PROTECTIVE PROPERTY OF P3-ALCβ AGAINST A NEUROTOXICITY INDUCED BY Aβ OLIGOMER

Abstract

Neuronal p3-Alcβ peptide is generated from the precursor protein Alcadeinβ (Alcβ) by a cleavage of α- and γ-secretases. Alcβ generates the C-terminal variant peptides including a major p3-Alcβ37, as does APP. It is understood that Aβ42 level tends to decrease in AD patients in cerebrospinal fluid (CSF) by deposition of Aβ aggregate in brain compared to age-matched non-demented subjects. Although, p3-Alcβ levels are comparable to those of Aβ levels, the trend of non-aggregatable p3-Alcβ levels in CSF of AD subjects has not been analyzed. Moreover, function of p3-Alcβ remains unclear. In this study, we analyzed the change of p3-Alcβ in CSF of AD and explored the function of p3-Alcβ, especially in the role to prevent Aβ oligomer-induced neurotoxicity. We developed a new sandwich ELISA to quantify p3-Alcβ37. The primary cultures of mixed mouse cortical and hippocampal neurons were used to assess functions of p3-Alcβ in Aβ oligomer-induced neurotoxicity. Partial sequence peptides of p3-Alcβ were examined to identify functional regions of p3-Alcβ in vivo and in vitro. To analyze pharmacokinetics of the short peptide including functional amino acid sequence in mouse, we developed another sELISA. CSF p3-Alcβ level significantly decreased in Alzheimer's disease (AD) and/or mild cognitive impairment, compared to age-matched non-demented subjects (see Poster by Hata et al). Interestingly, a synthetic p3-Alcβ37 preserved primary cultured neurons from an impairment by Aβ42 oligomers in dose-dependent manner. Independent study identified the functional amino acid sequence in p3-Alcβ, which restored a cognitive impairment induced by Aβ oligomers in mouse. To develop a new drug therapy with this short peptide/a lead peptide including the functional amino acid sequence, we examined levels of the lead peptide in blood and CSF with sELISA. Following the subcutaneous administration of the lead peptide into mice, the peptide was detected in blood quickly and followed in CSF, indicating the brain transport of the peptide by a peripheral administration. The p3-Alcβ shows a protective effect against neurotoxicity induced by Aβ oligomer. Shorter peptide of p3-Alcβ is a drugable lead with an ability of brain transport by peripheral administration.