The Inside-Out Amyloid Hypothesis and Synapse Pathology in Alzheimer's Disease

Cumulative evidence in brains and cultured neurons of Alzheimer's disease (AD) transgenic mouse models, as well as in human postmortem AD brains, highlights that age-related increases in beta-amyloid peptide (A beta), particularly in endosomes near synapses, are involved in early synapse dysfunction. Our immunoelectron microscopy and high-resolution innnnunofluorescence microscopy studies show that this early subcellular A beta accumulation leads to progressive A beta aggregation and pathology, particularly within dystrophic neurites and synapses. These studies confirm that neuritic/synaptic A beta accumulation is the nidus of plaque formation. A beta-dependent synapse pathology in AD models is modulated by synaptic activity and is plaque independent. The annyloid precursor protein (APP) is normally transported down neurites and appears to be preferentially processed to A beta at synapses. Synapses are sites of early A beta accumulation and aberrant tau phosphorylation in AD, which alter the synaptic composition at early stages of the disease. Elucidating the normal role of APP, and potentially of A beta, at synapses should provide important insights into the mechanism(s) of A beta-induced synapse dysfunction in AD and how to therapeutically mitigate these dysfunctions. (C) 2013 S. Karger AG, Basel