| First Author | Willén K | Year | 2017 |
| Journal | J Alzheimers Dis | Volume | 60 |
| Issue | 2 | Pages | 511-524 |
| PubMed ID | 28869466 | Mgi Jnum | J:351695 |
| Mgi Id | MGI:7664249 | Doi | 10.3233/JAD-170262 |
| Citation | Willen K, et al. (2017) Heterogeneous Association of Alzheimer's Disease-Linked Amyloid-beta and Amyloid-beta Protein Precursor with Synapses. J Alzheimers Dis 60(2):511-524 |
| abstractText | 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 (Abeta) have emerged as mediators of synapse dysfunction. Abeta binds to, accumulates, and aggregates in synapses. However, the anatomical and neurotransmitter specificity of Abeta and the amyloid-beta protein precursor (AbetaPP) in AD remain poorly understood. In addition, the relative roles of Abeta and AbetaPP 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 Abeta/AbetaPP. We demonstrate that Abeta 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 Abeta42 accumulates in both glutamatergic and GABAergic AbetaPP/PS1 transgenic primary neurons, but at varying levels. Moreover, upon knock-out of presenilin 1 or inhibition of gamma-secretase AbetaPP C-terminal fragments accumulate both pre- and post-synaptically; however earlier pre-synaptically, consistent with a higher rate of AbetaPP processing in axons. A better understanding of the synaptic and anatomical selectivity of Abeta/AbetaPP in AD can be important for the development of more effective new therapies for this major disease of aging. |
