mp300352c_si_001.pdf (282.88 kB)
Traffic Jam at the Blood–Brain Barrier Promotes Greater Accumulation of Alzheimer’s Disease Amyloid‑β Proteins in the Cerebral Vasculature
journal contribution
posted on 2016-02-19, 10:03 authored by Edward
K. Agyare, Sarah R. Leonard, Geoffry L. Curran, Caroline C. Yu, Val J. Lowe, Anant K. Paravastu, Joseph F. Poduslo, Karunya K. KandimallaAmyloid-β (Aβ) deposition in the brain vasculature
results in cerebral amyloid angiopathy (CAA), which occurs in about
80% of Alzheimer’s disease (AD) patients. While Aβ42
predominates parenchymal amyloid plaques in AD brain, Aβ40 is
prevalent in the cerebrovascular amyloid. Dutch mutation of Aβ40
(E22Q) promotes aggressive cerebrovascular accumulation and leads
to severe CAA in the mutation carriers; knowledge of how DutchAβ40
drives this process more efficiently than Aβ40 could reveal
various pathophysiological events that promote CAA. In this study
we have demonstrated that DutchAβ40 shows preferential accumulation
in the blood–brain-barrier (BBB) endothelial cells due to its
inefficient blood-to-brain transcytosis. Consequently, DutchAβ40
establishes a permeation barrier in the BBB endothelium, prevents
its own clearance from the brain, and promotes the formation of amyloid
deposits in the cerebral microvessels. The BBB endothelial accumulation
of native Aβ40 is not robust enough to exercise such a significant
impact on its brain clearance. Hence, the cerebrovascular accumulation
of Aβ40 is slow and may require other copathologies to precipitate
into CAA. In conclusion, the magnitude of Aβ accumulation in
the BBB endothelial cells is a critical factor that promotes CAA;
hence, clearing vascular endothelium of Aβ proteins may halt
or even reverse CAA.