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 (sAPP?), which promotes neuroprotection, neurotrophism, neurogenesis and synaptic plasticity. The underlying molecular mechanisms recruited by sAPP? 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 sAPP? in rat hippocampal organotypic slice cultures. Slices were exposed to 1 nM sAPP? or phosphate buffered saline for 15 min, 2 h or 24 h and sAPP?-associated gene expression profiles were produced for each time-point using Affymetrix Rat Gene 1.0 ST arrays (moderated t-test using Limma: p?ResultsTreatment of organotypic hippocampal slice cultures with 1 nM sAPP? induced temporally distinct gene expression profiles, including mRNA and microRNA associated with Alzheimer's disease. Having demonstrated that treatment with human recombinant sAPP? was protective against N-methyl d-aspartate-induced toxicity, we next explored the sAPP?-induced gene expression profiles. Ingenuity Pathway Analysis predicted that short-term exposure to sAPP? 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-?B. Importantly, dynamic regulation of NF-?B appears to be integral to the transcriptional response across all time-points. In contrast, medium and long exposure to sAPP? resulted in an overall downregulation of gene expression. While these results suggest commonality between sAPP? 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 sAPP? were associated with inflammatory response, apoptosis, neurogenesis and cell survival; functions likely to be the basis of the neuroprotective effects of sAPP?.

Conclusions

Our results demonstrate that sAPP? 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 sAPP?.

SUBMITTER: Ryan MM 

PROVIDER: S-EPMC3691674 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature