Cerebral amyloid induces aberrant axonal sprouting and ectopic terminal formation in amyloid precursor protein transgenic mice

A characteristic feature of Alzheimer's disease (AD) is the formation of am yloid plaques in the brain. Although this hallmark pathology has been well described, the biological effects of plaques are poorly understood. To stud y the effect of amyloid plaques on axons and neuronal connectivity, we have examined the axonal projections from the entorhinal cortex in aged amyloid precursor protein (APP) transgenic mice that exhibit cerebral amyloid depo sition in plaques and vessels (APP23 mice). Here we report that entorhinal axons form dystrophic boutons around amyloid plaques in the entorhinal term ination zone of the hippocampus. More importantly, entorhinal boutons were found associated with amyloid in ectopic locations within the hippocampus, the thalamus, white matter tracts, as well as surrounding vascular amyloid. Many of these ectopic entorhinal boutons were immunopositive for the growt h-associated protein GAP-43 and showed light and electron microscopic chara cteristics of axonal terminals. Our findings suggest that (1) cerebral amyl oid deposition has neurotropic effects and is the main cause of aberrant sp routing in AD brain; (2) the magnitude and significance of sprouting in AD have been underestimated; and (3) cerebral amyloid leads to the disruption of neuronal connectivity which, in turn, may significantly contribute to AD dementia.