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bioRxiv · 10.1101/2025.08.01.667924

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.
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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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Kapadia, A. B., Schuhmann, F., Daskin, E., Walter, J., Lindahl, I., Rahmani, N., Pezeshkian, W., Hafner, A.-S.. 2025-08-01. Amyloidogenic proteolysis of APP regulates glutamatergic presynaptic function. https://doi.org/10.1101/2025.08.01.667924

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