Amyloidogenic proteolysis of APP regulates glutamatergic presynaptic function

Disease causing mutations of Alzheimerś 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 probability of synaptic vesicles. Strickingly, 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.