Amyloidogenic proteolysis of APP regulates glutamatergic presynaptic function

Akshay Kapadia; Fabian Schuhmann; Ezgi Daşkın; Jochen Walter; Isabell Lindahl; Neda Rahmani; Tjado H. J. Morrema; Annemieke J.M. Rozemüller; Baayla D.C. Boon; Weria Pezeshkian; Anne‐Sophie Hafner

doi:10.1038/s44318-026-00899-6

NeuroscienceThe EMBO JournalSep 1, 2026

Peer-reviewed journal article

Amyloidogenic proteolysis of APP regulates glutamatergic presynaptic function

Akshay Kapadia iD, Fabian Schuhmann iD, Ezgi Daşkın iD, Jochen Walter iD, Isabell Lindahl iD, Neda Rahmani, Tjado H. J. Morrema, Annemieke J.M. Rozemüller iD, Baayla D.C. Boon iD, Weria Pezeshkian iD, Anne‐Sophie Hafner iD

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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