Brain p3-Alcβ peptide restores neuronal viability impaired by Alzheimer's amyloid β-peptide.

Autor: Hata S; Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.; Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan., Saito H; Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.; Advanced Prevention and Research Laboratory for Dementia, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan., Kakiuchi T; Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Japan., Fukumoto D; Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Japan., Yamamoto S; Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Japan., Kasuga K; Molecular Genetics, Niigata University Brain Research Institute, Nigata, Japan., Kimura A; Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan., Moteki K; Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.; Advanced Prevention and Research Laboratory for Dementia, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan., Abe R; Advanced Prevention and Research Laboratory for Dementia, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan., Adachi S; Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan., Kinoshita S; Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.; Advanced Prevention and Research Laboratory for Dementia, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan., Yoshizawa-Kumagaye K; Peptide Institute, Inc., Ibaraki, Japan., Nishio H; Peptide Institute, Inc., Ibaraki, Japan., Saito T; Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science Institute, Wako, Japan.; Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan., Saido TC; Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science Institute, Wako, Japan., Yamamoto T; Department of Molecular Neurobiology, Factory of Medicine, Kagawa University, Takamatsu, Japan., Nishimura M; Molecular Neuroscience Research Center, Shiga University of Medical Science, Shiga, Japan., Taru H; Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.; Advanced Prevention and Research Laboratory for Dementia, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan., Sobu Y; Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.; Advanced Prevention and Research Laboratory for Dementia, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan., Ohba H; Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Japan., Nishiyama S; Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Japan., Harada N; Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Japan., Ikeuchi T; Molecular Genetics, Niigata University Brain Research Institute, Nigata, Japan., Tsukada H; Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Japan., Ouchi Y; Department of Biofunctional Imaging, Preeminent Medical Education & Research Center, Hamamatsu University School of Medicine, Hamamatsu, Japan., Suzuki T; Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.; Advanced Prevention and Research Laboratory for Dementia, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Jazyk: angličtina
Zdroj: EMBO molecular medicine [EMBO Mol Med] 2023 May 08; Vol. 15 (5), pp. e17052. Date of Electronic Publication: 2023 Mar 30.
DOI: 10.15252/emmm.202217052
Abstrakt: We propose a new therapeutic strategy for Alzheimer's disease (AD). Brain peptide p3-Alcβ37 is generated from the neuronal protein alcadein β through cleavage of γ-secretase, similar to the generation of amyloid β (Aβ) derived from Aβ-protein precursor/APP. Neurotoxicity by Aβ oligomers (Aβo) is the prime cause prior to the loss of brain function in AD. We found that p3-Alcβ37 and its shorter peptide p3-Alcβ9-19 enhanced the mitochondrial activity of neurons and protected neurons against Aβo-induced toxicity. This is due to the suppression of the Aβo-mediated excessive Ca 2+ influx into neurons by p3-Alcβ. Successful transfer of p3-Alcβ9-19 into the brain following peripheral administration improved the mitochondrial viability in the brain of AD mice model, in which the mitochondrial activity is attenuated by increasing the neurotoxic human Aβ42 burden, as revealed through brain PET imaging to monitor mitochondrial function. Because mitochondrial dysfunction is common in the brain of AD patients alongside increased Aβ and reduced p3-Alcβ37 levels, the administration of p3-Alcβ9-19 may be a promising treatment for restoring, protecting, and promoting brain functions in patients with AD.
(© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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