Decreased Plasma Aβ in Hyperlipidemic APPSL Transgenic Mice Is Associated with BBB Dysfunction

Area of Science:

• Neuroscience
• Pathology
• Vascular Biology

Background:

• Alzheimer's disease (AD) pathology involves amyloid-beta (Aβ) and tau, but vascular factors and inflammation are also implicated.
• The role of vascular changes in AD onset versus late-stage progression remains debated.
• Hyperlipidemia is a known vascular risk factor that may influence AD pathogenesis.

Purpose of the Study:

• To investigate the impact of high-fat diet (HFD)-induced hyperlipidemia on Aβ metabolism and brain vasculature in a mouse model of AD.
• To determine if HFD affects Aβ levels, clearance, cerebral vasculature, and blood-brain barrier (BBB) integrity.

Main Methods:

• Human APP transgenic (APPSL) mice and wildtype (WT) mice were fed a HFD for 12 weeks.
• Plasma and brain tissues were analyzed for Aβ distribution, insoluble Aβ, amyloid plaques, and vascular markers.
• Cerebral vasculature and BBB integrity were assessed in HFD-fed and control mice.

Main Results:

• HFD led to decreased plasma Aβ and increased insoluble Aβ and brain amyloid plaques in APPSL mice, indicating impaired Aβ clearance.
• HFD induced significant alterations in cerebral vasculature and BBB integrity specifically in APPSL mice, but not in WT mice.
• These findings suggest HFD exacerbates Aβ-dependent vascular and BBB dysfunction.

Conclusions:

• HFD-induced hyperlipidemia impairs Aβ clearance and promotes amyloid plaque deposition in the brain.
• HFD exacerbates Aβ-dependent cerebral vascular and blood-brain barrier dysfunction in AD models.
• Dietary interventions targeting vascular risk factors may be crucial for managing Alzheimer's disease progression.