Decreased Expression of GGA3 Protein in Alzheimer's Disease Frontal Cortex and Increased Co-Distribution of BACE With the Amyloid Precursor Protein

Neurobiol Dis. 2011 Jul;43(1):176-83. doi: 10.1016/j.nbd.2011.03.009. Epub 2011 Apr 3.

Abstract

BACE initiates the amyloidogenic processing of the amyloid precursor protein (APP) that results in the production of Aβ peptides associated with Alzheimer's disease (AD). Previous studies have indicated that BACE is elevated in the frontal cortex of AD patients. Golgi-localized γ-ear containing ADP ribosylation factor-binding proteins (GGA) control the cellular trafficking of BACE and may alter its levels. To investigate a link between BACE and GGA expression in AD, frontal cortex samples from AD (N = 20) and healthy, age-matched controls (HC, N =17) were analyzed by immunoblotting. After normalization to the neuronal marker β-tubulin III, the data indicate an average two-fold increase of BACE protein (p = 0.01) and a 64% decrease of GGA3 in the AD group compared to the HC (p = 0.006). GGA1 levels were also decreased in AD, but a statistical significance was not achieved. qRT-PCR analysis of GGA3 mRNA showed no difference between AD and HC. There was a strong correlation between GGA1 and GGA3 in both AD and HC, but no correlation between BACE and GGA levels. Subcellular fractionation of AD cortex with low levels of GGA proteins showed an alteration of BACE distribution and extensive co-localization with APP. These data suggest that altered compartmentalization of BACE in AD promotes the amyloidogenic processing of APP.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / antagonists & inhibitors*
  • Adaptor Proteins, Vesicular Transport / biosynthesis
  • Adaptor Proteins, Vesicular Transport / genetics
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Aspartic Acid Endopeptidases / genetics
  • Aspartic Acid Endopeptidases / metabolism*
  • Down-Regulation / genetics
  • Female
  • Frontal Lobe / metabolism
  • Frontal Lobe / physiology*
  • Humans
  • Male
  • Middle Aged
  • Nerve Degeneration / genetics
  • Nerve Degeneration / metabolism*
  • Nerve Degeneration / pathology
  • Up-Regulation / genetics
  • trans-Golgi Network / physiology

Substances

  • Adaptor Proteins, Vesicular Transport
  • Amyloid beta-Protein Precursor
  • GGA adaptor proteins
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human