Amyloid precursor protein ð>½CTF accumulates in synapses in sporadic and genetic forms of Alzheimer's disease

AimsAmyloid precursor protein (APP) ð>½‐C‐terminal fragment (ð>½CTF) may have a neurotoxic role in Alzheimer's disease (AD). ð>½CTF 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 ð>½CTF accumulates in synapses in SAD, autosomal dominant AD (ADAD) and Down syndrome (DS).MethodsWe used array tomography to determine APP at synapses in human AD tissue. We measured ð>½CTF, Að>½40, Að>½42 and phosphorylated tau181 (p‐tau181) concentrations in brain homogenates and synaptosomes of frontal and temporal cortex of SAD, ADAD, DS and controls.ResultsAPP colocalised with pre‐ and post‐synaptic markers in human AD brains. APP ð>½CTF was enriched in AD synaptosomes.ConclusionsWe demonstrate that ð>½CTF accumulates in synapses in SAD, ADAD and DS. This finding might suggest a role for ð>½CTF in synapse degeneration. Therapies aimed at mitigating ð>½CTF accumulation could be potentially beneficial in AD.