Assessing blood-brain barrier (BBB) integrity in an Alzheimer's disease mouse model: is the BBB globally or locally disrupted?

Abstract

Alzheimer's disease (AD), marked by amyloid-beta (Aβ) plaques and tau tangles, involves cerebral amyloid angiopathy (CAA), which may compromise blood-brain barrier (BBB) integrity. However, the extent and nature of BBB disruption in AD remain unclear. This study assessed BBB permeability in Tg2576 AD mice by evaluating unidirectional paracellular transport from blood to brain following intravenous injection of the stable isotope-labeled marker [¹³C₁₂]sucrose. Pharmacokinetic analysis of plasma and brain concentrations 30 min post-injection revealed minimal sucrose passage across the BBB in both AD and wild-type (WT) mice, suggesting preserved BBB integrity despite Aβ deposition. Regional clearance rates in the hippocampus, cortex, and cerebellum were similar across groups, with only the olfactory bulbs showing increased uptake. Immunohistochemical analysis of BBB tight junction proteins (claudin-5, occludin, ZO-1) revealed no significant differences between AD and WT mice. High-resolution imaging showed minor tight junction disruptions near Aβ plaques, but laser microdissection and LC-MS/MS analysis revealed no increased sucrose concentrations in regions with vascular Aβ-deposition, indicating localized changes do not substantially affect BBB permeability. Our findings challenge the assumption of widespread BBB leakiness in the Tg2576 AD model, highlighting the need for multi-method approaches to assess BBB integrity and optimize drug delivery in AD.