Dataset Information

The Tripeptide RER Mimics Secreted Amyloid Precursor Protein-Alpha in Upregulating LTP.

ABSTRACT: Secreted amyloid precursor protein-alpha (sAPPα), generated by enzymatic processing of the APP, possesses a range of neurotrophic and neuroprotective properties and plays a critical role in the molecular mechanisms of memory and learning. One of the key active regions of sAPPα is the central APP domain (E2) that contains within it the tripeptide sequence, RER. This sequence is exposed on the surface of a coiled coil substructure of E2. RER has by itself displayed memory-enhancing properties, and can protect newly formed engrams from interference in a manner similar to that displayed by sAPPα itself. In order to determine whether RER mimics other properties of sAPPα, we investigated the electrophysiological effects of the N-terminal protected acetylated RER (Ac-RER) and an isoform containing a chiral switch in the first amino acid from an l- to a d-orientation (Ac-rER), on synaptic plasticity. We found that, like sAPPα, exogenous perfusion with nanomolar concentrations of Ac-RER or Ac-rER enhanced the induction and stability of long-term potentiation (LTP) in area CA1 of rat and mouse hippocampal slices, in a protein synthesis- and trafficking-dependent manner. This effect did not occur with a control Ac-AAA or Ac-IFR tripeptide, nor with a full-length sAPPα protein where RER was substituted with AAA. Ac-rER also protected LTP against amyloid-beta (Aβ25 - 35)-induced LTP impairment. Our findings provide further evidence that the RER-containing region of sAPPα is functionally significant and by itself can produce effects similar to those displayed by full length sAPPα, suggesting that this tripeptide, like sAPPα, may have therapeutic potential.

SUBMITTER: Morrissey JA

PROVIDER: S-EPMC6813913 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundDifferential 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?<?0.05, and fold change?±?1.15).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?.ConclusionsOur 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?.

Dataset Information

The Tripeptide RER Mimics Secreted Amyloid Precursor Protein-Alpha in Upregulating LTP.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets