Protection against ß-amyloid neurotoxicity by a non-toxic endogenous N-terminal ß-amyloid fragment and its active hexapeptide core sequence.
J Neurochem
; 144(2): 201-217, 2018 01.
Article
em En
| MEDLINE
| ID: mdl-29164616
ABSTRACT
High levels (µM) of beta amyloid (Aß) oligomers are known to trigger neurotoxic effects, leading to synaptic impairment, behavioral deficits, and apoptotic cell death. The hydrophobic C-terminal domain of Aß, together with sequences critical for oligomer formation, is essential for this neurotoxicity. However, Aß 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 Aß. An N-terminal Aß fragment (1-15/16), found in cerebrospinal fluid, was also shown to be a highly active neuromodulator and to reverse Aß-induced impairments of long-term potentiation. Here, we show the impact of this N-terminal Aß fragment and a shorter hexapeptide core sequence in the Aß fragment (Aßcore 10-15) to protect or reverse Aß-induced neuronal toxicity, fear memory deficits and apoptotic death. The neuroprotective effects of the N-terminal Aß fragment and Aßcore on Aß-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 Aß fragment and Aßcore against spatial memory processing deficits in amyloid precursor protein/PSEN1 (5XFAD) mice was demonstrated in contextual fear conditioning. Stabilized derivatives of the N-terminal Aßcore were also shown to be fully protective against Aß-triggered oxidative stress. Together, these findings indicate an endogenous neuroprotective role for the N-terminal Aß fragment, while active stabilized N-terminal Aßcore derivatives offer the potential for therapeutic application.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
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Peptídeos beta-Amiloides
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Fármacos Neuroprotetores
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article