Abstract
Neurodegenerative diseases are characterized by the presence of abnormal aggregates of proteins in brain tissue. Among them, the presence of aggregates of phosphorylated Tau protein (p-Tau) is the hallmark of Alzheimer’s disease (AD) and other major neurodegenerative disorders such as corticobasal degeneration and frontotemporal dementia among others. Although Tau protein has previously been assumed to be exclusive to the central nervous system, it is also found in peripheral tissues. The purpose of this study was to determine whether there is a differential Tau expression in oral mucosa cells according to cognitive impairment. Eighty-one subjects were enrolled in the study and classified per Mini-Mental State Examination test score into control, mild cognitive impairment (MCI), and severe cognitive impairment (SCI) groups. Immunocytochemistry and immunofluorescence revealed the presence of Tau and four p-Tau forms in the cytoplasm and nucleus of oral mucosa cells. More positivity was present in subjects with cognitive impairment than in control subjects, both in the nucleus and cytoplasm, in a speckle pattern. The mRNA expression of Tau by quantitative real-time polymerase chain reaction was higher in SCI as compared with the control group (P < 0.01). A significantly higher percentage of immunopositive cells in the SCI group was found via flow cytometry in comparison to controls and the MCI group (P < 0.01). These findings demonstrate the higher presence of p-Tau and Tau transcript in the oral mucosa of cognitively impaired subjects when compared with healthy subjects. The feasibility of p-Tau quantification by flow cytometry supports the prospective analysis of oral mucosa as a support tool for screening of proteinopathies in cognitively impaired patients.
Highlights
Dementia, or major neurocognitive disorder, is characterized by the deterioration of memory and intellect, alterations of behavior, and loss of the ability to perform everyday activities
Since it is widely demonstrated that Tau pathology is more significantly associated with cognitive deficit than amyloidopathy, the development of the positron emission tomography (PET) tracer flortaucipir, targeting tau aggregates, represents a promising tool for the early detection of tauopathies [29]. Both image and immunoassay procedures confirm Alzheimer’s disease (AD) diagnosis, but their high cost and invasive nature imply an obstacle to population studies and to public health systems. In light of these antecedents, the purpose of this study was to determine whether there is a differential Tau expression in oral mucosa cells according to cognitive impairment, as well as the development of a novel method based on flow cytometry to compare p-Tau presence among healthy and cognitively impaired individuals
A total of 81 subjects were enrolled in the study, 71% were from central Mexico, where the population is the result of a mix of Hispanic and indigenous native (Mexican mestizo) populations, while 29% were living in Tampa, FL, USA, most of whom were Caucasian participants
Summary
Major neurocognitive disorder, is characterized by the deterioration of memory and intellect, alterations of behavior, and loss of the ability to perform everyday activities. Altered protein synthesis has been mainly attributed to p-Tau interaction with ribosomes [8], to the triggering of the unfolded protein response pathway [9] and by its effect in the nucleus, where DNA fragmentation, loss of heterochromatin, activation of cell cycle, and alterations in the nuclear architecture [10] have been demonstrated. All these neurotoxic effects of p-Tau result in synaptic loss of vulnerable neurons from selected brain regions and may underlie the close association between Tau aggregation and cognitive deficit [11]. The gradual synaptic loss progresses to cell death due to alterations in proteostasis caused by the building up and inclusion of Tau aggregates, which mainly affects protein clearance through the ubiquitin proteasome system and autophagy [15]
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