Amyloidogenic proteolysis of APP regulates glutamatergic presynaptic function
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Disease causing mutations of Alzheimer’s disease (AD) point to dysregulations of APP proteolysis. During asymptomatic and early stages of AD, brain recordings revealed hyperexcitation reverting into over-inhibition as dementia progresses. Here, we show that endogenous APP and its proteolytic product APP-CTFβ, the precursors of Aβ, accumulate preferentially at excitatory synapses. Using pharmacological treatments to modulate physiological concentrations of APP-CTFβ and Aβ, we identify APP-CTFβ as a key regulator of glutamatergic synaptic transmission. Accumulation of APP-CTFβ increases the release probability of synaptic vesicles. Strikingly, monomeric Aβ counteracts this APP-CTFβ-driven hyperexcitability. This suggests that therapeutic strategies clearing monomeric Aβ could be detrimental during the early hyperexcitability phase of AD.
