| First Author | Forest KH | Year | 2018 |
| Journal | J Neurochem | Volume | 144 |
| Issue | 2 | Pages | 201-217 |
| PubMed ID | 29164616 | Mgi Jnum | J:257177 |
| Mgi Id | MGI:6116059 | Doi | 10.1111/jnc.14257 |
| Citation | Forest KH, et al. (2018) Protection against beta-amyloid neurotoxicity by a non-toxic endogenous N-terminal beta-amyloid fragment and its active hexapeptide core sequence. J Neurochem 144(2):201-217 |
| abstractText | High levels (muM) of beta amyloid (Abeta) oligomers are known to trigger neurotoxic effects, leading to synaptic impairment, behavioral deficits, and apoptotic cell death. The hydrophobic C-terminal domain of Abeta, together with sequences critical for oligomer formation, is essential for this neurotoxicity. However, Abeta 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 Abeta. An N-terminal Abeta fragment (1-15/16), found in cerebrospinal fluid, was also shown to be a highly active neuromodulator and to reverse Abeta-induced impairments of long-term potentiation. Here, we show the impact of this N-terminal Abeta fragment and a shorter hexapeptide core sequence in the Abeta fragment (Abetacore: 10-15) to protect or reverse Abeta-induced neuronal toxicity, fear memory deficits and apoptotic death. The neuroprotective effects of the N-terminal Abeta fragment and Abetacore on Abeta-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 Abeta fragment and Abetacore against spatial memory processing deficits in amyloid precursor protein/PSEN1 (5XFAD) mice was demonstrated in contextual fear conditioning. Stabilized derivatives of the N-terminal Abetacore were also shown to be fully protective against Abeta-triggered oxidative stress. Together, these findings indicate an endogenous neuroprotective role for the N-terminal Abeta fragment, while active stabilized N-terminal Abetacore derivatives offer the potential for therapeutic application. |
