Proteomic changes in cerebrospinal fluid of presymptomatic and affected persons carrying familial Alzheimer disease mutations.
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.


METHODS
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.


METHODS
A tertiary dementia referral center and a proteomic biomarker discovery laboratory.


METHODS
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, α(1)β-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.
Mary S. Easton Center for Alzheimer's Disease Research, 10911 Weyburn Ave, Ste 200, Los Angeles, CA 90095, USA. jringman@mednet.ucla.edu
John M
JM
Ringman
Howard
H
Schulman
Chris
C
Becker
Ted
T
Jones
Yuchen
Y
Bai
Fred
F
Immermann
Gregory
G
Cole
Sophie
S
Sokolow
Karen
K
Gylys
Daniel H
DH
Geschwind
Jeffrey L
JL
Cummings
Hong I
HI
Wan
D000328:Adult; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000175:diagnosis* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D002556:Cerebrospinal Fluid Proteins / Q000378:metabolism*; D002853:Chromatography, Liquid; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009154:Mutation; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D053764:Presenilin-1 / Q000235:genetics; D040901:Proteomics; D018709:Statistics, Nonparametric; D053719:Tandem Mass Spectrometry; D016875:tau Proteins / Q000134:cerebrospinal fluid
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002556:Cerebrospinal Fluid Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); D016875:tau Proteins