| First Author | Forest KH | Year | 2021 |
| Journal | Front Mol Neurosci | Volume | 14 |
| Pages | 576038 | PubMed ID | 33912008 |
| Mgi Jnum | J:348179 | Mgi Id | MGI:6811073 |
| Doi | 10.3389/fnmol.2021.576038 | Citation | Forest KH, et al. (2021) The Neuroprotective Beta Amyloid Hexapeptide Core Reverses Deficits in Synaptic Plasticity in the 5xFAD APP/PS1 Mouse Model. Front Mol Neurosci 14:576038 |
| abstractText | Alzheimer's disease (AD) is the most common cause of dementia in the aging population. Evidence implicates elevated soluble oligomeric Abeta as one of the primary triggers during the prodromic phase leading to AD, effected largely via hyperphosphorylation of the microtubule-associated protein tau. At low, physiological levels (pM-nM), however, oligomeric Abeta has been found to regulate synaptic plasticity as a neuromodulator. Through mutational analysis, we found a core hexapeptide sequence within the N-terminal domain of Abeta (N-Abetacore) accounting for its physiological activity, and subsequently found that the N-Abetacore peptide is neuroprotective. Here, we characterized the neuroprotective potential of the N-Abetacore against dysfunction of synaptic plasticity assessed in ex vivo hippocampal slices from 5xFAD APP/PS1 mice, specifically hippocampal long-term potentiation (LTP) and long-term depression (LTD). The N-Abetacore was shown to reverse impairment in synaptic plasticity in hippocampal slices from 5xFAD APP/PS1 model mice, both for LTP and LTD. The reversal by the N-Abetacore correlated with alleviation of downregulation of hippocampal AMPA-type glutamate receptors in preparations from 5xFAD mice. The action of the N-Abetacore depended upon a critical di-histidine sequence and involved the phosphoinositide-3 (PI3) kinase pathway via mTOR (mammalian target of rapamycin). Together, the present findings indicate that the non-toxic N-Abetacore hexapeptide is not only neuroprotective at the cellular level but is able to reverse synaptic dysfunction in AD-like models, specifically alterations in synaptic plasticity. |
