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Calpain and caspase regulate Aβ peptide production via cleavage of KINDLIN2 encoded by the AD-associated gene FERMT2

Chloé Najdek1, Pauline Walle1, Amandine Flaig1

  • 1Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille 59019, France.

Neurobiology of Aging
|April 24, 2025
PubMed

Insights

The adapter protein KINDLIN2, crucial for Alzheimer's disease (AD) pathology, is cleaved by caspases and calpain I. This cleavage impairs KINDLIN2's function in regulating amyloid precursor protein (APP) processing and synaptic plasticity.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • The adapter protein KINDLIN2, encoded by the Alzheimer's disease (AD) genetic risk factor FERMT2, modulates amyloid precursor protein (APP) processing.
  • KINDLIN2 underexpression impairs long-term potentiation in an APP-dependent manner, suggesting its loss detrimentally affects synaptic function and promotes AD pathophysiology.

Purpose of the Study:

  • To identify novel regulatory mechanisms of KINDLIN2 function at the synapse.
  • To investigate the role of KINDLIN2 cleavage by caspases and calpain I in AD pathophysiology.

Main Methods:

  • Identification of KINDLIN2 as a substrate for caspases and calpain I.
  • Analysis of KINDLIN2 cleavage products and their impact on protein structure and function.
  • Assessment of KINDLIN2's role in APP processing and synaptic plasticity.

Main Results:

  • KINDLIN2 is a novel substrate of caspases and calpain I, cysteine proteases involved in synaptic plasticity.
  • Cleavage by these proteases causes dissociation of KINDLIN2's F0 and F1 domains, essential for its adapter protein function.
  • These cleavages decrease KINDLIN2's ability to regulate APP processing.

Conclusions:

  • KINDLIN2 cleavage by caspases and calpain I represents a new regulatory mechanism for its synaptic function.
  • These cleavage events may contribute to the pathophysiology of Alzheimer's disease by affecting APP processing and synaptic function.
Keywords:
KINDLIN2 ALZHEIMER APP

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