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.
Kapadia et al. (Fri,) studied this question.