Calpain and caspase regulate Aβ peptide production via cleavage of KINDLIN2 encoded by the AD-associated gene FERMT2
Abstract
The adapter protein KINDLIN2, encoded by the Alzheimer's disease (AD) genetic risk factor FERMT2, was identified as a modulator of APP processing. KINDLIN2 directly interacts with APP to modulate its metabolism, and KINDLIN2 underexpression impairs long-term potentiation in an APP-dependent manner. Altogether, these data suggest that loss of KINDLIN2 could have a detrimental effect on synaptic function and promote AD pathophysiological process. In this study, we identified KINDLIN2 as a novel substrate of caspases and calpain I, two well-characterized cysteine proteases involved in the regulation of synaptic plasticity. These cleavages resulted in the dissociation of the F0 and F1 domains of KINDLIN2 that are necessary for it to function as an adapter protein. Furthermore, we demonstrate that these cleavages lead to a decrease in KINDLIN2's ability to control APP processing. Overall, these KINDLIN2 cleavages appear as potential new mechanisms in the regulation of KINDLIN2 functions at the synapse and could be of interest for the pathophysiology of AD.
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BibTeX
@article{najdek2026calpain,
title = {{Calpain and caspase regulate Aβ peptide production via cleavage of KINDLIN2 encoded by the AD-associated gene FERMT2}},
author = {Chloé Najdek and Pauline Walle and Amandine Flaig and Anne-Marie Ayral and Florie Demiautte and Audrey Coulon and Valérie Buiche and Erwan Lambert and Philippe Amouyel and Carla Gelle and Dolores Siedlecki-Wullich and Julie Dumont and Devrim Kilinc and Fanny Eysert and Jean-Charles Lambert and Julien Chapuis},
journal = {Neurobiology of Aging},
year = {2026},
month = oct,
doi = {10.1016/j.neurobiolaging.2025.04.009},
url = {https://hal.science/hal-05776233v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Calpain and caspase regulate Aβ peptide production via cleavage of KINDLIN2 encoded by the AD-associated gene FERMT2
AU - Chloé Najdek
AU - Pauline Walle
AU - Amandine Flaig
AU - Anne-Marie Ayral
AU - Florie Demiautte
AU - Audrey Coulon
AU - Valérie Buiche
AU - Erwan Lambert
AU - Philippe Amouyel
AU - Carla Gelle
AU - Dolores Siedlecki-Wullich
AU - Julie Dumont
AU - Devrim Kilinc
AU - Fanny Eysert
AU - Jean-Charles Lambert
AU - Julien Chapuis
PY - 2026
DA - 2026/10/02
JO - Neurobiology of Aging
DO - 10.1016/j.neurobiolaging.2025.04.009
UR - https://hal.science/hal-05776233v1
AB - The adapter protein KINDLIN2, encoded by the Alzheimer's disease (AD) genetic risk factor FERMT2, was identified as a modulator of APP processing. KINDLIN2 directly interacts with APP to modulate its metabolism, and KINDLIN2 underexpression impairs long-term potentiation in an APP-dependent manner. Altogether, these data suggest that loss of KINDLIN2 could have a detrimental effect on synaptic function and promote AD pathophysiological process. In this study, we identified KINDLIN2 as a novel substrate of caspases and calpain I, two well-characterized cysteine proteases involved in the regulation of synaptic plasticity. These cleavages resulted in the dissociation of the F0 and F1 domains of KINDLIN2 that are necessary for it to function as an adapter protein. Furthermore, we demonstrate that these cleavages lead to a decrease in KINDLIN2's ability to control APP processing. Overall, these KINDLIN2 cleavages appear as potential new mechanisms in the regulation of KINDLIN2 functions at the synapse and could be of interest for the pathophysiology of AD.
SN - 0197-4580
ER -