β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis

Area of Science:

• Neuroscience
• Immunology
• Aging Research

Background:

• Aging negatively impacts adult brain cognition and regeneration.
• Circulating factors in 'old blood' contribute to brain aging phenotypes.
• Heterochronic parabiosis suggests blood-borne factors drive brain aging.

Purpose of the Study:

• Identify specific circulating factors driving age-related cognitive and regenerative impairments.
• Investigate the role of beta-2 microglobulin (B2M) in brain aging.
• Explore therapeutic potential of targeting B2M.

Main Methods:

• Heterochronic parabiosis experiments in mice.
• Measuring B2M levels in blood and hippocampus of young and aged mice.
• Systemic and local hippocampal administration of B2M in young mice.
• Analysis of B2M effects in transporter associated with antigen processing 1 (Tap1)-deficient mice.
• Assessing cognitive function and neurogenesis.

Main Results:

• B2M levels increase in the blood and hippocampus with age.
• Exogenous B2M impairs cognitive function and neurogenesis in young mice.
• Reduced B2M effects observed in Tap1-deficient mice with lower MHC I expression.
• Absence of endogenous B2M prevents age-related cognitive decline and enhances neurogenesis in aged mice.

Conclusions:

• Systemic B2M accumulation in aging blood promotes cognitive dysfunction and impairs neurogenesis.
• B2M exerts its effects, in part, via major histocompatibility complex class 1 (MHC I).
• B2M represents a potential therapeutic target for age-related cognitive decline.