Biophysical Society Thematic Meeting | Bucharest 2026

Biophysics of Membrane Reactions in Brian

Tuesday Speaker Abstracts

CLEAVAGE AT THE MEMBRANE: HOW GAMMA-SECRETASE COMPLEX MODULATES NEURONAL COMPLEXITY Maria L Franco; Andrea Benito Martinez; Elena Juarez; Marçal Vilar ; Institute of Biomedicine of Valencia CSIC, Valencia, Spain Loss of basal forebrain cholinergic neurons (BFCNs) is a hallmark of Alzheimer’s disease (AD), yet the processes driving their degeneration are still poorly understood. The neurotrophin receptor p75NTR and the accumulation of amyloid- β (A β ), particularly A β 42, have both been linked to disease progression. We find that increased A β 42 interferes with γ -secretase activity, leading to the buildup of unprocessed protein fragments and activation of p75-dependent neuronal death pathways. In cultured neurons, blocking γ -secretase causes marked changes in BFCN morphology and disrupts synaptic connectivity in hippocampal networks. These effects are eliminated in neurons lacking p75NTR, highlighting its central role. Together, our results suggest that elevated A β 42 contributes to neuronal dysfunction by inhibiting γ -secretase and provide insight into why γ -secretase inhibitors have produced negative cognitive outcomes in clinical studies.

13