Presynaptic Accumulation of APP-CTFβ May Contribute to Synaptic Dysfunction in Alzheimer's Disease.

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. Dysregulation of amyloid precursor protein (APP) proteolysis is involved in Alzheimer’s disease. This study shows that APP processing generates functionally distinct intermediates at the synapse, i.e. presynaptic APP-CTFβ, accumulation of which causes neuronal network hyperactivity, and extracellular amyloid-β (Aβ), which can counteract APP-CTFβ-induced network hyperactivity. APP-CTFβ, the precursor of amyloid-β, can accumulate in the active zone of excitatory synapses and promote neuronal network excitation/inhibition imbalance.