Chronic Neuroinflammation Induced by Lipopolysaccharide Injection into the Third Ventricle Induces Behavioral Changes

Area of Science:

• Neuroscience
• Immunology
• Metabolic Disorders

Background:

• Recent studies show Gram-negative bacteria and lipopolysaccharide (LPS) in the brain.
• LPS colocalization with amyloid plaques suggests a microbial link to Alzheimer's disease (AD) and chronic neuroinflammation.

Purpose of the Study:

• To investigate behavioral changes from infectious neuroinflammation induced by LPS.
• To explore the role of cholesterol metabolism in LPS-induced neuroinflammation.

Main Methods:

• Single LPS injection into the third ventricle of male Wistar rats (20 μg or 80 μg).
• Behavioral tests for depressive-like symptoms and spatial learning.
• Analysis of cholesterol metabolism enzymes (CYP46A1, HMGCR) in rat hippocampus and cell lines (SH-SY5Y, U251).
• Investigation of the TLR4/MyD88/NF-κB signaling pathway.

Main Results:

• LPS injection induced depressive-like behaviors and impaired spatial learning.
• No development of AD pathological hallmarks (e.g., tau phosphorylation) observed for 10 months.
• Accelerated cholesterol metabolism (CYP46A1) and retarded cholesterol synthesis (HMGCR) in the hippocampus.
• Inflammatory stimulators altered CYP46A1 and HMGCR via the TLR4/MyD88/NF-κB pathway.

Conclusions:

• Chronic neuroinflammation induced by LPS may cause depressive symptoms.
• Cholesterol loss could be a biomarker for chronic neuroinflammation.
• Gram-negative bacterial infection may not be the sole cause of AD, as AD hallmarks were absent in the model.