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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 57:M64-M70 (2002)
© 2002 The Gerontological Society of America

The {tau} Protein of Oral Epithelium Increases in Alzheimer's Disease

Hideyuki Hattoria, Masayuki Matsumotoa, Kunimitu Iwaia, Hiroshi Tsuchiyaa, Eiji Miyauchia, Mikihiro Takasakia, Kouzin Kaminoa, Junichi Munehiraa, Yasuhiro Kimuraa, Kenichi Kawanishia, Tomoko Hoshinoa, Hiroshi Muraia, Hajime Ogataa, Hidemichi Maruyamaa and Hiroshi Yoshidab

a Department of Geriatric Medicine, Kanazawa Medical University, Ishikawa, Japan
b Diagnostic Department of Research and Development Center, Nissho Corporation, Shiga, Japan

Hideyuki Hattori, Department of Geriatric Medicine, Kanazawa Medical University, Daigaku 1-1, Uchinada-Machi, Kahoku-Gun, Ishikawa 920-0293, Japan E-mail: hideyuki{at}kanazawa-med.ac.jp.

Decision Editor: John E. Morley, MB, BCh


   Abstract
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 Abstract
Methods
 Results
 Discussion
 References
 
Background. Alzheimer's disease (AD) is an important problem that should be solved in the 21st century. Prior to treatment, a simple and easy diagnostic method using biological markers should be available. As a method to attain this goal, we detected and determined {tau} protein in oral mucosal epithelium.

Methods. Oral epithelium was exfoliated from 34 patients with AD or 29 patients with vascular dementia, and 33 young and 34 age-matched controls. Western blot was performed for determining the molecular weight of oral {tau} protein. The {tau} protein level was determined with an enzyme-linked immunosorbent assay (ELISA) kit for cerebrospinal fluid (CSF). CSF {tau} was also measured and compared with oral {tau}.

Results. Western blot analysis using an anti–non-phosphorylated {tau}-protein antibody showed two bands, one at 65 Kd and the other at 110 Kd. The {tau}-protein level in oral epithelia showed a significant positive correlation with those in the CSF (p < .05). The patients with AD had significantly higher levels of {tau} protein than the patients with vascular dementia and the controls (p < .01). AD patients with a younger age at onset of the study showed a higher level of the {tau} protein than the patients with later age at onset (p < .05).

Conclusions. Like other nonneural tissues, oral epithelium contains small {tau} and big {tau}. The {tau} protein in oral epithelium reflects the pathological changes, as does the CSF {tau}. Individuals who develop AD may have had high levels of the {tau} protein in oral mucosal epithelium since early childhood. The {tau}-protein level in oral epithelia could be helpful in diagnosing AD.

THE definitive diagnosis of Alzheimer's disease (AD) is made by postmortem examination of the brain. However, antemortem diagnosis of the disease is desired because of subsequent treatment considerations. In recent years, studies at the gene level have confirmed the implication of apolipoprotein E (1) and a mutation of presenilin in AD (2). On the other hand, pathological changes, such as oxidation damage (3)(4) and accumulation of the Aß protein (5)(6) in nonneural tissue, have been noted. Of interest, the immunoreactivity of the {tau} protein was increased in culturing fibroblasts from the skin (7).

With the progress of studies of such pathological changes in nonneural tissue in AD, the diagnostic applicability of biological markers has been expanded. In particular, the {tau} protein and Aß protein, which form senile plaques and neurofibrillary tangles as main pathological changes in brain tissue, have been regarded as very promising biological markers. Specifically, studies of {tau} protein in the cerebrospinal fluid (CSF) have shown that {tau}-protein levels in the CSF are elevated in AD (8)(9)(10).

Brain biopsy is clinically limited, and a noninvasive approach is desirable for the diagnosis of AD. Therefore, it will be clinically very useful if pathological changes reflecting AD pathology can be obtained noninvasively from nonneural tissue. In contrast to skin biopsy for fibroblast study, oral epithelium is composed of a single type of stratified squamous epithelium cell. Using this epithelium, we established a method for the determination of epithelial {tau} protein and tested its applicability to the diagnosis of AD.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Determination of {tau} Protein in Oral Epithelium
The study population consisted of 34 patients with AD and 29 patients with vascular dementia (VD), all of whom were diagnosed in the Department of Geriatric Medicine, Kanazawa Medical University, Japan. Thirty-four age-matched controls aged 65 years or older and 33 young controls aged less than 65 years old were also obtained. None of the age-matched controls showed neurological symptoms, signs, or dementia. They were ascertained to have no hematological or diagnostic imaging abnormalities. In addition, lumbar puncture was performed on several subjects for differential diagnosis as described later. Informed consent from all the subjects was obtained after full explanation of the aim and schedule of the study. All patients fit the diagnosis of probable AD on the basis of the criteria of the National Institute of Neurological and Communicative Disorders–Alzheimer's Disease and Related Disorders Association (11). The criteria of the National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherche et L'Enseignement en Neurosciences (12) were used for the diagnosis of VD. Table 1 summarizes the age, gender, and Mini-Mental State Examination (MMSE) scores for all subjects and the functional assessment staging score for the patients with AD.


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  		Table 1. Age, Sex, and MMSE and FAST Scores of the Subject Groups

 
Collection of oral mucosal epithelium.-- The subjects rinsed their mouths by repeated gargling with a 0.1% popidone iodine solution. After confirming that the mouth was free from food debris and inflammatory lesions, the examiner scraped bilateral buccal mucous membranes several times with a blunt spatula. This procedure allowed the exfoliation of epithelial cell without pain.

Normal bacterial flora adherent to the epithelium were first removed. The epithelium was pasteurized according to the procedure of Neugebauer and colleagues (13). At first, the epithelium taken on the spatula was suspended in 5 ml of Dalbecco's Modified Eagle Medium (Lifetechnologies, Rockville, MD) containing a 5% antibiotic antimycotic solution (Lifetechnologies, Rockville, MD). The suspension was incubated for 3 hours at 4°C and then centrifuged at 1500 rpm for 10 minutes. The pellet was shaken for 30 minutes at 4°C after the addition of 5 ml of 2% popidone iodine solution. After centrifugation at 1500 rpm for 10 minutes, the pellet was washed twice with 8 ml of 10 mmol/l phosphate buffer (pH 7.4) and then centrifuged at 1500 rpm for 10 minutes. The resulting pellet was sonicated for 5 seconds (Sonifier 250, Branson, Danbury, CT) after the addition of 400 µl of lysate buffer (2% sodium dodecyl sulfate [SDS] + 35 mmol/l Tris-HCl), and was boiled at 90°C for 5 minutes according to Ingelson and colleagues' method (14). Using this lysate, Western blot analysis, enzyme-linked immunosorbent assay (ELISA), and protein determination were performed.

Western blot.-- To determine the molecular weight of {tau} protein present in oral mucosal epithelium, we performed Western blot analysis of specimens from 2 patients with Alzheimer-type dementia and 2 age-matched controls. A 20-µl lysate was electrophoresed with X Cell II Mini-Cell (Novex, San Diego, CA) at 45 mA (Power Pac 1000, Biorad, Hercules, CA) on a 7.5% SDS-polyacrylamide gel (NuPage4-12% Bis-Tris gel, Novex, San Diego, CA), followed by transfer onto a nitrocellulose membrane (Immun-Blot PVDF membrane, Biorad, Hercules, CA) with Trans-Blot SD (Biorad, Hercules, CA). Monoclonal antibody BT-2 (Innogenetics, Belgium), which reacts with nonphosphorylated {tau} protein, and monoclonal antibody AT-8 (Innogenetics, Belgium), which reacts with phosphorylated {tau} protein, were used as the first antibodies. Antimouse IgG linked to horseradish peroxidase (Roche Diagnostics, Switzerland) was used as the second antibody. Protein bands were visualized with diaminobenzidine (Sigma-Aldrich, Saint Louis, MO).

ELISA.-- To determine the amount of {tau} protein, we performed ELISA on all specimens, using the measurement kit for CSF {tau} (Innotest h-Tau, Innogenetics, Belgium). AT-120 was used as the first antibody, and HT-7 and BT-2 were used as the second antibodies. The specimen was tested in duplicate using two wells, and the mean absorbance was calculated. The {tau} protein was determined from the calibration curve, which had been plotted using purified {tau} protein attached to the kit.

Determination of protein.-- Since the amount of epithelium taken varied with the individual, the total protein of the epithelium was determined using a BCA protein assay kit (Pierce, Rockford, IL) to calculate the ratio of {tau} protein to total protein. This ratio was used as the {tau}-protein concentration that was evaluated in this study.

Determination of {tau} Protein in the CSF
Along with quantification of {tau} protein in oral epithelium, 14 patients with AD, 9 patients with VD, and 6 age-matched controls were subjected to lumbar puncture for differential diagnosis and were examined by the previously mentioned ELISA for the determination of {tau} protein in CSF. The relationship between these results and {tau}-protein concentrations in oral mucosal epithelia and in CSF was investigated.

Statistical Analysis
For the comparison of {tau}-protein concentration of AD, VD, and control groups, we tested continuous variables using the Kruskal-Wallis analysis of variance for between-group comparisons and the Mann-Whitney U test for within-group comparisons. Spearman correlation coefficients were used to examine the relationship between oral and CSF {tau}-protein concentrations and to evaluate whether oral {tau}-protein concentration correlates with age of control, age at onset, and MMSE.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
As shown in Fig. 1, treatment of collected epithelia with antibiotics followed by rinsing in popidone iodine was effective in eliminating normal bacterial flora, enabling us to isolate squamous epithelial cells. Therefore, {tau}-protein levels measured using our method can be regarded as representing those in the epithelium.



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  		Figure 1. Many bacteria were observed in the oral epithelium before rinsing, A, but, as shown in B, few were observed after rinsing. Giemsa stain. Magnification: x400.

 
As depicted in Fig. 2, Western blotting with BT-2 antibody detected a band at 65 Kd and 110 Kd each. These molecular weights differed from those of {tau} protein in normal brain tissue, suggesting the possibility of the existence of oral epithelium–specific proteins. In CSF, some bands were observed at about 62 Kd (data not shown), which were also different from those of oral {tau}.



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  		Figure 2. Expression of {tau} protein in the oral epithelium. Since the total amount of protein varies with the individual, the density of bands on a Western blot does not reflect the concentration of {tau} protein. C = control; A = Alzheimer's disease; P = {tau} protein of paired helical filament; B = normal brain tissue; M = marker proteins.

 
On the other hand, the AT-8 antibody, which reacts with phosphorylated {tau} protein present in neurofibrillary tangles, was not capable of detecting a protein band (data not shown).

We investigated the difference in {tau}-protein concentration ({tau} protein/total protein) among patients with AD or VD, age-matched controls, and young controls. As shown in Fig. 3, the patients with AD showed a significantly higher {tau}-protein concentration than the other three groups (p = .0023 vs VD, p = .0034 vs young controls, and p = .0019 vs age-matched controls). No significant difference was noted between the patients with VD and the control groups or between the age-matched and young control groups.



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  		Figure 3. Oral {tau}-protein concentration in AD and VD groups, and age-matched and young controls. AD = Alzheimer's disease, 0.93 ± 0.11 pg/ml; VD = vascular dementia, 0.49 ± 0.06 pg/ml; AC = age-matched controls, 0.53 ± 0.06 pg/ml; YC = young controls, 0.52 ± 0.05 pg/ml. All values are mean ± SEM. *p = .0023; **p = .0034; ***p = .0019.

 
We investigated the relationship between CSF {tau} protein and oral epithelial {tau} protein. As shown in Fig. 4, a positive significant correlation was observed between the levels of {tau} protein in CSF and oral epithelium (r = .43, p = .011).



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  		Figure 4. Correlation between oral {tau} and cerebrospinal fluid (CSF) {tau} in 29 patients. Filled triangles = Alzheimer's disease; filled circles = vascular dementia; open circles = age-matched controls.

 
We investigated the relationship between age and oral epithelial {tau}-protein concentration of the control group. In controls, the amount of {tau} protein did not correlate with age (r = .06, not significant [NS]; Fig. 5a).

The relationship between the concentration of {tau} protein and age at onset was investigated in 34 patients with AD whose oral epithelial {tau} protein was determined. In patients with AD, the amount of {tau} protein showed a significant correlation with age at onset (r = -.45, p = .014; Fig. 5b). Finally, an investigation of the relationship between the concentration of {tau} protein of AD, with MMSE score as an index of severity of dementia, revealed no significant correlation (r = .08, NS; Fig. 5c).


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
The {tau} protein, which is the main component of neurofibrillary tangles in AD, appears in senile plaques and dystrophic neurites in an insoluble form, which is difficult to remove, and causes neuronal death. The current amyloid cascade theory (15) interprets the degeneration and deposition of {tau} protein as the result of amyloid protein abnormalities. However, a mutant gene encoding the {tau} protein has recently been discovered in frontal dementia (16). As a result, {tau}-protein abnormality has started to attract attention again as an important etiologic factor in AD.

The {tau} protein is known to have various molecular weights and interacts with microtubules, actin filaments, and intermediate filaments to play a key role in regulating the organization and integrity of the cytoskelton (17). This function of {tau} protein is regulated by intramolecular partial phosphorylation and maintains the polarity of neurons in neuronal tissue (18). In the human adult brain, {tau} proteins range from 48 to 67 Kd of molecular weight and are designated as small {tau} (19). Also, {tau} protein is known to be distributed among various tissues outside the central nervous system (20)(21)(22). {tau} protein with 110 to 120 Kd molecular weight was originally found in the peripheral tissue, and in peripheral neuron-like cell lines, and designated as big {tau} (23). However, small and big {tau} are simultaneously detected in most nonneural tissues (24). Our Western blot results do not rule out the possibility of having detected cross-reactivity with non-{tau} molecules. However, we considered that we could detect the expression of {tau}-protein molecules in oral epithelium because both big and small {tau} were expressed, in addition to other nonneural tissues, and the 65-Kd band almost corresponded with that of small {tau} found in other nonneural tissues (24). The paucity of bands detected can be interpreted as being due to a mode of expression different from that in other tissues.

We were unable to demonstrate the phosphorylation of {tau} protein in oral epithelium because of the failure of AT8, an antibody to detect phosphorylated {tau}, to give a band. We speculate that this is because phosphorylation of {tau} protein does not occur in oral epithelium, or because the phosphorylated protein with modification, such as glication, and processing cannot be detected with the conventional antibody to phosphorylated {tau} protein. Therefore, it will be necessary to test the detectability by Western blotting with various antibodies to the phosphorylated {tau} protein. It will also be necessary to examine the cross-reactivity with the {tau} protein of neurofibrillary tangles using the antibodies produced by immunization with extracted oral epithelial {tau} protein.

In this study, we did not find any significant correlation between severity of dementia and oral epithelial {tau}-protein concentration. However, considering that there was no difference in {tau}-protein concentration between the young and age-matched controls, and that the younger the age at onset, the higher the {tau}-protein concentration, it is possible that the concentration of {tau} protein in oral epithelium remains unchanged from early childhood, and that individuals with high levels of {tau} protein are susceptible to AD. To prove this hypothesis, a combination of prospective study and genetic study is necessary.

Efforts have continued to find an application for pathological changes in CSF, serum, and nonneural tissue for clinical use, since it is still extremely difficult to perform clinical laboratory tests using AD brain biopsy specimens. So far, serum antichymotrypsin (25), serum melanotransferrin (26), platelet amyloid-precursor protein (27), and a neuronal substance appearing in the urine (28) have been reported, but efforts to use abnormal nonneural tissue as a marker do not appear to have reached the clinical application stage as yet. Currently, only the determination of {tau} protein in the CSF has acquired the reputation as the biological marker of AD. This method has high sensitivity and specificity for the diagnosis of AD and has a great value as a pathology-based diagnostic procedure (8). However, since lumbar puncture is an invasive procedure, this method possesses difficulties as a screening test. In contrast, the collection of oral mucosal epithelium is easy and causes no pain to the examinee. Oral mucosa is made of stratified squamous epithelium, which is of ectodermal origin and embryologically closer to the nervous system, and which can be easily collected noninvasively. In addition, we also demonstrated a significant correlation between the levels of {tau} protein in oral epithelium and CSF. We will examine more patients in the future to test the sensitivity and specificity of our method. If a high accuracy is obtained, the determination of {tau} protein in oral mucosal epithelium might be a reliable screening test for AD.





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  		Figure 5. A, relationship between age and oral {tau} protein of control subjects (n = 67). B, relationship between age at onset of Alzheimer's disease (AD) and oral {tau} protein for 34 subjects. C, relationship between Mini-Mental State Examination (MMSE) score and oral {tau} protein in patients with AD (n = 34).

 

   Acknowledgments
 
This study was supported, in part, by a grant from the Sasakawa Health Science Foundation and the Sumitomo Marine Welfare Foundation.

Received February 20, 2001

Accepted April 12, 2001


   References
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 Methods
 Results
 Discussion
 References
 

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