Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid

Transgenic mice that overexpress mutant human amyloid precursor protein (AP P) exhibit one hallmark of Alzheimer's disease pathology namely the extrace llular deposition of amyloid plaques. Here, we describe significant deposit ion of amyloid beta (A beta) in the cerebral vasculature [cerebral amyloid angiopathy (CAA)] in aging APP23 mice that had striking similarities to tha t observed in human aging and Alzheimer's disease. Amyloid deposition occur red preferentially in arterioles and capillaries and within individual Vess els showed a wide heterogeneity (ranging from a thin ring of amyloid in the vessel wall to large plaque-like extrusions into the neuropil). CAA was as sociated with local neuron loss, synaptic abnormalities, microglial activat ion, and microhemorrhage. Although several factors may contribute to CAA in humans, the neuronal origin of transgenic APP, high levels of A beta in ce rebrospinal fluid, and regional localization of CAA in APP23 mice suggest t ransport and drainage pathways rather than local production or blood uptake of A beta as a primary mechanism underlying cerebrovascular amyloid format ion. APP23 mice on an App-null background developed a similar degree of bot h plaques and CAA, providing further evidence that a neuronal source of APP /A beta is sufficient to induce cerebrovascular amyloid and associated neur odegeneration.