| First Author | Tyan SH | Year | 2012 |
| Journal | Mol Cell Neurosci | Volume | 51 |
| Issue | 1-2 | Pages | 43-52 |
| PubMed ID | 22884903 | Mgi Jnum | J:203584 |
| Mgi Id | MGI:5527497 | Doi | 10.1016/j.mcn.2012.07.009 |
| Citation | Tyan SH, et al. (2012) Amyloid precursor protein (APP) regulates synaptic structure and function. Mol Cell Neurosci 51(1-2):43-52 |
| abstractText | The amyloid precursor protein (APP) plays a critical role in Alzheimer's disease (AD) pathogenesis. APP is proteolytically cleaved by beta- and gamma-secretases to generate the amyloid beta-protein (Abeta), the core protein component of senile plaques in AD. It is also cleaved by alpha-secretase to release the large soluble APP (sAPP) luminal domain that has been shown to exhibit trophic properties. Increasing evidence points to the development of synaptic deficits and dendritic spine loss prior to deposition of amyloid in transgenic mouse models that overexpress APP and Abeta peptides. The consequence of loss of APP, however, is unsettled. In this study, we investigated whether APP itself plays a role in regulating synaptic structure and function using an APP knock-out (APP-/-) mouse model. We examined dendritic spines in primary cultures of hippocampal neurons and CA1 neurons of hippocampus from APP-/- mice. In the cultured neurons, there was a significant decrease (~35%) in spine density in neurons derived from APP-/- mice compared to littermate control neurons that were partially restored with sAPPalpha-conditioned medium. In APP-/- mice in vivo, spine numbers were also significantly reduced but by a smaller magnitude (~15%). Furthermore, apical dendritic length and dendritic arborization were markedly diminished in hippocampal neurons. These abnormalities in neuronal morphology were accompanied by reduction in long-term potentiation. Strikingly, all these changes in vivo were only seen in mice that were 12-15 months in age but not in younger animals. We propose that APP, specifically sAPP, is necessary for the maintenance of dendritic integrity in the hippocampus in an age-associated manner. Finally, these age-related changes may contribute to AD pathology independent of Abeta-mediated synaptic toxicity. |
