Lentivirus-Mediated Expression of Human Secreted Amyloid Precursor Protein-Alpha Promotes Long-Term Induction of Neuroprotective Genes and Pathways in a Mouse Model of Alzheimer's Disease

Background: Secreted amyloid precursor protein-alpha (sAPP alpha) can enhance memory and is neurotrophic and neuroprotective across a range of disease-associated insults, including amyloid-beta toxicity. In a significant step toward validating sAPP alpha as a therapeutic for Alzheimer's disease (AD), we demonstrated that long-term overexpression of human sAPP alpha (for 8 months) in a mouse model of amyloidosis (APP/PS1) could prevent the behavioral and electrophysiological deficits that develop in these mice. Objective: To explore the underlying molecular mechanisms responsible for the significant physiological and behavioral improvements observed in sAPP alpha-treated APP/PS1 mice. Methods: We assessed the long-term effects on the hippocampal transcriptome following continuous lentiviral delivery of sAPP alpha or empty-vector to male APP/PS1 mice and wild-type controls using Affymetrix Mouse Transcriptome Assays. Data analysis was carried out within the Affymetrix Transcriptome Analysis Console and an integrated analysis of the resulting transcriptomic data was performed with Ingenuity Pathway analysis (IPA). Results: Mouse transcriptome assays revealed expected AD-associated gene expression changes in empty-vector APP/PS1 mice, providing validation of the assays used for the analysis. By contrast, there were specific sAPP alpha-associated gene expression profiles which included increases in key neuroprotective genes such as Decorin, betaine-GABA transporter and protocadherin beta-5, subsequently validated by qRT-PCR. An integrated biological pathways analysis highlighted regulation of GABA receptor signaling, cell survival and inflammatory responses. Furthermore, upstream gene regulatory analysis implicated sAPP alpha activation of Interleukin-4, which can counteract inflammatory changes in AD. Conclusion: This study identified key molecular processes that likely underpin the long-term neuroprotective and therapeutic effects of increasing sAPP alpha levels in vivo.