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

Aims: Amyloid precursor protein (APP) -C-terminal fragment (CTF) may have a neurotoxic role in Alzheimer's disease (AD). 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 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 beta CTF, A beta 40, A beta 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 CTF was enriched in AD synaptosomes. Conclusions: We demonstrate that CTF accumulates in synapses in SAD, ADAD and DS. This finding might suggest a role for CTF in synapse degeneration. Therapies aimed at mitigating CTF accumulation could be potentially beneficial in AD.