Amyloid precursor protein đ˝CTF accumulates in synapses in sporadic and genetic forms of Alzheimer's disease
Paula FerrerâRaventĂłs, David PuertollanoâMartĂn, Marta QuerolâVilaseca, Ărika SĂĄnchezâAced, Natalia ValleâTamayo, Alba CervantesâGonzĂĄlez, RaĂşl NúùezâLlaves, Jordi Pegueroles, Oriol DolsâIcardo, M. Florencia Iulita, IbĂĄn Aldecoa, Laura MolinaâPorcel, Raquel SĂĄnchezâValle, Juan Fortea, Olivia Belbin, Sònia Sirisi, Alberto LleĂł
Abstract
AIMS: Amyloid precursor protein (APP) đ˝-C-terminal fragment (đ˝CTF) may have a neurotoxic role in Alzheimer's disease (AD). đ˝CTF accumulates in the brains of patients with sporadic (SAD) and genetic forms of AD. Synapses degenerate early during the pathogenesis of AD. We studied whether the đ˝CTF accumulates in synapses in SAD, autosomal dominant AD (ADAD) and Down syndrome (DS). METHODS: We used array tomography to determine APP at synapses in human AD tissue. We measured đ˝CTF, Ađ˝40, Ađ˝42 and phosphorylated tau181 (p-tau181) concentrations in brain homogenates and synaptosomes of frontal and temporal cortex of SAD, ADAD, DS and controls. RESULTS: APP colocalised with pre- and post-synaptic markers in human AD brains. APP đ˝CTF was enriched in AD synaptosomes. CONCLUSIONS: We demonstrate that đ˝CTF accumulates in synapses in SAD, ADAD and DS. This finding might suggest a role for đ˝CTF in synapse degeneration. Therapies aimed at mitigating đ˝CTF accumulation could be potentially beneficial in AD.