Pre-synaptic localization of the γ-secretase-inhibiting protein p24α2 in the mammalian brain

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 p24α2 reportedly attenuates Aβ generation by inhibiting γ-secretase processing of amyloid precursor protein; however, the pattern of expression and localization of p24α2 in the brain remains unknown. We performed immunohistochemical staining and subcellular fractionation for p24α2 in the mouse brain. Immunostaining showed that p24α2 is broadly distributed in the gray matter of the central nervous system and is predominantly localized to synapses. Subcellular fractionation revealed prominent localization of p24α2 in the pre-synaptic terminals. Immunoisolation of synaptic vesicles (SV) indicated that p24α2 is condensed at active zone-docked SV. During development, p24α2 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 p24α2 in the regulation of synaptic transmission and synaptogenesis, and provide evidence for the participation of p24α2 in the regulation of Aβ generation and secretion in the brain. The p24 family member p24α2 attenuates amyloid-β (Aβ) generation by inhibiting the γ-secretase processing. We report that p24α2 is condensed at active zone-docked synaptic vesicles in the brain. p24α2 expression is highest in the post-natal period and gradually decreases with age. Our results suggest a novel function for p24α2 at the synapse, including the regulation of brain Aβ generation.