Pathogenesis and Mechanism of Cerebral Amyloidosis in APP Transgenic Mice

Transgenic mice that overexpress mutant human amyloid precursor protein (APP) exhibit one hallmark of Alzheimer's disease pathology, namely the extracellular deposition of amyloid in plaques and vessels. In an effort to study the impact of cerebral amyloidosis on neurodegeneration, we have shown that amyloid plaque formation in APP transgenic mice is accompanied by region-specific neuron loss, synaptic changes, alterations in the cholinergic system, and a severe disruption of neuronal circuits. The deposition of amyloid in the vessel wall leads to smooth muscle cell degeneration and spontaneous hemorrhagic stroke. In humans several mechanisms may contribute to cerebral amyloidosis. Results from transgenic mice, however, suggest that a neuronal source of APP/A beta is sufficient for the development of both amyloid plaques and cerebrovascular amyloid. Moreover, our results implicate neuronal transport and drainage mechanisms rather than local production or blood uptake of A beta as a primary mechanism underlying cerebral amyloidosis in these mice. Aging and APP expression levels have been suggested to be key factors that potentiate amyloid deposition. But there are several other risk factors, such as apolipoprotein E and transforming growth factor TGF beta1, that have been identified and analyzed in association with APP transgenic mice. In conclusion, transgenic mouse models of cerebral amyloidosis have provided many clues about the significance and mechanism of cerebral amyloidosis. The continued analysis of these mice will provide the tools to develop therapeutic intervention in AD, cerebral amyloid angiopathy, and hemorrhagic stroke.