Brain Proteomics

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patient groups and found that the protein composition of the plaques was sig-

nificantly different. In addition, findings regarding the abundance of synaptic

proteins in rpAD plaques pointed to the importance of synaptic dysfunction

in plaque development. [39]. Furthermore, the applicability of various strate-

gies such as MACS, FACS, BONCAT and FUNCAT to proteomic studies will

accelerate the creation of cell type-specific proteome catalogs [33, 46].

Consistent results of Aβ42, t-tau and p-tau measurements in CSF from

various studies also indicate that they may be important in clinical prac-

tice for the early diagnosis of AD. A comprehensive meta-analysis evaluating

these findings showed that lower Aβ42 and higher t-tau and p-tau levels in

CSF can discriminate between disease-related mild cognitive impairment and

stable mild cognitive impairment [47]. Another evaluation revealed that 48

proteins associated with steroid esterification and protein activation cascade

processes were upregulated in CSF [10]. A recent deep proteomic analysis

of brain and CSF samples allowed the identification of approximately 3500

proteins in 40 CSF samples and close to 12000 proteins in 27 brain tissues.

Interestingly, 70% of the CSF proteome was shared with proteins in brain tis-

sue, and some of the proteins were involved in synaptic, vascular, myelination,

inflammatory and metabolic pathways [48]. The fact that cellular processes

are reflected in the CSF, which is in direct contact with the brain, makes it a

valuable resource in this respect. Sathe et al. also identified 2327 proteins, 139

of which showed significant changes in AD compared to control. Although a

small number of CSF samples were used in the study, they were able to confirm

that neuronal pentraxin 2 (NPTX2) and VGF nerve growth factor inducible

(VGF) proteins decreased and 14-3-3 protein gamma (YWHAG) and pyru-

vate kinase (PKM) proteins increased with the targeted PRM method [49].

According to a review of CSF proteomic studies, nearly half of previously re-

ported protein alterations showed consistent results. However, the fact that

the study results are not directly comparable may have affected the num-

ber of common proteins. The same review showed enrichment of haemosta-

sis, lipoprotein, and extracellular matrix for pathway outcomes of AD-related

proteins. Additionally, while there are very few studies evaluating the im-

pact of patients’ demographic characteristics on the CSF proteome, further

research in this direction may provide clues to explain the heterogeneity in AD

[50].

Although they have not yet been reflected in the clinic other than plaque

and tau pathology, candidate protein markers that can support the diagnosis

in various body fluids are recommended. One research group has performed

comprehensive proteome characterization in serum as well as human cerebral

cortex and CSF. They also used TOMAHAQ-targeted MS analysis for valida-

tion in their study, which allowed direct profiling of human serum and CSF

without depleting proteins for biomarker discovery. In the study, nearly 5000

serum proteins and nearly 6000 CSF proteins were identified, especially the

altered proteins that were related to mitochondrial function [51–53].