Abstract
Alzheimer disease (AD) is the most prevalent neurodegenerative disease in the elderly, characterized by accumulation in the brain of misfolded proteins, inflammation, and oxidative damage leading to neuronal cell death. By considering the viewpoint that AD onset and worsening may be influenced by environmental factors causing infection, oxidative stress, and inflammatory reaction, we investigated the changes of the salivary proteome in a population of patients with respect to that in healthy controls (HCs). Indeed, the possible use of saliva as a diagnostic tool has been explored in several oral and systemic diseases. Moreover, the oral cavity continuously established adaptative and protective processes toward exogenous stimuli. In the present study, qualitative/quantitative variations of 56 salivary proteoforms, including post-translationally modified derivatives, have been analyzed by RP-HPLC-ESI-IT-MS and MS/MS analyses, and immunological methods were applied to validate MS results. The salivary protein profile of AD patients was characterized by significantly higher levels of some multifaceted proteins and peptides that were either specific to the oral cavity or also expressed in other body districts: (i) peptides involved in the homeostasis of the oral cavity; (ii) proteins acting as ROS/RNS scavengers and with a neuroprotective role, such as S100A8, S100A9, and their glutathionylated and nitrosylated proteoforms; cystatin B and glutathionylated and dimeric derivatives; (iii) proteins with antimicrobial activity, such as α-defensins, cystatins A and B, histatin 1, statherin, and thymosin β4, this last with a neuroprotective role at the level of microglia. These results suggested that, in response to injured conditions, Alzheimer patients established defensive mechanisms detectable at the oral level. Data are available via ProteomeXchange with identifier PXD021538.
Highlights
Alzheimer disease (AD) is a neurodegenerative disease, and it is the leading cause of progressive dementia in the elderly population (McKhann et al, 2011)
As a mirror of oral and systemic health, provides valuable information because it contains proteins secreted by the salivary glands (Messana et al, 2008) and proteins derived from the gingival crevicular fluid (Ghallab, 2018; Iavarone et al, 2020) from oral microflora (Grassl et al, 2016) and plasmatic proteins transported from blood to saliva by both intracellular and extracellular pathways
Among the proteins not secreted by the salivary glands, this study highlighted a higher level of proteins with a multifaceted nature, namely, S100A8 and S100A9, α-defensins 1–4, thymosin β4 (Tβ4), and cystatins A and B
Summary
Alzheimer disease (AD) is a neurodegenerative disease, and it is the leading cause of progressive dementia in the elderly population (McKhann et al, 2011). A small portion of AD cases has genetic causes while the majority (95%) are sporadic and occur in people over 65 years (Scheltens et al, 2016). The sporadic form of AD is more complex since it likely results from a combination of genetic and environmental factors. It has been recently hypothesized that prolonged exposure to several heavy metals (aluminium, arsenic, cadmium, lead, mercury), particulate air, some pesticides, metal-containing nanoparticles and the alteration of oral and gut microbiota may increase the risk of AD (Rahman et al, 2020). The oral and gut microbiota-induced neuronal inflammation is a gradually emerging idea promoted by the discovery that brain infections, involving bacteria or viruses as external risk factors, can trigger Aβ deposition and AD development (Mawanda and Wallace, 2013; Hill et al, 2014)
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