title: Calsyntenin-3 C-terminal fragment accumulates in dystrophic neurites surrounding aβ plaques in tg2576 mouse and Alzheimer disease brains: its neurotoxic role in mediating dystrophic neurite formation.
abstract: Dystrophic neurites surrounding β-amyloid (Aβ) plaques precede neuronal death in Alzheimer disease. These neuritic alterations may be one of the initial stages for synaptic loss and dysfunction. However, intracellular pathways that cause local disruption of neuronal processes by Aβ remain to be fully elucidated. The identification of Aβ-induced genes that mediate neuritic pathology would provide considerable insight into the mechanisms of Alzheimer's disease. Previously, we reported that selective up-regulation of calsyntenin-3 (Cst-3) by Aβ and accumulation of neurotoxic Cst-3 in dystrophic neurites surrounding Aβ plaques may lead to local disruption of these neurites. Like amyloid precursor protein, Cst-3 undergoes two-step proteolytic processing: the primary cleavage with α-secretase generates an N-terminal ectodomain and a C-terminal fragment (CTF). The CTF is subsequently cleaved into p3 peptide and an intracellular domain via γ-secretase. It would be interesting to know whether accumulated Cst-3 in dystrophic neurites surrounding Aβ plaques is the full-length version or a CTF. Herein, we show that the CTF but not full-length Cst-3 accumulated in dystrophic neurites surrounding Aβ plaques in Tg2576 mouse and Alzheimer disease brains. In vitro experiments with Cst-3 fragments have revealed that only the CTF resulted in acceleration of neuronal death. These results indicate that accumulation of the neurotoxic CTF in neurites surrounding Aβ plaques may lead to local disruption of neuronal processes and development of dystrophic neurites.
authors.affiliation: Department of Molecular Neurobiology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan. 57uchida@tmig.or.jp
authors.forename: Yoko
authors.initials: Y
authors.lastname: Uchida
authors.forename: Fujiya
authors.initials: F
authors.lastname: Gomi
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murayama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takahashi
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000737:chemistry; D005260:Female; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D051379:Mice; D008822:Mice, Transgenic; D016501:Neurites / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D051381:Rats
chemical_list: C472553:CLSTN3 protein, human; C585112:CLSTN3 protein, rat; D002135:Calcium-Binding Proteins; C472554:Clstn3 protein, mouse; D017077:Culture Media, Conditioned; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D061988:Proteasome Inhibitors; D053829:Amyloid Precursor Protein Secretases; D046988:Proteasome Endopeptidase Complex