Accumulation of APP-CTF induces mitophagy dysfunction in the iNSCs model of Alzheimer's disease

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Detecting Amyloid-β Accumulation via Immunofluorescent Staining in a Mouse Model of Alzheimer's Disease
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Detecting Amyloid-β Accumulation via Immunofluorescent Staining in a Mouse Model of Alzheimer's Disease

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Seung-Eun Lee1, Daekee Kwon2, Nari Shin1

  • 1Adult Stem Cell Research Center and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea.

Cell Death Discovery
|January 11, 2022
PubMed

Insights

Amyloid precursor protein fragments (APP-CTFs) accumulate in mitochondria, causing dysfunction and mitophagy failure in Alzheimer's disease (AD) models. This study reveals APP-CTFs as a key factor in AD pathology, linking mitochondrial damage to disease progression.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Genetics

Background:

  • Mitochondrial dysfunction is a known hallmark of familial Alzheimer's disease (fAD).
  • Amyloid precursor protein (APP) processing generates amyloid-beta (Aβ), but the role of other APP fragments in pathology is less understood.
  • Accumulation of damaged mitochondria contributes to Alzheimer's disease (AD) progression.

Purpose of the Study:

  • To investigate the role of amyloid precursor protein-derived C-terminal fragments (APP-CTFs) in mitochondrial dysfunction and mitophagy in Alzheimer's disease.
  • To elucidate the pathological mechanisms involving APP-CTFs in induced neural stem cells (iNSCs) from AD patients and presenilin knockout models.

Main Methods:

  • Utilized induced neural stem cells (iNSCs) derived from Alzheimer's disease (AD) patient fibroblasts.
  • Analyzed APP-CTFs accumulation within mitochondrial domains.
  • Assessed mitophagy failure using markers like LC3-II, p62, and PTEN-induced kinase 1 (PINK1)/Parkin.
  • Validated findings in presenilin knockout iNSCs (PSEN KO-iNSCs) to confirm the role of gamma-secretase activity.

Main Results:

  • Demonstrated that APP-CTFs accumulate within mitochondria, acting as both a cause and consequence of mitochondrial dysfunction.
  • Showed that APP-CTFs accumulation leads to mitophagy failure, evidenced by altered protein levels and impaired mitochondrial-lysosomal fusion.
  • Confirmed the pathological loop of APP-CTFs accumulation and mitophagy impairment in both AD patient-derived iNSCs and PSEN KO-iNSCs.

Conclusions:

  • APP-CTFs accumulation is a significant contributor to mitochondrial dysfunction and mitophagy failure in Alzheimer's disease.
  • The findings highlight a novel pathological mechanism involving APP-CTFs in AD, distinct from solely Aβ toxicity.
  • Targeting APP-CTFs or enhancing mitophagy may offer new therapeutic strategies for Alzheimer's disease.

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