title: Time-dependent changes in gene expression induced by secreted amyloid precursor protein-alpha in the rat hippocampus.
abstract: BACKGROUND
  Differential processing of the amyloid precursor protein liberates either amyloid-ß, a causative agent of Alzheimer's disease, or secreted amyloid precursor protein-alpha (sAPPα), which promotes neuroprotection, neurotrophism, neurogenesis and synaptic plasticity. The underlying molecular mechanisms recruited by sAPPα that underpin these considerable cellular effects are not well elucidated. As these effects are enduring, we hypothesised that regulation of gene expression may be of importance and examined temporally specific gene networks and pathways induced by sAPPα in rat hippocampal organotypic slice cultures. Slices were exposed to 1 nM sAPPα or phosphate buffered saline for 15 min, 2 h or 24 h and sAPPα-associated gene expression profiles were produced for each time-point using Affymetrix Rat Gene 1.0 ST arrays (moderated t-test using Limma: p < 0.05, and fold change ± 1.15).
  
  
  RESULTS
  Treatment of organotypic hippocampal slice cultures with 1 nM sAPPα induced temporally distinct gene expression profiles, including mRNA and microRNA associated with Alzheimer's disease. Having demonstrated that treatment with human recombinant sAPPα was protective against N-methyl d-aspartate-induced toxicity, we next explored the sAPPα-induced gene expression profiles. Ingenuity Pathway Analysis predicted that short-term exposure to sAPPα elicited a multi-level transcriptional response, including upregulation of immediate early gene transcription factors (AP-1, Egr1), modulation of the chromatin environment, and apparent activation of the constitutive transcription factors CREB and NF-κB. Importantly, dynamic regulation of NF-κB appears to be integral to the transcriptional response across all time-points. In contrast, medium and long exposure to sAPPα resulted in an overall downregulation of gene expression. While these results suggest commonality between sAPPα and our previously reported analysis of plasticity-related gene expression, we found little crossover between these datasets. The gene networks formed following medium and long exposure to sAPPα were associated with inflammatory response, apoptosis, neurogenesis and cell survival; functions likely to be the basis of the neuroprotective effects of sAPPα.
  
  
  CONCLUSIONS
  Our results demonstrate that sAPPα rapidly and persistently regulates gene expression in rat hippocampus. This regulation is multi-level, temporally specific and is likely to underpin the neuroprotective effects of sAPPα.
authors.affiliation: Brain Health Research Centre, University of Otago, PO Box 56, Dunedin New Zealand. margaret.ryan@otago.ac.nz
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Ryan
authors.forename: Gary P
authors.initials: GP
authors.lastname: Morris
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Mockett
authors.forename: Katie
authors.initials: K
authors.lastname: Bourne
authors.forename: Wickliffe C
authors.initials: WC
authors.lastname: Abraham
authors.forename: Warren P
authors.initials: WP
authors.lastname: Tate
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Williams
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D008297:Male; D016202:N-Methylaspartate / Q000633:toxicity; D055495:Neurogenesis / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D059467:Transcriptome / Q000187:drug effects*
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D016202:N-Methylaspartate