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Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs

Hindupur K Anandatheerthavarada1, Gopa Biswas, Marie-Anne Robin

  • 1Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

The Journal of Cell Biology
|April 16, 2003
PubMed

Insights

Alzheimer's amyloid precursor protein (APP) targets neuronal mitochondria, contributing to mitochondrial dysfunction and impaired energy metabolism in Alzheimer's disease models. This discovery reveals a novel role for APP in brain mitochondria.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Alzheimer's disease (AD) is linked to amyloid beta (Abeta) peptides derived from amyloid precursor protein (APP).
  • APP is typically a plasma membrane protein.
  • The exact cellular localization and function of APP in neuronal mitochondria are not fully understood.

Purpose of the Study:

  • To investigate the mitochondrial targeting of APP in neuronal cells.
  • To elucidate the mechanism and consequences of APP accumulation in mitochondria.
  • To explore the role of APP in mitochondrial dysfunction in Alzheimer's disease.

Main Methods:

  • Utilized a transgenic mouse model for Alzheimer's disease.
  • Employed chemical cross-linking and immunoelectron microscopy to study mitochondrial APP.
  • Conducted mutational studies to identify critical domains of APP for mitochondrial targeting and function.

Main Results:

  • Demonstrated that APP is targeted to mitochondria in cortical neuronal cells and specific brain regions of AD mouse models.
  • Identified positively charged residues (40, 44, 51) as crucial for the mitochondrial-targeting signal of APP.
  • Showed that APP accumulates in mitochondria in a transmembrane-arrested form, interacting with translocase proteins.
  • Found that full-length APP accumulation in mitochondria, but not variants lacking the acidic domain, leads to mitochondrial dysfunction and impaired energy metabolism.

Conclusions:

  • Established that APP is targeted to neuronal mitochondria under physiological and pathological conditions.
  • Revealed a novel mechanism involving APP's transmembrane arrest in mitochondria.
  • Linked mitochondrial APP accumulation to impaired energy metabolism, suggesting a new pathway in Alzheimer's pathogenesis.

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