The blood-brain barrier (BBB) remains largely intact in a widely used mouse model of Alzheimer’s disease, according to new findings from researchers at the Texas Tech University Health Sciences Center (TTUHSC). The study, published in Fluids and Barriers of the CNS, suggests that the BBB does not exhibit the widespread leakage previously assumed in Alzheimer’s research – potentially reshaping strategies for drug delivery.
To test the integrity of the barrier, the team used Tg2576 transgenic mice, which express human amyloid precursor protein and develop amyloid-beta plaques – a hallmark of Alzheimer’s disease. The mice were injected with [¹³C₁₂]sucrose, a molecule that poorly crosses the BBB. Using liquid chromatography–tandem mass spectrometry and laser microdissection to analyze regional sucrose levels, they found that sucrose concentrations remained low in Alzheimer’s mice and controls alike, across multiple brain regions and time points.
No differences in sucrose concentration were detected between wild-type and transgenic mice in any of the dissected areas, and sucrose concentrations in the cortex, hippocampus, and cerebellum remained below 0.25 µL/g brain water, consistent with previous studies in normal mice.
The study also examined tight junction proteins around amyloid plaques using immunofluorescence staining for claudin‑5, ZO‑1, and occludin. These proteins appeared mostly preserved, suggesting that BBB architecture remains structurally sound despite amyloid accumulation.
“Our findings challenge the assumption of widespread BBB leakiness in Alzheimer’s disease,” said Ehsan Nozohouri, lead author and graduate research assistant at TTUHSC, in a recent press release. “This means that drug delivery strategies may need to be designed with the understanding that the barrier is not broadly compromised.”
The researchers note that while minor, localized permeability changes cannot be ruled out, the BBB appears largely resilient in this model. Future studies will explore whether newer Alzheimer’s treatments, such as monoclonal antibodies, affect barrier function through microhemorrhages or brain swelling.
“We still have much to learn about how Alzheimer’s disease impacts the brain’s defenses,” Nozohouri added. “Our ultimate goal is to better predict how drugs behave in patients, so we can design therapies that truly work.”
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