Intraneuronal A beta Accumulation, Amyloid Plaques, and Synapse Pathology in Alzheimer's Disease

Background: beta-Amyloid (A beta) plaques are a pathological hallmark of Alzheimer's disease (AD) and multiple lines of evidence have linked A beta with AD. However, synapse loss is known as the best pathological correlate of cognitive impairment in AD, and intraneuronal A beta accumulation has been shown to precede plaque pathology. The progression of A beta accumulation to synapse loss and plaque formation remains incomplete. The objective is to investigate the progression of intraneuronal A beta accumulation in the brain. Methods: To visualize and analyze the development of A beta pathology we perform immunohistochemistry and immunofluorescence microscopy using antibodies against different A beta conformations, synaptic proteins and structural neuronal proteins in brain tissue of AD transgenic mouse models. Results: Our results show the intraneuronal onset of A beta 42 accumulation in AD mouse brains with aging. We observe an inverse correlation of A beta and amyloid fibrils with structural proteins within neurites. Images reveal aggregated amyloid within selective pyramidal neurons, neurites and synapses in AD transgenic mice as plaques arise. Conclusion: The data support that A beta 42 accumulation and aggregation begin within AD-vulnerable neurons in the brain. Progressive intraneuronal A beta 42 aggregation disrupts the normal cytoarchitecture of neurites. Copyright (C) 2012 S. Karger AG, Base