Amyloidogenic proteolysis of APP regulates glutamatergic presynaptic function
Kapadia, A. B.; Schuhmann, F.; Daskin, E.; Walter, J.; Lindahl, I.; Rahmani, N.; Pezeshkian, W.; Hafner, A.-S.
Show abstract
Disease causing mutations of Alzheimers 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-CTF{beta}, the precursors of A{beta}, accumulate preferentially at excitatory synapses. Using pharmacological treatments to modulate physiological concentrations of APP-CTF{beta} and A{beta}, we identify APP-CTF{beta} as a key regulator of glutamatergic synaptic transmission. Accumulation of APP-CTF{beta} increases the release probability of synaptic vesicles. Strikingly, monomeric A{beta} counteracts this APP-CTF{beta}-driven hyperexcitability. This suggests that therapeutic strategies clearing monomeric A{beta} could be detrimental during the early hyperexcitability phase of AD.
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