Alzheimer's disease (AD) is the most common cause of dementia in the aging population. Evidence implicates elevated soluble oligomeric Aβ 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 Aβ 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 Aβ (N-Aβcore) accounting for its physiological activity, and subsequently found that the N-Aβcore peptide is neuroprotective. Here, we characterized the neuroprotective potential of the N-Aβcore 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-Aβcore 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-Aβcore correlated with alleviation of downregulation of hippocampal AMPA-type glutamate receptors in preparations from 5xFAD mice. The action of the N-Aβcore 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-Aβcore 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.
Keywords: Alzheimer’s disease; beta amyloid (Aβ); hippocampal slice; long-term depression; long-term potentiation; neuroprotection.
Copyright © 2021 Forest, Taketa, Arora, Todorovic and Nichols.