Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer's disease

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Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer's disease

Visser, P. J. (författare): Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands; Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden,Old Age Psychiatry, University Hospital Lausanne, Lausanne, Switzerland; Department of Geriatric Psychiatry, University Hospital of Psychiatry and University of Zürich, Zürich, Switzerland

Reus, L. M. (författare): Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

Gobom, Johan (författare): Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry,Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden

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Jansen, I. (författare): Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, Amsterdam, the Netherlands

Dicks, E. (författare): Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

Van der Lee, S. J. (författare): Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Section Genomics of Neurodegenerative Diseases and Aging, Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands,Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; AC Immune SA, Lausanne, Switzerland

Tsolaki, M. (författare): 1St Department of Neurology, AHEPA University Hospital, Thessaloniki, Makedonia, Greece

Verhey, F. R. J. (författare): Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands

Popp, J. (författare)

Martinez-Lage, P. (författare): Fundación CITA-Alzhéimer Fundazioa, San Sebastian, Spain

Vandenberghe, R. (författare): Neurology Service, University Hospitals Leuven, Leuven, Belgium; Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium

Lleo, A. (författare): IIB-Sant Pau, Hospital de La Santa Creu I Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain

Molinuevo, J. L. (författare): Barcelonaβeta Brain Research Center (BBRC), Barcelona, Spain; Alzheimer's Disease Unit and Other Cognitive Disorders Unit, Hospital Clinic de Barcelona, Barcelona, Spain

Engelborghs, S. (författare): Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Department of Neurology, UZ Brussel and Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium

Freund-Levi, Yvonne, 1956- (författare): Örebro universitet,Institutionen för medicinska vetenskaper,Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry at School of Medical Sciences, Örebro University, Örebro, Sweden

Froelich, L. (författare): Department of Geriatric Psychiatry, Zentralinstitut Für Seelische Gesundheit, University of Heidelberg, Mannheim, Germany

Sleegers, K. (författare): Complex Genetics Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

Dobricic, V. (författare): Lübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics and Cardiogenetics, University of Lübeck, Lübeck, Germany

Lovestone, S. (författare): Jansen UK, High Wycombe, UK

Streffer, J. (författare)

Vos, S. J. B. (författare): Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands

Bos, I. (författare): Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands

Smit, A. B. (författare): Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands

Blennow, Kaj, 1958 (författare): Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry,Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden

Scheltens, P. (författare): Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

Teunissen, C. E. (författare): Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam University Medical Centers (AUMC), Amsterdam Neuroscience, Netherlands

Bertram, L. (författare): Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium; Center for Lifespan Changes in Brain and Cognition, Dept. of Psychology, University of Oslo, Oslo, Norway

Zetterberg, Henrik, 1973 (författare): Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry,Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; Dementia Research Institute at UCL, London, UK

Tijms, B. M. (författare): Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

Adni,, Adni, (författare)

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2022-03-28
2022
Engelska.
Ingår i: Molecular Neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 17:1

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Tidskriftsartikel (refereegranskat)

Abstract Ämnesord

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Background Increased total tau (t-tau) in cerebrospinal fluid (CSF) is a key characteristic of Alzheimer's disease (AD) and is considered to result from neurodegeneration. T-tau levels, however, can be increased in very early disease stages, when neurodegeneration is limited, and can be normal in advanced disease stages. This suggests that t-tau levels may be driven by other mechanisms as well. Because tau pathophysiology is emerging as treatment target for AD, we aimed to clarify molecular processes associated with CSF t-tau levels. Methods We performed a proteomic, genomic, and imaging study in 1380 individuals with AD, in the preclinical, prodromal, and mild dementia stage, and 380 controls from the Alzheimer's Disease Neuroimaging Initiative and EMIF-AD Multimodality Biomarker Discovery study. Results We found that, relative to controls, AD individuals with increased t-tau had increased CSF concentrations of over 400 proteins enriched for neuronal plasticity processes. In contrast, AD individuals with normal t-tau had decreased levels of these plasticity proteins and showed increased concentrations of proteins indicative of blood-brain barrier and blood-CSF barrier dysfunction, relative to controls. The distinct proteomic profiles were already present in the preclinical AD stage and persisted in prodromal and dementia stages implying that they reflect disease traits rather than disease states. Dysregulated plasticity proteins were associated with SUZ12 and REST signaling, suggesting aberrant gene repression. GWAS analyses contrasting AD individuals with and without increased t-tau highlighted several genes involved in the regulation of gene expression. Targeted analyses of SNP rs9877502 in GMNC, associated with t-tau levels previously, correlated in individuals with AD with CSF concentrations of 591 plasticity associated proteins. The number of APOE-e4 alleles, however, was not associated with the concentration of plasticity related proteins. Conclusions CSF t-tau levels in AD are associated with altered levels of proteins involved in neuronal plasticity and blood-brain and blood-CSF barrier dysfunction. Future trials may need to stratify on CSF t-tau status, as AD individuals with increased t-tau and normal t-tau are likely to respond differently to treatment, given their opposite CSF proteomic profiles.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)

Nyckelord

Alzheimer's disease
Molecular mechanisms
Biomarker discovery
Heterogeneity
Neuronal plasticity
Cerebrospinal fluid proteomics
amyloid precursor protein
cell-cycle progression
blood-brain-barrier
biomarkers
enrichment
adult
rest
wide
transcription
generation
Neurosciences & Neurology
Alzheimer's disease

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MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Medicinska och f ...; och Neurovetenskaper

Artiklar i publikationen: Molecular Neurod ...

Av lärosätet: Göteborgs universitet; Örebro universitet; Karolinska Institutet

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