The Neuroprotective Beta Amyloid Hexapeptide Core Reverses Deficits in Synaptic Plasticity in the 5xFAD APP/PS1 Mouse Model

Abstract

Alzheimers disease (AD) is the most common cause of dementia in the aging population. Evidence implicates elevated soluble oligomeric A{beta} 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 A{beta} 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 A{beta} (N-A{beta}core) accounting for its physiological activity, and subsequently found that the N-A{beta}core peptide is neuroprotective. Here, we characterized the neuroprotective potential of the N-A{beta}core 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-A{beta}core 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-A{beta}core correlated with alleviation of downregulation of hippocampal AMPA-type glutamate receptors in preparations from 5xFAD mice. The action of the N-A{beta}core depended upon a critical di-histidine sequence and involved the PI3 kinase pathway via mTOR. Together, the present findings indicate that the non-toxic N-A{beta}core 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.