Inflammation, insulin signaling and cognitive function in aged APP/PS1 mice

Area of Science:

• Neuroscience
• Gerontology
• Pathology

Background:

• Alzheimer's disease (AD) and normal aging involve cognitive dysfunction and neuroinflammation.
• Brain insulin resistance is implicated in AD pathophysiology.
• Distinguishing AD from normal aging is crucial for diagnostics and therapeutics.

Purpose of the Study:

• To investigate cognitive function, neuroinflammation, insulin signaling, oxidative stress, and synapse density in aged APP/PS1 mice compared to wild-type littermates.
• To identify pathological distinctions between AD and normal aging in the brain.

Main Methods:

• Utilized aged APP/PS1 and wild-type mice (15-18 months old).
• Assessed cognitive function using novel object recognition, Morris water maze, and reversal water maze tasks.
• Measured peripheral and central insulin signaling, glucose tolerance, insulin sensitivity, inflammatory markers (IFNγ, IL-4), oxidative stress, and synapse density.

Main Results:

• Cognitive impairments and learning deficits were observed in APP/PS1 mice.
• While overall glucose tolerance and insulin sensitivity were similar, increased IRS-1 phosphorylation (pSer616) was noted in the cortex and dentate gyrus of APP/PS1 mice.
• Elevated brain levels of IFNγ and IL-4 were found in APP/PS1 mice compared to wild-type controls.

Conclusions:

• Normal aging is associated with increased neuroinflammation, oxidative stress, and cognitive decline.
• APP/PS1 mice exhibit specific brain inflammation and insulin signaling alterations, alongside cognitive domain distinctions, compared to normal aging.
• Clarifying pathological differences between AD and aging is essential for advancing diagnostic tools and therapeutic strategies.