Morphine via nitric oxide modulates beta-amyloid metabolism: a novel protective mechanism for Alzheimer's disease

Med Sci Monit. 2005 Oct;11(10):BR357-66. Epub 2005 Sep 26.


Background: The deposition of intracellular and extracellular beta-amyloid peptide (Abeta) in the brain is a pathologic feature of Alzheimer's disease (AD), a prevalent neurodegenerative disorder. However, the exact role of the Abeta peptide in causing AD's symptoms is unclear.

Material/methods: CRL-2266 SH-SY5Y human neuroblastoma cells (ATCC, USA) and HTB-11 human neuroblastoma cells (ATCC, USA) were cultured. Reverse transcription-polymerase chain reaction (RT-PCR) was performed to analyze the effects of beta25-35, morphine, and SNAP treatments upon BACE-1 and BACE-2 mRNA expression semi-quantitative RT-PCR. The production of NO in SH-SY5Y cells was detected using the Apollo 4000 Free Radical Analyzer (World Precision Instruments).

Results: Untreated HTB-11 neuroblastoma cells constitutively express BACE-1 and BACE-2 mRNA. Morphine down regulates the expression of BACE-1 and up regulates the expression of BACE-2 in a naloxone antagonizable manner. When HTB-11 cells were treated with L-NAME, a cNOS inhibitor; the effects of morphine were blocked. SNAP (a NO donor) mimicked the effect of morphine. In SH-SY5Y cells, Abeta treated cells show a dose-dependent decrease in NO release, demonstrating that Ab is dose-dependently inhibiting the release of constitutive NO.

Conclusions: Ab and morphine/NO each inhibit the production of the other. This suggests that a deficiency of basal NO or endogenous morphine may trigger drastically reduced levels of basal NO. The outcome is chronic vasoconstriction and brain hypoperfusion and eventual neuronal death. This novel theorized mechanism for AD supports an increasingly-accepted vascular pathological hypothesis for the disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alzheimer Disease / enzymology
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / prevention & control*
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Peptides / metabolism*
  • Aspartic Acid Endopeptidases / genetics
  • Cell Line, Tumor
  • Endopeptidases / genetics
  • Gene Expression Regulation, Enzymologic / physiology
  • Humans
  • Morphine / pharmacology*
  • Nitric Oxide / physiology*
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction


  • Amyloid beta-Peptides
  • RNA, Messenger
  • Nitric Oxide
  • Morphine
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE2 protein, human
  • BACE1 protein, human