Amyloid precursor protein βCTF accumulates in synapses in sporadic and genetic forms of Alzheimer's disease

Abstract

Aims: Amyloid precursor protein (APP) β-C-terminal fragment (βCTF) may have a neurotoxic role in Alzheimer's disease (AD). βCTF 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 βCTF 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 βCTF, Aβ40, Aβ42 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 βCTF was enriched in AD synaptosomes. Conclusions: We demonstrate that βCTF accumulates in synapses in SAD, ADAD and DS. This finding might suggest a role for βCTF in synapse degeneration. Therapies aimed at mitigating βCTF accumulation could be potentially beneficial in AD.