PCSK9 and High-Fat Diet Synergistically Induce Neurovascular Dysfunction and Neuroinflammation

Area of Science:

• Neuroscience
• Metabolic Syndrome Research
• Cerebrovascular Diseases

Background:

• Cerebral small vessel disease (CSVD) is a major cause of vascular cognitive impairment and dementia, strongly associated with metabolic risk factors.
• The interplay between genetic and environmental factors in metabolic syndrome-driven cerebrovascular pathology remains unclear.

Purpose of the Study:

• To investigate neuroinflammatory and neurodegenerative changes in a mouse model of metabolic syndrome with atherosclerosis.
• To identify cellular phenotypes and pathological mechanisms linking metabolic stress to CSVD and cognitive deficits.

Main Methods:

• Utilized a mouse model with hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) overexpression and high-fat diet (HFD) to induce metabolic syndrome and atherosclerosis.
• Employed three-dimensional light sheet microscopy and immunophenotyping to analyze cerebrovascular integrity, microglial activation, and amyloid-β deposition.
• Assessed cognitive function using behavioral tests for recognition memory and anxiety.

Main Results:

• PCSK9+HFD mice exhibited hallmark CSVD features: vascular rarefaction, impaired neurovascular coupling, blood-brain barrier disruption, white matter injury, neuronal loss, and cognitive deficits.
• Identified lipid-droplet accumulating microglia (LDAM) as a novel phenotype associated with metabolic stress and cerebrovascular dysfunction.
• Observed vascular amyloid-β deposition in PCSK9+HFD mice, suggesting metabolic stress contributes to cerebrovascular amyloid pathology, and noted recognition memory deficits and increased anxiety.

Conclusions:

• Severe hypercholesterolemia significantly accelerates CSVD pathogenesis.
• LDAM represent a distinct pathological feature connecting systemic metabolic syndrome to cerebrovascular dysfunction and cognitive impairment.
• Understanding these mechanisms is crucial for developing therapeutic strategies against metabolic-related cognitive decline.