Intracellular Aβ and cognitive deficits precede β-amyloid deposition in transgenic arcAβ mice

The brain pathology of Alzheimer's disease is characterized by abnormally aggregated A beta in extracellular beta-amyloid plaques and along blood vessel walls, but the relation to intracellular A beta remains unclear. To address the role of intracellular A beta deposition in vivo, we expressed human APP with the combined Swedish and Arctic mutations in mice (arcA beta mice). Intracellular punctate deposits of A beta occurred concomitantly with robust cognitive impairments at the age of 6 months before the onset of beta-amyloid plaque formation and cerebral beta-amyloid angiopathy. beta-Amyloid plaques from arcAP mice had distinct dense-core morphologies with blood vessels appearing as seeding origins, suggesting reduced clearance of A beta across blood vessels in arcA beta mice. The co-incidence of intracellular A beta deposits with behavioral deficits support an early role of intracellular A beta in the pathophysiological cascade leading to beta-amyloid formation and functional impairment. (C) 2006 Elsevier Inc. All rights reserved.