Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease
| Autor: | Mirsada Causevic, Christian Spenger, Hilkka Soininen, Sue Parkins, Magda Tsolaki, Susan M. Resnick, Malcolm Ward, Steven Lynham, Abdul Hye, Martin Broadstock, Paul T. Francis, Luigi Ferrucci, Yi Zhang, James Campbell, Angela Hodges, John Powell, Lars-Olof Wahlund, Gerome Breen, Patrizia Mecocci, Eric Westman, Bruno Vellas, Jill C. Richardson, Catherine Foy, Cathy Mitchelmore, Madhav Thambisetty, Petroula Proitsi, Declan G. Murphy, Simon J. Furney, Catherine Tunnard, Yun Zhou, Sally I. Sharp, Rufina Leung, Dean F. Wong, Andreas Güntert, Robert J. Williams, Alan C. Evans, Latha Velayudhan, David R. Howlett, Richard Killick, Anna Kinsey, Sebastian Muehlboeck, Simon Lovestone, Andrew Simmons, Darragh O'Brien, Katie Lunnon, Fahd Choudhry, Iwona Kłoszewska |
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| Rok vydání: | 2010 |
| Předmět: |
Genetically modified mouse
Male Proteomics Pathology medicine.medical_specialty Aging Genotype Gene Expression Mice Transgenic Polymorphism Single Nucleotide Severity of Illness Index Article Pathogenesis Mice Atrophy Arts and Humanities (miscellaneous) Alzheimer Disease medicine Animals Entorhinal Cortex Humans Longitudinal Studies Pathological Aged Amyloid beta-Peptides Clusterin biology Brain Entorhinal cortex medicine.disease Blood proteins eye diseases Psychiatry and Mental health Disease Models Animal biology.protein Disease Progression Female sense organs Alzheimer's disease Psychology Cognition Disorders Molecular Chaperones |
| Zdroj: | Karolinska Institutet |
| ISSN: | 1538-3636 |
| Popis: | CONTEXT: Blood-based analytes may be indicators of pathological processes in Alzheimer disease (AD). OBJECTIVE: To identify plasma proteins associated with AD pathology using a combined proteomic and neuroimaging approach. DESIGN: Discovery-phase proteomics to identify plasma proteins associated with correlates of AD pathology. Confirmation and validation using immunodetection in a replication set and an animal model. SETTING: A multicenter European study (AddNeuroMed) and the Baltimore Longitudinal Study of Aging. PARTICIPANTS: Patients with AD, subjects with mild cognitive impairment, and healthy controls with standardized clinical assessments and structural neuroimaging. MAIN OUTCOME MEASURES: Association of plasma proteins with brain atrophy, disease severity, and rate of clinical progression. Extension studies in humans and transgenic mice tested the association between plasma proteins and brain amyloid. RESULTS: Clusterin/apolipoprotein J was associated with atrophy of the entorhinal cortex, baseline disease severity, and rapid clinical progression in AD. Increased plasma concentration of clusterin was predictive of greater fibrillar amyloid-beta burden in the medial temporal lobe. Subjects with AD had increased clusterin messenger RNA in blood, but there was no effect of single-nucleotide polymorphisms in the gene encoding clusterin with gene or protein expression. APP/PS1 transgenic mice showed increased plasma clusterin, age-dependent increase in brain clusterin, as well as amyloid and clusterin colocalization in plaques. CONCLUSIONS: These results demonstrate an important role of clusterin in the pathogenesis of AD and suggest that alterations in amyloid chaperone proteins may be a biologically relevant peripheral signature of AD. |
| Databáze: | OpenAIRE |
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