Exploring How Signals from the Body Influence Alzheimer’s Disease

The goal is to create the first map of plasma proteins secreted from peripheral tissues that reach the brain across an intact blood-brain barrier, define how they support brain function and change in early Alzheimer’s disease, and leverage this pathway to deliver targeted therapies.

The brain is protected by the blood brain barrier (BBB), which controls what enters from the bloodstream. While often regarded as a rigid shield, our previous research showed that plasma can cross the healthy BBB and interact with brain cells. In this proposal, we will identify these proteins under normal conditions and examine how their transport changes in the early Alzheimer’s disease (AD). This work will reveal how signals from the body support or harm brain function and guide new strategies to slow AD progression by modulating BBB transport of specific plasma proteins.

By pairing bioorthogonal labeling with mass spectrometry, this proposal reframes the blood-brain barrier (BBB) as an active bridge that relays circulating plasma proteins as peripheral messengers engaging specific brain cell types to maintain brain health. Tracking this plasma-BBB-brain axis across WT and Alzheimer’s disease (AD) models uncovers a previously hidden layer of peripheral-CNS crosstalk that predispose the brain to AD onset, and yields the first proteome-scale catalog of BBB-permeable plasma proteins in health and their alterations in AD. Importantly, the endogenous plasma protein-BBB receptor pairs identified here open a new paradigm for precise AD drug delivery across the BBB.

For the research field, this study will deliver the first systematic atlas of blood-brain barrier (BBB)-permeable plasma proteins and their brain cell targets, establishing a new framework for studying how systemic input regulates brain function and how its dysfunction drives Alzheimer’s disease (AD). It will further accelerate the development of brain shuttles that leverage these proteins for efficient drug delivery into the brain. Building on these contributions, the public will benefit from blood-based biomarkers for earlier AD risk detection and next-generation AD therapies, reinforcing that a healthy periphery and circulation are essential to brain health.