Beta-amyloid inhibits NOS activity by subtracting NADPH availability.

Giorgio Venturini, Marco Colasanti, Tiziana Persichini, Emanuela Fioravanti, Paolo Ascenzi, Letizia Palomba, Orazio Cantoni, Giovanni Musci

Research output: Contribution to journalArticle

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Abstract

The amyloid peptides Abeta1-42 and Abeta25-35 strongly inhibited the activity of constitutive neuronal and endothelial nitric oxide synthases (i.e., NOS-I and NOS-III, respectively) in cell-free assays. The molecular mechanism of NOS inhibition by Ab fragments was studied in detail with Abeta25-35. The inhibitory ability was mostly NADPH-dependent and specific for the soluble form of Abeta25-35. Optical, fluorescence, and NMR spectroscopy showed that the soluble, but not aggregated, Abeta25-35 interacted with NADPH, thus suggesting that a direct recruitment of NADPH may result in diminished availability of the redox cofactor for NOS functioning. To assess the physiological relevance of our findings, rat neuronal-like PC12 and glioma C6 cell lines were used as cellular models. After Abeta25-35 internalization into cells was verified, the activity of constitutive NOS was measured using the DAF-2DA detection system and found to be severely impaired upon Abeta25-35 uptake. Consistent with previous results on the molecular cross-talk between NOS isoforms, repression of constitutive NOS by Abeta25-35 resulted in enhanced expression of inducible NOS (NOS-II) mRNA in C6 cells. Our results represent the first evidence that amyloid fragments impair constitutive NOS activity in cell-free and cellular systems, providing a possible molecular mechanism for the onset and/or maintenance of Alzheimer's disease.

Original languageEnglish
Pages (from-to)1970-1972
Number of pages3
JournalFASEB Journal
Volume16
Issue number14
Publication statusPublished - 2002

Fingerprint

NADP
Amyloid
Availability
Nitric Oxide Synthase Type I
Aptitude
Cell-Free System
Nitric Oxide Synthase Type III
Fluorescence Spectrometry
Fluorescence spectroscopy
Nitric Oxide Synthase Type II
amyloid beta-protein (25-35)
Glioma
Nuclear magnetic resonance spectroscopy
Oxidation-Reduction
Rats
Assays
Alzheimer Disease
Protein Isoforms
Magnetic Resonance Spectroscopy
Cells

Cite this

Venturini, G., Colasanti, M., Persichini, T., Fioravanti, E., Ascenzi, P., Palomba, L., ... Musci, G. (2002). Beta-amyloid inhibits NOS activity by subtracting NADPH availability. FASEB Journal, 16(14), 1970-1972.

Beta-amyloid inhibits NOS activity by subtracting NADPH availability. / Venturini, Giorgio; Colasanti, Marco; Persichini, Tiziana; Fioravanti, Emanuela; Ascenzi, Paolo; Palomba, Letizia; Cantoni, Orazio; Musci, Giovanni.

In: FASEB Journal, Vol. 16, No. 14, 2002, p. 1970-1972.

Research output: Contribution to journalArticle

Venturini, G, Colasanti, M, Persichini, T, Fioravanti, E, Ascenzi, P, Palomba, L, Cantoni, O & Musci, G 2002, 'Beta-amyloid inhibits NOS activity by subtracting NADPH availability.', FASEB Journal, vol. 16, no. 14, pp. 1970-1972.
Venturini G, Colasanti M, Persichini T, Fioravanti E, Ascenzi P, Palomba L et al. Beta-amyloid inhibits NOS activity by subtracting NADPH availability. FASEB Journal. 2002;16(14):1970-1972.
Venturini, Giorgio ; Colasanti, Marco ; Persichini, Tiziana ; Fioravanti, Emanuela ; Ascenzi, Paolo ; Palomba, Letizia ; Cantoni, Orazio ; Musci, Giovanni. / Beta-amyloid inhibits NOS activity by subtracting NADPH availability. In: FASEB Journal. 2002 ; Vol. 16, No. 14. pp. 1970-1972.
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