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

Kelly H Forest,Komal Arora,Cedomir Todorovic,Robert A Nichols,Ruth Taketa

doi:10.3389/fnmol.2021.576038

Kelly H Forest, Komal Arora + Show 3 more

Open Access

https://doi.org/10.3389/fnmol.2021.576038

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Abstract

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.

Highlights

Alzheimer’s disease (AD) is clinically characterized by impairments in cognitive memory and function
We investigated whether the N-Aβcore could rescue long-term potentiation (LTP) and long-term depression (LTD) dysfunction resulting from prolonged, elevated levels of Aβ in an APP/PS1 transgenic mouse model harboring mutations found in familial Alzheimer’s disease (FAD), while assessing the impact on AMPA-type glutamate receptor expression in reference to the neuroprotective action of the N-Aβcore in Aβ-synaptotoxicity (Forest et al, 2020)
Treatment with 500 nM N-Aβcore during baseline recordings induced increases in baseline synaptic transmissions for both 5xFAD and B6.SJL, but was only significant in the B6.SJL slices (Figure 1B; average increase relative to untreated controls: 110% ± 2% SD), similar to that observed for the N-terminal Aβ fragment over the same time period (Lawrence et al, 2014), where the increased field excitatory postsynaptic potentials (fEPSPs) were found to extend through the high-frequency stimulation and post-tetanic potentiation

Summary

Introduction

Alzheimer’s disease (AD) is clinically characterized by impairments in cognitive memory and function. Cognitive decline and synaptic plasticity deficits are reported to occur prior to the accumulation of Aβ plaques and tau neurofibrillary tangles in the prodromic phase leading to AD (Oddo et al, 2003), supporting the idea that synaptic dysfunction and mild cognitive impairment are early events driven by soluble oligomeric Aβ rising to abnormally high levels years prior to AD diagnosis. Synaptic dysfunction and eventual degeneration lead to abnormal synaptic transmission and impaired long-term potentiation (LTP) and/or long-term depression (LTD), which are important in synaptic plasticity and learning and memory. Low physiological levels (pM) of Aβ was found to enhance LTP and memory, indicating a hormetic effect of Aβ on synaptic plasticity (Puzzo et al, 2008, 2012; Lawrence et al, 2014; Gulisano et al, 2019)

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