Impairments in brain-to-blood transport of amyloid-β and reabsorption of cerebrospinal fluid in an animal model of Alzheimer's disease are reversed by antisense directed against amyloid-β protein precursor.

The blood-brain barrier (BBB) influences brain levels of amyloid-beta (A beta) by transporting A beta out of the brain (efflux) and by the reabsorption of cerebrospinal fluid (CSF) into the blood stream (bulk flow). In Alzheimer's disease (AD) and normal aging, unknown factors impair A beta efflux and bulk flow in aging and in AD. These impairments have been proposed as mechanisms by which the A beta burden in brain can increase. Impairment in A beta efflux occurs in animal models of AD, including the aged SAMP8 mouse. Here, we show that CSF reabsorption is also reduced by about 50% in SAMP8 mice (p < 0.05). We then determined whether an antisense directed at the A beta region of the amyloid-beta protein precursor (A beta PP) and previously shown to decrease brain levels of A beta PP and to reverse the cognitive impairments of the SAMP8 mouse was able to reverse these impairments. We found that the antisense restored both the CSF reabsorption, more than doubling the rate of efflux, and the saturable efflux of A beta. These findings suggest that A beta PP/A beta itself contributes to the impairments in bulk flow and saturable efflux of A beta and that reduction of A beta PP/A beta levels can restore normal function of the BBB.