d-serine levels in Alzheimer's disease: implications for novel biomarker development.
Alzheimer's disease (AD) is a severe neurodegenerative disorder still in search of effective methods of diagnosis. Altered levels of the NMDA receptor co-agonist, d-serine, have been associated with neurological disorders, including schizophrenia and epilepsy. However, whether d-serine levels are deregulated in AD remains elusive. Here, we first measured D-serine levels in post-mortem hippocampal and cortical samples from nondemented subjects (n=8) and AD patients (n=14). We next determined d-serine levels in experimental models of AD, including wild-type rats and mice that received intracerebroventricular injections of amyloid-β oligomers, and APP/PS1 transgenic mice. Finally, we assessed d-serine levels in the cerebrospinal fluid (CSF) of 21 patients with a diagnosis of probable AD, as compared with patients with normal pressure hydrocephalus (n=9), major depression (n=9) and healthy controls (n=10), and results were contrasted with CSF amyloid-β/tau AD biomarkers. d-serine levels were higher in the hippocampus and parietal cortex of AD patients than in control subjects. Levels of both d-serine and serine racemase, the enzyme responsible for d-serine production, were elevated in experimental models of AD. Significantly, d-serine levels were higher in the CSF of probable AD patients than in non-cognitively impaired subject groups. Combining d-serine levels to the amyloid/tau index remarkably increased the sensitivity and specificity of diagnosis of probable AD in our cohort. Our results show that increased brain and CSF d-serine levels are associated with AD. CSF d-serine levels discriminated between nondemented and AD patients in our cohort and might constitute a novel candidate biomarker for early AD diagnosis.
Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
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Madeira
Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
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Lourenco
Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
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Vargas-Lopes
Discipline of Geriatrics, University of São Paulo Medical School, Sao Paulo, Brazil.
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Suemoto
Institute of Psychiatry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
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Brandão
Institute of Psychiatry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
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0000000217797226
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Reis
Department of Pathology, University of São Paulo Medical School, Sao Paulo, Brazil.
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Leite
Institute of Psychiatry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
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Laks
Discipline of Geriatrics, University of São Paulo Medical School, Sao Paulo, Brazil.
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Jacob-Filho
Department of Pathology, University of São Paulo Medical School, Sao Paulo, Brazil.
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Pasqualucci
1] Department of Pathology, University of São Paulo Medical School, Sao Paulo, Brazil [2] Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.
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Grinberg
1] Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil [2] Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
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Ferreira
1] Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil [2] Institute of Psychiatry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
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Panizzutti
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000633:toxicity; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D015415:Biomarkers / Q000134:cerebrospinal fluid / Q000378:metabolism*; D016022:Case-Control Studies; D002540:Cerebral Cortex / Q000378:metabolism*; D003865:Major Depressive Disorder / Q000134:cerebrospinal fluid; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D006850:Hydrocephalus, Normal Pressure / Q000134:cerebrospinal fluid; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D051381:Rats; D012694:Serine
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; D012694:Serine