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 Aβ in extracellular β-amyloid plaques and along blood vessel walls, but the relation to intracellular Aβ remains unclear. To address the role of intracellular Aβ deposition in vivo, we expressed human APP with the combined Swedish and Arctic mutations in mice (arcAβ mice). Intracellular punctate deposits of Aβ occurred concomitantly with robust cognitive impairments at the age of 6 months before the onset of β-amyloid plaque formation and cerebral β-amyloid angiopathy. β-Amyloid plaques from arcAβ mice had distinct dense-core morphologies with blood vessels appearing as seeding origins, suggesting reduced clearance of Aβ across blood vessels in arcAβ mice. The co-incidence of intracellular Aβ deposits with behavioral deficits support an early role of intracellular Aβ in the pathophysiological cascade leading to β-amyloid formation and functional impairment.