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Novel tau fragments...
Novel tau fragments in cerebrospinal fluid : relation to tangle pathology and cognitive decline in Alzheimer’s disease
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- Cicognola, Claudia (author)
- Gothenburg University,Göteborgs universitet,University of Gothenburg,University of Pennsylvania,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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- Brinkmalm, Gunnar (author)
- Gothenburg University,Göteborgs universitet,University of Gothenburg,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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- Wahlgren, Jessica, 1975 (author)
- Gothenburg University,Göteborgs universitet,University of Gothenburg,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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- Portelius, Erik (author)
- University of Gothenburg,Sahlgrenska University Hospital
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- Gobom, Johan (author)
- Gothenburg University,Göteborgs universitet,University of Gothenburg,Sahlgrenska University Hospital,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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- Cullen, Nicholas C. (author)
- University of Pennsylvania
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- Hansson, Oskar (author)
- Lund University,Lunds universitet,Klinisk minnesforskning,Forskargrupper vid Lunds universitet,Clinical Memory Research,Lund University Research Groups,Skåne University Hospital
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- Parnetti, Lucilla (author)
- Ospedale Santa Maria della Misericordia,University of Perugia
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- Constantinescu, Radu (author)
- University of Gothenburg
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- Wildsmith, Kristin (author)
- Genentech, Inc
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- Chen, Hsu Hsin (author)
- Genentech, Inc
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- Beach, Thomas G. (author)
- Banner Sun Health Research Institute
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- Lashley, Tammaryn (author)
- University College London
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- Zetterberg, Henrik (author)
- Gothenburg University,Göteborgs universitet,University of Gothenburg,Sahlgrenska University Hospital,University College London,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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- Blennow, Kaj (author)
- Gothenburg University,Göteborgs universitet,University of Gothenburg,Sahlgrenska University Hospital,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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- Höglund, Kina, 1976 (author)
- Gothenburg University,Göteborgs universitet,Karolinska Institute,University of Gothenburg,Sahlgrenska University Hospital,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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(creator_code:org_t)
- 2018-12-13
- 2019
- English.
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In: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 137:2, s. 279-296
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Abstract
Subject headings
Close
- Tau is an axonal microtubule-binding protein. Tau pathology in brain and increased tau concentration in the cerebrospinal fluid (CSF) are hallmarks of Alzheimer’s disease (AD). Most of tau in CSF is present as fragments. We immunoprecipitated tau from CSF and identified several endogenous peptides ending at amino acid (aa) 123 or 224 using high-resolution mass spectrometry. We raised neo-epitope-specific antibodies against tau fragments specifically ending at aa 123 and 224, respectively. With these antibodies, we performed immunohistochemistry on brain tissue and designed immunoassays measuring N-123, N-224, and x-224 tau. Immunoassays were applied to soluble brain fractions from pathologically confirmed subjects (81 AD patients, 33 controls), CSF from three cross-sectional and two longitudinal cohorts (a total of 133 AD, 38 MCI, 20 MCI-AD, 31 PSP, 15 CBS patients, and 91 controls), and neuronally- and peripherally-derived extracellular vesicles (NDEVs and PDEVs, respectively) in serum from four AD patients and four controls. Anti-tau 224 antibody stained neurofibrillary tangles and neuropil threads, while anti-tau 123 only showed weak cytoplasmic staining in AD. N-224 tau was lower in the AD soluble brain fraction compared to controls, while N-123 tau showed similar levels. N-224 tau was higher in AD compared to controls in all CSF cohorts (p < 0.001), but not N-123 tau. Decrease in cognitive performance and conversion from MCI to AD were associated with increased baseline CSF levels of N-224 tau (p < 0.0001). N-224 tau concentrations in PSP and CBS were significantly lower than in AD (p < 0.0001) and did not correlate to t-tau and p-tau. In a longitudinal cohort, CSF N-224 tau levels were stable over 6 months, with no significant effect of treatment with AChE inhibitors. N-224 tau was present in NDEVs, while N-123 tau showed comparable concentrations in both vesicle types. We suggest that N-123 tau is produced both in CNS and PNS and represents a general marker of tau metabolism, while N-224 tau is neuron-specific, present in the tangles, secreted in CSF, and upregulated in AD, suggesting a link between tau cleavage and propagation, tangle pathology, and cognitive decline.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Keyword
- Alzheimer’s disease
- Cerebrospinal fluid
- Immunohistochemistry
- Mass spectrometry
- Tau fragments
Publication and Content Type
- art (subject category)
- ref (subject category)
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Cicognola, Claud ...
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Brinkmalm, Gunna ...
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Wahlgren, Jessic ...
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Portelius, Erik
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Gobom, Johan
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Cullen, Nicholas ...
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Hansson, Oskar
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Parnetti, Lucill ...
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Constantinescu, ...
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Wildsmith, Krist ...
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Chen, Hsu Hsin
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Beach, Thomas G.
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Lashley, Tammary ...
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Zetterberg, Henr ...
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Blennow, Kaj
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Höglund, Kina, 1 ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Neurology
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Neurosciences
- Articles in the publication
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Acta Neuropathol ...
- By the university
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Lund University
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Karolinska Institutet
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University of Gothenburg