title: Decreased levels of guanosine 3', 5'-monophosphate (cGMP) in cerebrospinal fluid (CSF) are associated with cognitive decline and amyloid pathology in Alzheimer's disease.
abstract: OBJECTIVE
  Levels of the cyclic nucleotides guanosine 3', 5'-monophosphate (cGMP) or adenosine 3', 5'-monophosphate (cAMP) that play important roles in memory processes are not characterized in Alzheimer's disease (AD). The aim of this study was to analyse the levels of these nucleotides in cerebrospinal fluid (CSF) samples from patients diagnosed with clinical and prodromal stages of AD and study the expression level of the enzymes that hydrolyzed them [phosphodiesterases (PDEs)] in the brain of AD patients vs.
  
  
  METHODS
  For cGMP and cAMP CSF analysis, the cohort (n = 79) included cognitively normal participants (subjective cognitive impairment), individuals with stable mild cognitive impairment or AD converters (sMCI and cMCI), and mild AD patients. A high throughput liquid chromatography-tandem mass spectrometry method was used. Interactions between CSF cGMP or cAMP with mini-mental state examination (MMSE) score, CSF Aβ(1-42) and CSF p-tau were analysed. For PDE4, 5, 9 and 10 expression analysis, brains of AD patients vs. controls (n = 7 and n = 8) were used.
  
  
  RESULTS
  cGMP, and not cAMP levels, were significantly lower in the CSF of patients diagnosed with mild AD when compared with nondemented controls. CSF levels of cGMP showed a significant association with MMSE-diagnosed clinical dementia and with CSF biomarker Aβ42 in AD patients. Significant increase in PDE5 expression was detected in temporal cortex of AD patients compared with that of age-matched healthy control subjects. No changes in the expression of others PDEs were detected.
  
  
  CONCLUSIONS
  These results support the potential involvement of cGMP in the pathological and clinical development of AD. The cGMP reduction in early stages of AD might participate in the aggravation of amyloid pathology and cognitive decline.
authors.affiliation: Small Molecule Discovery Platform, Molecular Therapeutics Program, University of Navarra, Pamplona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Ugarte
authors.affiliation: Neurobiology of Alzheimer's Disease, Neurosciences Division, Center for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Gil-Bea
authors.affiliation: Neurobiology of Alzheimer's Disease, Neurosciences Division, Center for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: García-Barroso
authors.affiliation: KI-Alzheimer's Disease Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Cedazo-Minguez
authors.affiliation: Department of Pharmacology, University of Navarra, Pamplona, Spain.
authors.forename: M Javier
authors.initials: MJ
authors.lastname: Ramírez
authors.affiliation: Department of Biochemistry and Molecular Biology, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Franco
authors.affiliation: Neurobiology of Alzheimer's Disease, Neurosciences Division, Center for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: García-Osta
authors.affiliation: Small Molecule Discovery Platform, Molecular Therapeutics Program, University of Navarra, Pamplona, Spain.
authors.forename: Julen
authors.initials: J
authors.lastname: Oyarzabal
authors.affiliation: Neurobiology of Alzheimer's Disease, Neurosciences Division, Center for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain.|Department of Anatomy, University of Navarra, Pamplona, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Cuadrado-Tejedor
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000201:enzymology / Q000473:pathology; D001921:Brain / Q000201:enzymology / Q000473:pathology; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid / Q000201:enzymology / Q000473:pathology; D000242:Cyclic AMP / Q000134:cerebrospinal fluid; D006152:Cyclic GMP / Q000134:cerebrospinal fluid*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D010727:Phosphoric Diester Hydrolases
chemical_list: D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP
keywords: cGMP; cerebrospinal fluid; memory function; phosphodiesterase