The blood-brain barrier imports diverse neuroprotective proteins through pathways impaired early in Alzheimer's disease models.

Abstract

The blood-brain barrier (BBB) has been defined primarily by what it excludes, yet the scale and function of physiological blood-to-brain protein transport remain largely unknown. Using bioorthogonal proteomics, we find that the healthy BBB samples 191 plasma proteins and permits 92 into the brain parenchyma. Enriched for carrier and metabolic functions, these proteins home to distinct brain cell types, such as apolipoprotein A1 (APOA1) to astrocytes and alpha-1 antitrypsin (SERPINA1) to microglia. This cell-type tropism relies on a BBB-parenchyma receptor hand-off: APOA1 crosses the BBB via SR-B1 and engages astrocytic ATP-binding cassette transporter A1 (ABCA1), a key Alzheimer's risk gene, driving cholesterol efflux that supports synapse integrity. Unlike LPS-induced nonspecific leakage, early-stage 5xFAD mice show selective BBB transport remodeling, with reduced APOA1 and increased SERPINA1 uptake. Hepatic APOA1 overexpression restores APOA1 in the 5xFAD brain, rescuing astrocytic, synaptic, and behavioral deficits. These findings recast the BBB as a selective interface that recruits neuroprotective circulatory proteins for brain health.

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