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Original Contributions |

Proteomic Changes in Cerebrospinal Fluid of Presymptomatic and Affected Persons Carrying Familial Alzheimer Disease Mutations

John M. Ringman, MD, MS; Howard Schulman, PhD; Chris Becker, PhD; Ted Jones, PhD; Yuchen Bai, PhD; Fred Immermann, MA, MStat; Gregory Cole, PhD; Sophie Sokolow, PhD; Karen Gylys, PhD; Daniel H. Geschwind, MD, PhD; Jeffrey L. Cummings, MD; Hong I. Wan, PhD
Arch Neurol. 2012;69(1):96-104. doi:10.1001/archneurol.2011.642.
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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 late-onset AD, including amyloid precursor protein, transferrin, α1β-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 (α-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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Figure 1. Network 1 (antigen presentation, cell-mediated immune response, and humoral immune response) generated by pathway analysis of the hot list. This network is displayed as nodes (genes or gene products) and edges. “Acts on” and “inhibits” edges may also include a binding event. Lines indicate biological relationships between nodes. Blue proteins are downregulated in individuals who are mutation carriers, and red proteins are upregulated. Uncolored proteins were not found to be different in our study but are linked by pathway analyses. Fx indicates function.

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Figure 2. Network 2 (metabolic disease, renal and urologic disease, and molecular transport) generated by pathway analysis of the hot list. This network is also displayed as nodes (genes or gene products) and edges. Fx indicates function. *Indicates that components mapped to multiple protein database entries of a single gene. For further explanation of the lines and symbols used, see Figure 1 and its legend.

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