Autophagy enhancer carbamazepine alleviates memory deficits and cerebral amyloid-β pathology in a mouse model of Alzheimer's disease

Curr Alzheimer Res. 2013 May 1;10(4):433-41. doi: 10.2174/1567205011310040008.

Abstract

Autophagy plays an important role in Alzheimer's disease (AD). It has been reported that autophagic flux is altered in patients with AD, and application of the autophagy enhancer rapamycin may alleviate the cognitive impairment and amyloid-β (Aβ) neuropathology in transgenic animal model of AD. Since rapamycin is also an immune suppressor, there is a concern that long-term use of rapamycin may bring severe unwanted side effects. The aim of this study is to test if carbamazepine (CBZ), an anti-epileptic drug that has a potent autophagy enhancement effect, has anti-AD effects in APP(swe)/PS1(deltaE9) transgenic mice model of AD. We found that APP(swe)/PS1(deltaE9) mice display increased autophagic activity accompanied by decreased mTOR activity. After three months treatment with CBZ in the APP(swe)/PS1(deltaE9) mice, we demonstrated that the spatial learning and memory deficits in these mice are significantly alleviated. We also documented that the cerebral amyloid plaque burden and Aβ42 levels in these mice are significantly reduced. Furthermore, we showed that CBZ significantly enhances the autophagic flux in the APP(swe)/PS1(deltaE9) mice which is unlikely via mTOR-dependent autophagy pathway. These data suggest that long-term CBZ treatment may have a protective effect in AD mouse model possibly through enhancing the autophagic flux.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / complications*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology*
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Analgesics, Non-Narcotic / therapeutic use*
  • Analysis of Variance
  • Animals
  • Aspartic Acid Endopeptidases / metabolism
  • Carbamazepine / therapeutic use*
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism*
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Humans
  • Maze Learning / drug effects
  • Memory Disorders / drug therapy*
  • Memory Disorders / etiology*
  • Mice
  • Mice, Transgenic
  • Microtubule-Associated Proteins / metabolism
  • Mutation / genetics
  • Nerve Tissue Proteins / metabolism
  • Peptide Fragments / metabolism
  • Presenilin-1 / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Time Factors

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Analgesics, Non-Narcotic
  • Map1lc3b protein, mouse
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • PSEN1 protein, human
  • Peptide Fragments
  • Presenilin-1
  • amyloid beta-protein (1-42)
  • Carbamazepine
  • mTOR protein, mouse
  • TOR Serine-Threonine Kinases
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse