**4. Proteomic biomarkers of dementia**

During the characterization of the human brain amyloidal plaque from dementia patients, deamidation of aggregated proteins was noted. The extensively deamidated proteins were S100A9, ferritine, and hemoglobin. In addition to these proteins, proteins such as S100 calciumbinding protein B (S100-B), α2(IV), and α2(I) chains of human collagen, extracellular matrix such as laminin subunit β-2 was found to be deamidated. Further, these authors found deamidated adhesion junction plaque protein dystonin (isoform 3) and many others [34]. Proteins coronin-1A and syntaxin-binding protein 2, which were previously been implicated in the neurodegeneration of the hippocampus, were also found deamidated detected in brain tissue sample of demented patients. Deamidation introduces negative charge at sites of modification. This change in charge promotes protein aggregation and remains as a patho‐ logical hallmark of age-related disorders and neurodegenerative diseases. Thus, the multiple deamidated residues of S100A9 (**Figure 3C** and **D**) could introduce a negative charge to form pathological aggregates in the brain. Hence, an accurate identification of DMPs and modifi‐ cation sites is important to understand the role of DPMs in human diseases. A comprehensive investigation including method development for accurate identification of DPMs has been

performed for biomedical research [24, 26, 27, 30, 31, 34, 35].

/K+

yellow color and deamidation sites in magenta and blue. EF hands alone are shown in (D).


shown in blue and cyan color, domain P is shown in yellow, while domain N is shown in green. The deamidation sites (N210, D220, and N715) are shown in red color (adapted with permission from Adav et al. [24]). The deamidation sites of protein S100A9 (RCSB Protein Data Bank accession code: 1XK4) are shown in (C). EF hands have been displayed in

Loss of synapses is one of the most significant contributors to the cognitive impairment manifest in VaD and other neurodegenerative diseases. Following synapses loss, the remain‐ ing synapses alter their shape. According to recent literature [26], synaptic immunoglobulins were perturbed proteins in VaD temporal cortices, while SNAP25 was substantially upregulated. Further, deamidation studies revealed that the protein synapsin 1 displayed

**Figure 3.** Structural models of Na+

118 Update on Dementia

Mass spectrometry-based proteomics has been widely used for biomarkers of dementia and AD [64]. Proteins such as Aβ40, Aβ42, and their ratio Aβ42:Aβ40 have been linked with AD and dementia [65]. Proteins such as Apolipoprotein E (ApoE) level in serum of AD patients [66], interleukins (IL-1α, IL-6) [67], clusterin [68], and α-1-antichymotrypsin (α-ACT) [69] have been considered as biomarkers of AD. Other than blood, cerebrospinal fluid (CSF), which directly interacts with the space of the brain and reflects biochemical changes that occurs in the brain, has also been used for the biomarker of dementia and AD. Proteins such as phospholipases A2, visinin-like 1, microtubule-associated protein *tau*, neurofilament proteins, and many more that were reviewed by Liu et al. [70] have been considered as CSF biomarkers of AD. The increase in the generation of 2,4-dihydroxybutyrate with the progression of MCI was noted and considered as a promising biomarker of AD [51, 71]. Using human CSF samples and adopting targeted approach, Shi et al [72] proposed a panel consisting of five peptides/ proteins such as osteopontin (SPP1), prolow-density lipoprotein receptor-related protein 1 (LRP1), macrophage colony-stimulating factor 1 receptor (CSF1R), ephrin type-A receptor 4 (EPHA4), and metalloproteinase inhibitor 1 (TIMP1) are biomarkers of PD or AD. Alzheimer's Disease Neuroimaging Initiative (ADNI) biomarker core progress has been reviewed by Kang et al. [73].
