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P4‐545: DEVELOPMENT OF ALZHEIMER'S DISEASE BIOMARKER USING Aβ*56 SOLUBLE OLIGOMER IN HUMAN NASAL SECRETIONS
Author(s) -
Wang Sheng-Min,
Lim Hyun Kook
Publication year - 2019
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2019.08.092
Subject(s) - biomarker , dementia , receiver operating characteristic , medicine , pathogenesis , pathology , amyloid (mycology) , alzheimer's disease , disease , gastroenterology , oncology , chemistry , biochemistry
Background: There is a large gap between the growing awareness regarding the importance of microglia in the pathogenesis of neurodegenerative disorders like Alzheimer’s and Parkinson’s disease and the availability of microglia-related molecular biomarkers in practice. Heterogeneity due to comorbidities in human cohorts together with cost-intensive technologies is a major challenge in the search for novel CSF and blood-borne biomarkers. Transgenic mouse models, however, become increasingly appreciated for the interpretation of fluid biomarker changes due to low variability and well-defined pathomechanisms. Methods: We applied a labelfree LC-MS/MS approach in order to do shotgun proteomics in CSF samples from two well-characterized mouse models of betaamyloidosis and alpha-synucleinopathy, APPPS1 (Radde et al. 2006 EMBORep) and A30PaS (Neumann et al. 2002 J Clin Invest), respectively. CSF was collected from 3and 18-month-old APPPS1 and 3-, 11and 18-month-old A30PaS and aged-matched nontransgenic mice (n1⁄45–10 per group) to analyze ageand transgene-related protein changes. A subset of findings was subsequently validated by Western blot or sandwich-immunoassay. Results: Our proteome screen identified 1,168 and 1,261 unique proteins in the CSF of APPPS1 and A30PaS mice, respectively. Label free quantification revealed no protein changes in young mice. However, eight proteins were significantly increased in aged APPPS1 mice after FDR correction, whereas 220 proteins showed a difference (predominantly increase) in 18-month-old A30PaS compared to non-transgenic control mice. Strikingly, roughly half of the 24 top hits showing an ageand transgene-related increase in both mouse models (p<0.05) were linked to microglia. Moreover, eight of these proteins have recently been assigned to a specific disease-associated microglia (DAM) phenotype (KerenShaul et al. 2017 Cell). Among them TREM2, a previously identified CSF biomarker and key player during DAM transition from activation stage 1 to 2. Conclusions: The current mouse CSF proteome study reveals a novel panel of microglia-related analytes including soluble TREM2. Their robust age-related increase, observed in two mouse models of distinct neurodegenerative diseases, holds promise in the search for much awaited reliable biomarkers to track the complex immune response to CNS damage in humans.