understood.

Purpose of the Study:

• To investigate the role of CD2AP in brain vascular endothelial cells in the context of Alzheimer's disease.
• To explore the functional consequences of CD2AP deficiency on cerebrovascular function and cognitive performance.
• To identify potential sex-specific therapeutic strategies targeting CD2AP in AD.

Main Methods:

• Analysis of CD2AP expression in cerebral blood vessels of AD subjects.
• Genetic downregulation of CD2AP in brain vascular endothelial cells of male mice.
• Assessment of cognitive function, cerebral blood flow, neurovascular coupling, and vascular responses to amyloid-beta (Aβ) in mice.
• Pharmacological interventions targeting endothelin-1 receptor A and reelin glycoprotein signaling.

Main Results:

• Reduced CD2AP in cerebral blood vessels correlates with cognitive decline in AD patients.
• Downregulation of CD2AP in male mice impairs memory, alters resting and activity-induced cerebral blood flow, and affects mural cell function.
• CD2AP deficiency leads to abnormal, sex-dependent vascular responses to Aβ; endothelin-1 receptor A antagonism shows partial rescue only in males.
• Reelin glycoprotein treatment improves cerebral blood flow and protects male mice against Aβ toxicity.

Conclusions:

• Endothelial CD2AP is crucial for maintaining normal cerebrovascular function and cognitive health.
• CD2AP deficiency contributes to AD-related vascular deficits in a sex-dependent manner.
• Targeting endothelial CD2AP offers a promising avenue for novel, sex-specific Alzheimer's disease therapies.