title: 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.
abstract: The blood-brain barrier (BBB) influences brain levels of amyloid-β (Aβ) by transporting Aβ 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 Aβ efflux and bulk flow in aging and in AD. These impairments have been proposed as mechanisms by which the Aβ burden in brain can increase. Impairment in Aβ 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 Aβ region of the amyloid-β protein precursor (AβPP) and previously shown to decrease brain levels of AβPP 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 Aβ. These findings suggest that AβPP/Aβ itself contributes to the impairments in bulk flow and saturable efflux of Aβ and that reduction of AβPP/Aβ levels can restore normal function of the BBB.
authors.affiliation: GRECC, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA. wabanks1@uw.edu
authors.forename: William A
authors.initials: WA
authors.lastname: Banks
authors.forename: Vijaya B
authors.initials: VB
authors.lastname: Kumar
authors.forename: Susan A
authors.initials: SA
authors.lastname: Farr
authors.forename: Ryota
authors.initials: R
authors.lastname: Nakaoke
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Robinson
authors.forename: John E
authors.initials: JE
authors.lastname: Morley
mesh_terms: D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D020319:Oligodeoxyribonucleotides, Antisense / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D020319:Oligodeoxyribonucleotides, Antisense