Presynaptic accumulation of APP-CTFβ may contribute to synaptic dysfunction in Alzheimer’s disease
Akshay Kapadia, Fabian Schuhmann, Ezgi Daskin, Jochen Walter, Isabell Lindahl, Neda Rahmani, Tjado H J Morrema, Annemieke J M Rozemuller, Baayla D C Boon, Weria Pezeshkian, Anne-Sophie Hafner
Abstract: The study of Alzheimer’s disease (AD)-associated mutations has implicated dysregulation of amyloid precursor protein (APP) proteolysis in the disease. Brain recordings have revealed synaptic hyperexcitation during asymptomatic and early stages of AD, reverting to overinhibition as dementia progresses. Here, we show that endogenous APP and its proteolytic C-terminal fragments (APP-CTFs), the precursors of amyloid-β (Aβ), are enriched at excitatory synapses. Pharmacological modulation of endogenous APP metabolite levels suggests a role for APP-CTFs, in particular APP-CTFβ, in regulating glutamatergic synaptic transmission. Presynaptic accumulation of APP-CTFβ promotes its oligomerization, increases synaptic vesicle docking, and causes vesicle release defects, accompanied by enhanced neuronal network activity. Examination of post-mortem AD patient brains yields consistent results, namely, elevated APP-CTFβ levels at synaptic compartments and enlarged excitatory presynaptic boutons. Strikingly, acute application of Aβ preparations enriched in monomeric species counteracts APP-CTFβ-induced hyperexcitability. Our findings indicate a role for presynaptic APP-CTFβ in modulating excitatory synaptic function and network activity, suggesting that amyloidogenic APP processing intermediates may contribute to early synaptic alterations in Alzheimer’s disease.