期刊
ARCHIVES OF NEUROLOGY
卷 69, 期 1, 页码 96-104出版社
AMER MEDICAL ASSOC
DOI: 10.1001/archneurol.2011.642
关键词
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资金
- National Institute on Aging [PHS K08 AG-22228]
- California Department of Health Services [0435522]
- Alzheimer's Disease Research Center [P50 AG-16570]
- National Institutes of Health [5RC2NS069502]
- Easton Consortium for Alzheimer's Disease Drug Discovery and Biomarkers
- Pfizer Pharmaceuticals
- General Clinical Research Center [M01-RR00865]
- Sidell Kagan Foundation
- Shirley and Jack Goldberg Trust
- California Alzheimer's Disease Center [09-11408]
Objective: To identify cerebrospinal fluid (CSF) protein changes in persons who will develop familial Alzheimer disease (FAD) due to PSEN1 and APP mutations, using unbiased proteomics. Design: We compared proteomic profiles of CSF from individuals with FAD who were mutation carriers (MCs) and related noncarriers (NCs). Abundant proteins were depleted and samples were analyzed using liquid chromatography-electrospray ionization-mass spectrometry on a high-resolution time-of-flight instrument. Tryptic peptides were identified by tandem mass spectrometry. Proteins differing in concentration between the MCs and NCs were identified. Setting: A tertiary dementia referral center and a proteomic biomarker discovery laboratory. Participants: Fourteen FAD MCs (mean age, 34.2 years; 10 are asymptomatic, 12 have presenilin-1 [PSEN1] gene mutations, and 2 have amyloid precursor protein [APP] gene mutations) and 5 related NCs (mean age, 37.6 years). Results: Fifty-six proteins were identified, represented by multiple tryptic peptides showing significant differences between MCs and NCs (46 upregulated and 10 downregulated); 40 of these proteins differed when the analysis was restricted to asymptomatic individuals. Fourteen proteins have been reported in prior proteomic studies in lateonset AD, including amyloid precursor protein, transferrin, alpha(1)beta-glycoprotein, complement components, afamin precursor, spondin 1, plasminogen, hemopexin, and neuronal pentraxin receptor. Many other proteins were unique to our study, including calsyntenin 3, AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) 4 glutamate receptor, CD99 antigen, di-N-acetyl-chitobiase, and secreted phosphoprotein 1. Conclusions: We found much overlap in CSF protein changes between individuals with presymptomatic and symptomatic FAD and those with late-onset AD. Our results are consistent with inflammation and synaptic loss early in FAD and suggest new presymptomatic biomarkers of potential usefulness in drug development.
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