Heterogeneous Association of Alzheimer's Disease-Linked Amyloid-β and Amyloid-β Protein Precursor with Synapses

Alzheimer's disease (AD) is increasingly viewed as a disease of synapses. Loss of synapses correlates better with cognitive decline than amyloid plaques and neurofibrillary tangles, the hallmark neuropathological lesions of AD. Soluble forms of amyloid-beta (A beta) have emerged as mediators of synapse dysfunction. A beta binds to, accumulates, and aggregates in synapses. However, the anatomical and neurotransmitter specificity of A beta and the amyloid-beta protein precursor (A beta PP) in AD remain poorly understood. In addition, the relative roles of A beta and A beta PP in the development of AD, at pre-versus post-synaptic compartments and axons versus dendrites, respectively, remain unclear. Here we use immunogold electron microscopy and confocal microscopy to provide evidence for heterogeneity in the localization of A beta/A beta PP. We demonstrate that A beta binds to a subset of synapses in cultured neurons, with preferential binding to glutamatergic compared to GABAergic neurons. We also highlight the challenge of defining pre-versus post-synaptic localization of this binding by confocal microscopy. Further, endogenous A beta(42) accumulates in both glutamatergic and GABAergic A beta PP/PS1 transgenic primary neurons, but at varying levels. Moreover, upon knock-out of presenilin 1 or inhibition of gamma-secretase A beta PP C-terminal fragments accumulate both pre-and post-synaptically; however earlier pre-synaptically, consistent with a higher rate of A beta PP processing in axons. A better understanding of the synaptic and anatomical selectivity of A beta/A beta PP in AD can be important for the development of more effective new therapies for this major disease of aging.