| First Author | Tan VTY | Year | 2018 |
| Journal | Mol Brain | Volume | 11 |
| Issue | 1 | Pages | 7 |
| PubMed ID | 29426354 | Mgi Jnum | J:351784 |
| Mgi Id | MGI:7666195 | Doi | 10.1186/s13041-018-0348-9 |
| Citation | Tan VTY, et al. (2018) Lentivirus-mediated expression of human secreted amyloid precursor protein-alpha prevents development of memory and plasticity deficits in a mouse model of Alzheimer's disease. Mol Brain 11(1):7 |
| abstractText | Alzheimer's disease (AD) is a neurodegenerative disease driven in large part by accumulated deposits in the brain of the amyloid precursor protein (APP) cleavage product amyloid-beta peptide (Abeta). However, AD is also characterised by reductions in secreted amyloid precursor protein-alpha (sAPPalpha), an alternative cleavage product of APP. In contrast to the neurotoxicity of accumulated Alphabeta, sAPPalpha has many neuroprotective and neurotrophic properties. Increasing sAPPalpha levels has the potential to serve as a therapeutic treatment that mitigates the effects of Abeta and rescue cognitive function. Here we tested the hypothesis that lentivirus-mediated expression of a human sAPPalpha construct in a mouse model of AD (APPswe/PS1dE9), begun before the onset of plaque pathology, could prevent later behavioural and electrophysiological deficits. Male mice were given bilateral intra-hippocampal injections at 4 months of age and tested 8-10 months later. Transgenic mice expressing sAPPalpha performed significantly better than untreated littermates in all aspects of the spatial water maze task. Expression of sAPPalpha also resulted in partial rescue of long-term potentiation (LTP), tested in vitro. These improvements occurred in the absence of changes in amyloid pathology. Supporting these findings on LTP, lentiviral-mediated expression of sAPPalpha for 3 months from 10 months of age, or acute sAPPalpha treatment in hippocampal slices from 18 to 20 months old transgenic mice, completely reversed the deficits in LTP. Together these findings suggest that sAPPalpha has wide potential to act as either a preventative or restorative therapeutic treatment in AD by mitigating the effects of Abeta toxicity and enhancing cognitive reserve. |
