Project Summary
The improvement in living standards and the advancement in modern medicine have greatly extended human
life expectancy. However, aging-related functional decline and diseases, in particular cognitive impairment and
neurodegeneration, also become more prevalent. Studies of heterochronic blood exchange reveal that the
aged systemic milieu inhibits neurogenesis and impairs cognitive functions in young animals, suggesting the
existence of age-elevated systemic factors detrimental to brain health. In particular, inflammation may become
excessive and chronic with aging (“inflammaging”) and impair normal brain functions. Thus proteins involved in
inflammatory responses, such as cytokines, are candidates of such systemic factors implicated in brain aging.
Building upon published literature and our recent finding, we hypothesize that aging-associated alterations in
systemic inflammatory factors activate microglia (resident immune cells in the central nervous system) and
lead to microglia-mediated synapse loss; restoring the expression pattern of such factors to the healthy young
state rescues synaptic defects and improves cognitive functions. In Aim 1, we will use bio-orthogonal non-
canonical amino acid tagging (BONCAT) to determine how treatment with a cocktail of Alk5 inhibitor (Alk5i)
and oxytocin (OT, a neurotrophic, anti-inflammatory peptide) or heterochronic blood exchange affects the
expression profile and distribution of inflammaging-related systemic factors in the brain and peripheral tissues.
Aim 2 examines how Alk5i+OT treatment and heterochronic blood exchange affect neuro-immune interaction
in the brain, taking advantage of in vivo two-photon imaging to study microglia-synaptic interactions and their
effects on synaptic integrity and dynamics in the cortex. Using Array Tomography, a high-throughput, super-
resolution proteomic imaging technique, Aim 3 conducts molecular dissection and reconstruction of large
populations of individual synapses and determines the effect of Alk5i+OT treatment and heterochronic blood
exchange on synaptic molecular signatures and inflammatory cytokine distribution in the brain. Together, these
studies will provide a comprehensive characterization of age-specific effects of blood on the brain proteome
and synaptic circuits, and outline candidate mechanism(s) responsible for brain aging.