Hypothalamic and hippocampal transcriptome changes in App^NL-G-F mice as a function of metabolic and inflammatory...

Area of Science:

• Neuroscience
• Metabolic Research
• Alzheimer's Disease Pathogenesis

Background:

• Alzheimer's disease (AD) progresses through a silent phase before cognitive symptoms appear.
• Metabolic factors, diet, and obesity are linked to AD, but mechanisms are unclear.
• The hypothalamus, crucial for metabolism, is affected during active AD.

Purpose of the Study:

• To investigate blood markers and hypothalamic/hippocampal gene expression in a mouse model of AD during silent and active phases.
• To identify early indicators of AD progression related to metabolism and inflammation.

Main Methods:

• Utilized App^NL-G-F mouse model under normal metabolic conditions.
• Analyzed blood markers and bulk gene expression in the hypothalamus and hippocampus of young and old mice.
• Correlated findings with AD silent and active phases, preceding plaque formation and cognitive decline.

Main Results:

• Increased inflammatory mediators and proteins potentially weakening the blood-brain barrier observed in young mice, not old.
• Differential gene expression in the hypothalamus and hippocampus, including GABRa2 receptor and Wdfy1, found in young mice and persisting in old mice.
• Leptin levels and hypothalamic gene expression changes identified prior to cognitive effects.

Conclusions:

• A panel of inflammatory mediators may serve as blood biomarkers for detecting silent AD.
• Hypothalamic leptin changes and specific gene expression alterations precede cognitive decline, linking metabolism to AD pathogenesis.
• Metabolic dysregulation appears coupled with amyloid plaque-induced cognitive decline in AD.