Huntingtin associated protein 1 regulates trafficking of the amyloid precursor protein and modulates amyloid beta levels in neurons

J Neurochem. 2012 Sep;122(5):1010-22. doi: 10.1111/j.1471-4159.2012.07845.x.

Abstract

Amyloid precursor protein (APP) is involved in the pathogenesis of Alzheimer's disease. It is axonally transported, endocytosed and sorted to different cellular compartments where amyloid beta (Aβ) is produced. However, the mechanism of APP trafficking remains unclear. We present evidence that huntingtin associated protein 1 (HAP1) may reduce Aβ production by regulating APP trafficking to the non-amyloidogenic pathway. HAP1 and APP are highly colocalized in a number of brain regions, with similar distribution patterns in both mouse and human brains. They are associated with each other, the interacting site is the 371-599 of HAP1. APP is more retained in cis-Golgi, trans-Golgi complex, early endosome and ER-Golgi intermediate compartment in HAP1-/- neurons. HAP1 deletion significantly alters APP endocytosis and reduces the re-insertion of APP into the cytoplasmic membrane. Amyloid precursor protein-YFP(APP-YFP) vesicles in HAP1-/- neurons reveal a decreased trafficking rate and an increased number of motionless vesicles. Knock-down of HAP1 protein in cultured cortical neurons of Alzheimer's disease mouse model increases Aβ levels. Our data suggest that HAP1 regulates APP subcellular trafficking to the non-amyloidogenic pathway and may negatively regulate Aβ production in neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Analysis of Variance
  • Animals
  • Autoantigens / metabolism
  • Biotinylation
  • Brain / metabolism
  • Cells, Cultured
  • Cerebral Cortex / pathology
  • Cytoplasm / metabolism
  • Disease Models, Animal
  • Endocytosis / genetics
  • Enzyme-Linked Immunosorbent Assay
  • Fluorescence Resonance Energy Transfer / methods
  • Heat-Shock Proteins / metabolism
  • Humans
  • Immunoprecipitation
  • Integrins / metabolism
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Lysosomal-Associated Membrane Protein 1 / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / metabolism*
  • Neurons / metabolism*
  • Neurons / ultrastructure
  • Photobleaching
  • Presenilin-1 / genetics
  • Presenilin-1 / metabolism
  • Protein Transport / genetics
  • RNA Interference / physiology
  • Transfection / methods
  • Vesicular Transport Proteins / metabolism
  • trans-Golgi Network / genetics
  • trans-Golgi Network / metabolism

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Autoantigens
  • Golgin subfamily A member 2
  • Hap1 protein, mouse
  • Heat-Shock Proteins
  • Integrins
  • Luminescent Proteins
  • Lysosomal-Associated Membrane Protein 1
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Presenilin-1
  • Vesicular Transport Proteins
  • early endosome antigen 1
  • molecular chaperone GRP78