CSF proteomic discovery in persons with autosomal dominant Alzheimer's disease mutations

Abstract

The identification of protein differences in the cerebrospinal fluid (CSF) from individuals with incipient or early Alzheimer's disease (AD) may assist in both early diagnosis and the identification of novel therapeutic targets. Proteomic CSF studies in individuals carrying fully-penetrant autosomal dominant Alzheimer's Disease (ADAD) mutations provide the opportunity to identify early changes in persons in whom the future diagnosis of AD is certain. We performed clinical evaluations and obtained CSF from 43 individuals either symptomatic from ADAD mutations (n=18, CDR = 0.5 in 12) or at 50% risk for inheriting such mutations (n=25). Among the 31 mutation carriers (MCs), 26 had PSEN1 mutations and 5 had the V717I APP mutation. CSF was depleted of 14 high abundance proteins, digested with trypsin and the resulting peptides were analyzed by liquid chromatography-mass spectrometry (LCMS). Peptides were identified by shotgun sequencing and clustered into their parent proteins. Peptide peaks were aligned across all samples and peak intensities were measured and compared to determine relative peptide and protein abundance in each sample. Protein levels were separately compared between mutation non-carriers (NCs, n=12) versus all ADAD MCs and versus all presymptomatic MCs (n=13). 1,018 proteins were differentially quantified and identified. Using an intensity difference of 2-fold, and p- and q-values (false discovery rate) of 0.05 as cut-offs for significance, we identified 12 proteins that were differentially expressed between ADAD MCs and NCs. Thrombospondin-2, LRP 11, NPDC1, Complement factor H, Fibronectin, Complement component C7, Transcription factor SOX-13, Clusterin, Fatty acid-binding protein, and APP were increased and Folate receptor alpha and CRP were decreased in ADAD MCs. An additional 22 proteins were differentially expressed with significant but smaller differences. When only presymptomatic ADAD mutation carriers were included, no protein was expressed with a 2-fold difference and only one (LRP1) was elevated with p- and q-values 0.05. Proteins associated with the cell matrix, inflammation, vascular remodeling, and Abeta transport are elevated in ADAD MCs Only LRP1 was elevated in presymptomatic MCs, suggesting that its overexpression represents an adaptive response to Abeta overproduction.