| First Author | Cimini S | Year | 2016 |
| Journal | Neurobiol Dis | Volume | 89 |
| Pages | 101-11 | PubMed ID | 26721320 |
| Mgi Jnum | J:259407 | Mgi Id | MGI:6141277 |
| Doi | 10.1016/j.nbd.2015.12.013 | Citation | Cimini S, et al. (2016) The cell-permeable Abeta1-6A2VTAT(D) peptide reverts synaptopathy induced by Abeta1-42wt. Neurobiol Dis 89:101-11 |
| abstractText | Alzheimer disease (AD) is the most prevalent form of dementia. Loss of hippocampal synapses is the first neurodegenerative event in AD. Synaptic loss has been associated with the accumulation in the brain parenchyma of soluble oligomeric forms of amyloid beta peptide (Abeta1-42wt). Clinical observations have shown that a mutation in the APP protein (A673V) causes an early onset AD-type dementia in homozygous carriers while heterozygous carriers are unaffected. This mutation leads to the formation of mutated Abeta peptides (Abeta1-42A2V) in homozygous patients, while in heterozygous subjects both Abeta1-42wt and Abeta1-42A2V are present. To better understand the impact of the A673V mutation in AD, we analyzed the synaptotoxic effect of oligomers formed by aggregation of different Abeta peptides (Abeta1-42wt or Abeta1-42A2V) and the combination of the two Abeta1-42MIX (Abeta1-42wt and Abeta1-42A2V) in an in vitro model of synaptic injury. We showed that Abeta1-42A2V oligomers are more toxic than Abeta1-42wt oligomers in hippocampal neurons, confirming the results previously obtained in cell lines. Furthermore, we reported that oligomers obtained by the combination of both wild type and mutated peptides (Abeta1-42MIX) did not exert synaptic toxicity. We concluded that the combination of Abeta1-42wt and Abeta1-42A2V peptides hinders the toxicity of Abeta1-42A2V and counteracts the manifestation of synaptopathy in vitro. Finally we took advantage of this finding to generate a cell-permeable peptide for clinical application, by fusing the first six residues of the Abeta1-42A2V to the TAT cargo sequence (Abeta1-6A2VTAT(D)). Noteworthy, the treatment with Abeta1-6A2VTAT(D) confers neuroprotection against both in vitro and in vivo synaptopathy models. Therefore Abeta1-6A2VTAT(D) may represent an innovative therapeutic tool to prevent synaptic degeneration in AD. |
