Journal of neurochemistryNov 23, 2017

Protection from beta-amyloid brain cell damage by a safe natural beta-amyloid fragment and its active six-amino-acid core

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Updated Apr 1, 2026

Abstract

High levels of beta amyloid oligomers are associated with neurotoxic effects, while low levels may act as neuromodulators.

The hydrophobic C-terminal domain of beta amyloid is essential for its neurotoxic effects.
Conversely, the hydrophilic N-terminal domain of beta amyloid could function as a positive neuromodulator.
An N-terminal beta amyloid fragment (1-15/16) may reverse impairments caused by beta amyloid on long-term potentiation.
The N-terminal fragment and a shorter hexapeptide core sequence (Aβcore: 10-15) could protect against Aβ-induced neuronal toxicity and fear memory deficits.
Neuroprotective effects were demonstrated through assessments of mitochondrial function, oxidative stress, and apoptotic neuronal death.
Stabilized derivatives of the N-terminal Aβcore may provide full protection against Aβ-triggered oxidative stress.

Simplified

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.

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Protection from beta-amyloid brain cell damage by a safe natural beta-amyloid fragment and its active six-amino-acid core

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