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Pre‐synaptic localization of the γ‐secretase‐inhibiting protein p24α 2 in the mammalian brain
Author(s) -
Liu Lei,
Fujino Kazunori,
Nishimura Masaki
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13000
Subject(s) - neuroscience , chemistry , biochemistry , biology
Dysregulated metabolism and consequent extracellular accumulation of amyloid‐β (Aβ) peptides in the brain underlie the pathogenesis of Alzheimer's disease. Extracellular Aβ in the brain parenchyma is mainly secreted from the pre‐synaptic terminals of neuronal cells in a synaptic activity‐dependent manner. The p24 family member p24α 2 reportedly attenuates Aβ generation by inhibiting γ‐secretase processing of amyloid precursor protein; however, the pattern of expression and localization of p24α 2 in the brain remains unknown. We performed immunohistochemical staining and subcellular fractionation for p24α 2 in the mouse brain. Immunostaining showed that p24α 2 is broadly distributed in the gray matter of the central nervous system and is predominantly localized to synapses. Subcellular fractionation revealed prominent localization of p24α 2 in the pre‐synaptic terminals. Immunoisolation of synaptic vesicles ( SV ) indicated that p24α 2 is condensed at active zone‐docked SV . During development, p24α 2 expression is highest in the post‐natal period and gradually decreases with age. We also confirmed that amyloid precursor protein and γ‐secretase components are localized at active zone‐docked SV . Our results suggest a novel functional role for p24α 2 in the regulation of synaptic transmission and synaptogenesis, and provide evidence for the participation of p24α 2 in the regulation of Aβ generation and secretion in the brain.The p24 family member p24α 2 attenuates amyloid‐β (Aβ) generation by inhibiting the γ‐secretase processing. We report that p24α 2 is condensed at active zone‐docked synaptic vesicles in the brain. p24α 2 expression is highest in the post‐natal period and gradually decreases with age. Our results suggest a novel function for p24α 2 at the synapse, including the regulation of brain Aβ generation.