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

ABSTRACT: 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-? (A?) have emerged as mediators of synapse dysfunction. A? binds to, accumulates, and aggregates in synapses. However, the anatomical and neurotransmitter specificity of A? and the amyloid-? protein precursor (A?PP) in AD remain poorly understood. In addition, the relative roles of A? and A?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?/A?PP. We demonstrate that A? 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?42 accumulates in both glutamatergic and GABAergic A?PP/PS1 transgenic primary neurons, but at varying levels. Moreover, upon knock-out of presenilin 1 or inhibition of ?-secretase A?PP C-terminal fragments accumulate both pre- and post-synaptically; however earlier pre-synaptically, consistent with a higher rate of A?PP processing in axons. A better understanding of the synaptic and anatomical selectivity of A?/A?PP in AD can be important for the development of more effective new therapies for this major disease of aging.

SUBMITTER: Willen K 

PROVIDER: S-EPMC5611798 | biostudies-other | 2017

REPOSITORIES: biostudies-other