Protection against β‐amyloid neurotoxicity by a non‐toxic endogenous N‐terminal β‐amyloid fragment and its active hexapeptide core sequence

Abstract

High levels (μM) of beta amyloid (Aβ) oligomers are known to trigger neurotoxic effects, leading to synaptic impairment, behavioral deficits, and apoptotic cell death. The hydrophobic C-terminal domain of Aβ, together with sequences critical for oligomer formation, is essential for this neurotoxicity. However, Aβ at low levels (pM-nM) has been shown to function as a positive neuromodulator and this activity resides in the hydrophilic N-terminal domain of Aβ. An N-terminal Aβ fragment (1-15/16), found in cerebrospinal fluid, was also shown to be a highly active neuromodulator and to reverse Aβ-induced impairments of long-term potentiation. Here, we show the impact of this N-terminal Aβ fragment and a shorter hexapeptide core sequence in the Aβ fragment (Aβcore: 10-15) to protect or reverse Aβ-induced neuronal toxicity, fear memory deficits and apoptotic death. The neuroprotective effects of the N-terminal Aβ fragment and Aβcore on Aβ-induced changes in mitochondrial function, oxidative stress, and apoptotic neuronal death were demonstrated via mitochondrial membrane potential, live reactive oxygen species, DNA fragmentation and cell survival assays using a model neuroblastoma cell line (differentiated NG108-15) and mouse hippocampal neuron cultures. The protective action of the N-terminal Aβ fragment and Aβcore against spatial memory processing deficits in amyloid precursor protein/PSEN1 (5XFAD) mice was demonstrated in contextual fear conditioning. Stabilized derivatives of the N-terminal Aβcore were also shown to be fully protective against Aβ-triggered oxidative stress. Together, these findings indicate an endogenous neuroprotective role for the N-terminal Aβ fragment, while active stabilized N-terminal Aβcore derivatives offer the potential for therapeutic application.

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

“…Other downstream pathways engaged by the N-Aβcore are not yet definitely identified, but we suspect that key players involved in synaptic modulation are affected, such as regulation of CREB, PKA, and/or CAMKII or downregulation of calcineurin and/or PP1, subsequently altering AMPA receptor trafficking to the synapses [23,24,39,40], consistent with the observed reversal of downregulation of hippocampal AMPARs by the N-Aβcore in 5FAD mouse hippocampus. Additionally, the enhancement of the basal synaptic transmission with the treatment of the N-Aβcore suggests a receptor-linked influx of Ca 2+ , which further supports the idea that the N-Aβcore activates an alternative neuroprotective pathway that enhances synaptic plasticity, consistent with results for neuroprotection by the N-Aβcore in Aβ-triggered neurotoxicity [19].…”

“…Through Aβ-interacting receptor-linked Ca 2+ and neurotoxicity assays, we had previously shown that mutating the tyrosine residue in the N-Aβcore to a serine [Y10S] or mutating the two histidine residues to two alanines [H13A,H14A] reduces activity, indicating these amino acid residues in the N-Aβcore sequence are essential for activity [13,19]. To confirm the specificity of the N-Aβcore in reversing LTP impairment in 5FAD hippocampal slices, we tested the reverse-sequence N-Aβcore compared to 5FAD).…”

“…The Aβ1-16 peptide sequence corresponds to the C-terminal 16 amino acid sequence in soluble amyloid precursor protein- (sAPP-), referred to as the CT16, which has also been shown to enhance synaptic plasticity [18]. An essential core sequence comprising amino acids 10-15 of Aβ (N-Aβcore) was identified as the active region of the N-terminal Aβ fragment and was further shown to protect against Aβ-induced neuronal toxicity [19]. Here, we aimed to better understand the neuroprotective mechanism of the N-Aβcore on synaptic plasticity.…”

Cellular microRNA-155 Regulates Virus-Induced Inflammatory Response and Protects against Lethal West Nile Virus Infection

“…MEFs were isolated from 1-day-old pups [31][32][33][34]. MEFs were grown in DMEM (Thermo Fisher Scientific, Norcross, GA, USA) supplemented with 10% FBS and 10 µg/mL gentamicin (Thermo Fisher Scientific, Norcross, GA, USA).…”

Transcriptome Profile of Nicotinic Receptor-Linked Sensitization of Beta Amyloid Neurotoxicity

“…Primary hippocampal culture. Primary hippocampal neuron cultures were prepared from neonatal (1-2d old) C57/B6J mouse pups 39 under an approved University of Hawaii IACUC protocol (16-2282-3) in accordance to all guidelines and regulations. Following rapid decapitation, brains were removed from the mice into ice-cold Neurobasal A medium (NB) containing B-27 supplement, 5% fetal bovine serum and Gentamicin (Serum NB).…”