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Current Alzheimer Research

Editor-in-Chief

ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

General Research Article

Salivary Aβ Secretion and Altered Oral Microbiome in Mouse Models of AD

Author(s): Angela M. Floden, Mona Sohrabi, Suba Nookala, Jay J. Cao and Colin K. Combs *

Volume 17, Issue 12, 2020

Page: [1133 - 1144] Pages: 12

DOI: 10.2174/1567205018666210119151952

Price: $65

Abstract

Background: Beta amyloid (Aβ) peptide containing plaque aggregations in the brain are a hallmark of Alzheimer’s Disease (AD). However, Aβ is produced by cell types outside of the brain suggesting that the peptide may serve a broad physiologic purpose.

Objective: Based upon our prior work documenting expression of amyloid β precursor protein (APP) in intestinal epithelium we hypothesized that salivary epithelium might also express APP and be a source of Aβ.

Methods: To begin testing this idea, we compared human age-matched control and AD salivary glands to C57BL/6 wild type, AppNL-G-F , and APP/PS1 mice.

Results: Both male and female AD, AppNL-G-F , and APP/PS1 glands demonstrated robust APP and Aβ immunoreactivity. Female AppNL-G-F mice had significantly higher levels of pilocarpine stimulated Aβ 1-42 compared to both wild type and APP/PS1 mice. No differences in male salivary Aβ levels were detected. No significant differences in total pilocarpine stimulated saliva volumes were observed in any group. Both male and female AppNL-G-F but not APP/PS1 mice demonstrated significant differences in oral microbiome phylum and genus abundance compared to wild type mice. Male, but not female, APP/PS1 and AppNL-G-F mice had significantly thinner molar enamel compared to their wild type counterparts.

Conclusion: These data support the idea that oral microbiome changes exist during AD in addition to changes in salivary Aβ and oral health.

Keywords: Microbiome, Alzheimer, amyloid, inflammation, saliva, biomarker.

« Previous
[1]
Haass C, Lemere CA, Capell A, et al. The Swedish mutation causes early-onset Alzheimer’s disease by beta-secretase cleavage within the secretory pathway. Nat Med 1995; 1(12): 1291-6.
[http://dx.doi.org/10.1038/nm1295-1291] [PMID: 7489411]
[2]
Evin G, Cappai R, Li QX, et al. Candidate gamma-secretases in the generation of the carboxyl terminus of the Alzheimer’s disease beta A4 amyloid: pPossible involvement of cathepsin D. Biochemistry 1995; 34(43): 14185-92.
[http://dx.doi.org/10.1021/bi00043a024] [PMID: 7578016]
[3]
Citron M, Teplow DB, Selkoe DJ. Generation of amyloid beta protein from its precursor is sequence specific. Neuron 1995; 14(3): 661-70.
[http://dx.doi.org/10.1016/0896-6273(95)90323-2] [PMID: 7695913]
[4]
Higaki J, Quon D, Zhong Z, Cordell B. Inhibition of beta-amyloid formation identifies proteolytic precursors and subcellular site of catabolism. Neuron 1995; 14(3): 651-9.
[http://dx.doi.org/10.1016/0896-6273(95)90322-4] [PMID: 7695912]
[5]
Haass C, Hung AY, Schlossmacher MG, Teplow DB, Selkoe DJ. beta-Amyloid peptide and a 3-kDa fragment are derived by distinct cellular mechanisms. J Biol Chem 1993; 268(5): 3021-4.
[http://dx.doi.org/10.1016/S0021-9258(18)53650-4] [PMID: 8428976]
[6]
Puig KL, Combs CK. Expression and function of APP and its metabolites outside the central nervous system. Exp Gerontol 2013; 48(7): 608-11.
[http://dx.doi.org/10.1016/j.exger.2012.07.009] [PMID: 22846461]
[7]
Akaaboune M, Allinquant B, Farza H, et al. Developmental regulation of amyloid precursor protein at the neuromuscular junction in mouse skeletal muscle. Mol Cell Neurosci 2000; 15(4): 355-67.
[http://dx.doi.org/10.1006/mcne.2000.0834] [PMID: 10845772]
[8]
Galloway S, Jian L, Johnsen R, Chew S, Mamo JC. Beta-amyloid or its precursor protein is found in epithelial cells of the small intestine and is stimulated by high-fat feeding. J Nutr Biochem 2007; 18(4): 279-84.
[http://dx.doi.org/10.1016/j.jnutbio.2006.07.003] [PMID: 16962759]
[9]
Herzog V, Kirfel G, Siemes C, Schmitz A. Biological roles of APP in the epidermis. Eur J Cell Biol 2004; 83(11-12): 613-24.
[http://dx.doi.org/10.1078/0171-9335-00401] [PMID: 15679106]
[10]
Lee YH, Tharp WG, Maple RL, Nair S, Permana PA, Pratley RE. Amyloid precursor protein expression is upregulated in adipocytes in obesity. Obesity (Silver Spring) 2008; 16(7): 1493-500.
[http://dx.doi.org/10.1038/oby.2008.267] [PMID: 18483477]
[11]
Sandbrink R, Masters CL, Beyreuther K. Beta A4-amyloid protein precursor mRNA isoforms without exon 15 are ubiquitously expressed in rat tissues including brain, but not in neurons. J Biol Chem 1994; 269(2): 1510-7.
[http://dx.doi.org/10.1016/S0021-9258(17)42286-1] [PMID: 8288617]
[12]
Selkoe DJ, Podlisny MB, Joachim CL, et al. Beta-amyloid precursor protein of Alzheimer disease occurs as 110- to 135-kilodalton membrane-associated proteins in neural and nonneural tissues. Proc Natl Acad Sci USA 1988; 85(19): 7341-5.
[http://dx.doi.org/10.1073/pnas.85.19.7341] [PMID: 3140239]
[13]
Yamada T, Sasaki H, Dohura K, Goto I, Sakaki Y. Structure and expression of the alternatively-spliced forms of mRNA for the mouse homolog of Alzheimer’s disease amyloid beta protein precursor. Biochem Biophys Res Commun 1989; 158(3): 906-12.
[http://dx.doi.org/10.1016/0006-291X(89)92808-8] [PMID: 2493250]
[14]
Puig KL, Lutz BM, Urquhart SA, et al. Overexpression of mutant amyloid-β protein precursor and presenilin 1 modulates enteric nervous system. J Alzheimers Dis 2015; 44(4): 1263-78.
[http://dx.doi.org/10.3233/JAD-142259] [PMID: 25408221]
[15]
Puig KL, Manocha GD, Combs CK. Amyloid precursor protein mediated changes in intestinal epithelial phenotype in vitro. PLoS One 2015; 10(3)e0119534
[http://dx.doi.org/10.1371/journal.pone.0119534] [PMID: 25742317]
[16]
Ashton NJ, Ide M, Schöll M, et al. No association of salivary total tau concentration with Alzheimer’s disease. Neurobiol Aging 2018; 70: 125-7.
[http://dx.doi.org/10.1016/j.neurobiolaging.2018.06.014] [PMID: 30007161]
[17]
Pekeles H, Qureshi HY, Paudel HK, Schipper HM, Gornistky M, Chertkow H. Development and validation of a salivary tau biomarker in Alzheimer’s disease. Alzheimer’s Demen (Amsterdam, Netherlands) 2019; 11: 53-60.
[18]
Shi M, Sui YT, Peskind ER, et al. Salivary tau species are potential biomarkers of Alzheimer’s disease. J Alzheimers Dis 2011; 27(2): 299-305.
[http://dx.doi.org/10.3233/JAD-2011-110731] [PMID: 21841250]
[19]
Bermejo-Pareja F, Antequera D, Vargas T, Molina JA, Carro E. Saliva levels of Abeta1-42 as potential biomarker of Alzheimer’s disease: a pilot study. BMC Neurol 2010; 10: 108.
[http://dx.doi.org/10.1186/1471-2377-10-108] [PMID: 21047401]
[20]
Lee M, Guo JP, Kennedy K, McGeer EG, McGeer PL. A method for diagnosing Alzheimer’s disease based on salivary amyloid-β protein 42 levels. J Alzheimers Dis 2017; 55(3): 1175-82.
[http://dx.doi.org/10.3233/JAD-160748] [PMID: 27792013]
[21]
Sabbagh MN, Shi J, Lee M, et al. Salivary beta amyloid protein levels are detectable and differentiate patients with Alzheimer’s disease dementia from normal controls: Preliminary findings. BMC Neurol 2018; 18(1): 155.
[http://dx.doi.org/10.1186/s12883-018-1160-y] [PMID: 30257642]
[22]
Figueira J, Jonsson P, Nordin Adolfsson A, et al. NMR analysis of the human saliva metabolome distinguishes dementia patients from matched controls. Mol Biosyst 2016; 12(8): 2562-71.
[http://dx.doi.org/10.1039/C6MB00233A] [PMID: 27265744]
[23]
Huan T, Tran T, Zheng J, et al. Metabolomics analyses of saliva detect novel biomarkers of Alzheimer’s disease. J Alzheimers Dis 2018; 65(4): 1401-16.
[http://dx.doi.org/10.3233/JAD-180711] [PMID: 30175979]
[24]
Ralbovsky NM, Halámková L, Wall K, Anderson-Hanley C, Lednev IK. Screening for Alzheimer’s disease using saliva: a new approach based on machine learning and Raman hyperspectroscopy. J Alzheimers Dis 2019; 71(4): 1351-9.
[http://dx.doi.org/10.3233/JAD-190675] [PMID: 31524171]
[25]
Yilmaz A, Geddes T, Han B, et al. Diagnostic biomarkers of Alzheimer’s disease as identified in saliva using 1H NMR-based metabolomics. J Alzheimers Dis 2017; 58(2): 355-9.
[http://dx.doi.org/10.3233/JAD-161226] [PMID: 28453477]
[26]
Aragón F, Zea-Sevilla MA, Montero J, et al. Oral health in Alzheimer’s disease: A multicenter case-control study. Clin Oral Investig 2018; 22(9): 3061-70.
[http://dx.doi.org/10.1007/s00784-018-2396-z] [PMID: 29476334]
[27]
Ship JA, DeCarli C, Friedland RP, Baum BJ. Diminished submandibular salivary flow in dementia of the Alzheimer type. J Gerontol 1990; 45(2): M61-6.
[http://dx.doi.org/10.1093/geronj/45.2.M61] [PMID: 2313044]
[28]
Kalia M. Dysphagia and aspiration pneumonia in patients with Alzheimer’s disease. Metabolism 2003; 52(10): 36-8.
[http://dx.doi.org/10.1016/S0026-0495(03)00300-7] [PMID: 14577062]
[29]
Scannapieco FA, Cantos A. Oral inflammation and infection, and chronic medical diseases: Implications for the elderly. Periodontol 2000 2016; 72(1): 153-75.
[http://dx.doi.org/10.1111/prd.12129] [PMID: 27501498]
[30]
Chen CK, Wu YT, Chang YC. Association between chronic periodontitis and the risk of Alzheimer’s disease: A retrospective, population-based, matched-cohort study. Alzheimers Res Ther 2017; 9(1): 56.
[http://dx.doi.org/10.1186/s13195-017-0282-6] [PMID: 28784164]
[31]
Foley NC, Affoo RH, Siqueira WL, Martin RE. A systematic review examining the oral health status of persons with dementia. JDR Clin Trans Res 2017; 2(4): 330-42.
[http://dx.doi.org/10.1177/2380084417714789] [PMID: 30931751]
[32]
Hatipoglu MG, Kabay SC, Güven G. The clinical evaluation of the oral status in Alzheimer-type dementia patients. Gerodontology 2011; 28(4): 302-6.
[http://dx.doi.org/10.1111/j.1741-2358.2010.00401.x] [PMID: 21054507]
[33]
Holmer J, Eriksdotter M, Schultzberg M, Pussinen PJ, Buhlin K. Association between periodontitis and risk of Alzheimer’s disease, mild cognitive impairment and subjective cognitive decline: A case-control study. J Clin Periodontol 2018; 45(11): 1287-98.
[http://dx.doi.org/10.1111/jcpe.13016] [PMID: 30289998]
[34]
Ide M, Harris M, Stevens A, et al. Periodontitis and cognitive decline in Alzheimer’s disease. PLoS One 2016; 11(3)e0151081
[http://dx.doi.org/10.1371/journal.pone.0151081] [PMID: 26963387]
[35]
Leira Y, Domínguez C, Seoane J, et al. iIs periodontal disease associated with Alzheimer’s disease? a systematic review with meta-analysis. Neuroepidemiology 2017; 48(1-2): 21-31.
[http://dx.doi.org/10.1159/000458411] [PMID: 28219071]
[36]
Martande SS, Pradeep AR, Singh SP, et al. Periodontal health condition in patients with Alzheimer’s disease. Am J Alzheimers Dis Other Demen 2014; 29(6): 498-502.
[http://dx.doi.org/10.1177/1533317514549650] [PMID: 25214647]
[37]
Minn YK, Suk SH, Park H, et al. Tooth loss is associated with brain white matter change and silent infarction among adults without dementia and stroke. J Korean Med Sci 2013; 28(6): 929-33.
[http://dx.doi.org/10.3346/jkms.2013.28.6.929] [PMID: 23772160]
[38]
Okamoto N, Morikawa M, Tomioka K, Yanagi M, Amano N, Kurumatani N. Association between tooth loss and the development of mild memory impairment in the elderly: The Fujiwara-kyo Study. J Alzheimers Dis 2015; 44(3): 777-86.
[http://dx.doi.org/10.3233/JAD-141665] [PMID: 25362033]
[39]
Oue H, Miyamoto Y, Koretake K, et al. Tooth loss might not alter molecular pathogenesis in an aged transgenic Alzheimer’s disease model mouse. Gerodontology 2016; 33(3): 308-14.
[http://dx.doi.org/10.1111/ger.12153] [PMID: 25243637]
[40]
Oue H, Miyamoto Y, Okada S, et al. Tooth loss induces memory impairment and neuronal cell loss in APP transgenic mice. Behav Brain Res 2013; 252: 318-25.
[http://dx.doi.org/10.1016/j.bbr.2013.06.015] [PMID: 23773908]
[41]
Takeuchi K, Ohara T, Furuta M, et al. Tooth loss and risk of dementia in the community: The Hisayama Study. J Am Geriatr Soc 2017; 65(5): e95-e100.
[http://dx.doi.org/10.1111/jgs.14791] [PMID: 28272750]
[42]
Tiisanoja A, Syrjala AM, Tertsonen M, et al. Oral diseases and inflammatory burden and Alzheimer's disease among subjects aged 75 years or older Oral diseases and inflammatory burden and Alzheimer's disease among subjects aged 75 years or older 2019; 39(2): 158-65.
[http://dx.doi.org/10.1111/scd.12357]
[43]
Kamer AR, Pirraglia E, Tsui W, et al. Periodontal disease associates with higher brain amyloid load in normal elderly. Neurobiol Aging 2015; 36(2): 627-33.
[http://dx.doi.org/10.1016/j.neurobiolaging.2014.10.038] [PMID: 25491073]
[44]
Saito T, Matsuba Y, Mihira N, et al. Single App knock-in mouse models of Alzheimer’s disease. Nat Neurosci 2014; 17(5): 661-3.
[http://dx.doi.org/10.1038/nn.3697] [PMID: 24728269]
[45]
Kumar DK, Choi SH, Washicosky KJ, et al. Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci Transl Med 2016; 8(340)340ra72
[http://dx.doi.org/10.1126/scitranslmed.aaf1059] [PMID: 27225182]
[46]
Moir RD, Lathe R, Tanzi RE. The antimicrobial protection hypothesis of Alzheimer’s disease. Alzheimers Dement 2018; 14(12): 1602-14.
[http://dx.doi.org/10.1016/j.jalz.2018.06.3040] [PMID: 30314800]
[47]
Soscia SJ, Kirby JE, Washicosky KJ, et al. The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS One 2010; 5(3)e9505
[http://dx.doi.org/10.1371/journal.pone.0009505] [PMID: 20209079]
[48]
Akbari E, Asemi Z, Daneshvar Kakhaki R, et al. Effect of probiotic supplementation on cognitive function and metabolic status in alzheimer’s disease: A randomized, double-blind and controlled trial. Front Aging Neurosci 2016; 8: 256.
[http://dx.doi.org/10.3389/fnagi.2016.00256] [PMID: 27891089]
[49]
Nimgampalle M, Kuna Y. Anti-Alzheimer properties of probiotic, Lactobacillus plantarum MTCC 1325 in Alzheimer’s disease induced albino rats. J Clin Diagn Res 2017; 11(8): KC01-5.
[http://dx.doi.org/10.7860/JCDR/2017/26106.10428] [PMID: 28969160]
[50]
Dinan TG, Stilling RM, Stanton C, Cryan JF. Collective unconscious: How gut microbes shape human behavior. J Psychiatr Res 2015; 63: 1-9.
[http://dx.doi.org/10.1016/j.jpsychires.2015.02.021] [PMID: 25772005]
[51]
Vogt NM, Kerby RL, Dill-McFarland KA, et al. Gut microbiome alterations in Alzheimer’s disease. Sci Rep 2017; 7(1): 13537.
[http://dx.doi.org/10.1038/s41598-017-13601-y] [PMID: 29051531]
[52]
Balin BJ, Little CS, Hammond CJ, et al. Chlamydophila pneumoniae and the etiology of late-onset Alzheimer’s disease. J Alzheimers Dis 2008; 13(4): 371-80.
[http://dx.doi.org/10.3233/JAD-2008-13403] [PMID: 18487846]
[53]
Harach T, Marungruang N, Duthilleul N, et al. Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci Rep 2017; 7: 41802.
[http://dx.doi.org/10.1038/srep41802] [PMID: 28176819]
[54]
Pistollato F, Sumalla Cano S, et al. Role of gut microbiota and nutrients in amyloid formation and pathogenesis of Alzheimer disease. Nutr Rev 2016; 74(10): 624-34.
[http://dx.doi.org/10.1093/nutrit/nuw023] [PMID: 27634977]
[55]
Austin SA, Combs CK. Amyloid precursor protein mediates monocyte adhesion in AD tissue and apoE(-)/(-) mice. Neurobiol Aging 2010; 31(11): 1854-66.
[http://dx.doi.org/10.1016/j.neurobiolaging.2008.10.013] [PMID: 19058878]
[56]
Wu SC, Cao ZS, Chang KM, Juang JL. Intestinal microbial dysbiosis aggravates the progression of Alzheimer’s disease in Drosophila. Nat Commun 2017; 8(1): 24.
[http://dx.doi.org/10.1038/s41467-017-00040-6] [PMID: 28634323]
[57]
Shimizu K, Hanaoka Y, Akama T, Kono I. Ageing and free-living daily physical activity effects on salivary beta-defensin 2 secretion. J Sports Sci 2017; 35(7): 617-23.
[http://dx.doi.org/10.1080/02640414.2016.1182640] [PMID: 27237844]
[58]
Gillum TL, Kuennen MR, Castillo MN, Williams NL, Jordan-Patterson AT. Exercise, but not acute sleep loss, increases salivary antimicrobial protein secretion. J Strength Cond Res 2015; 29(5): 1359-66.
[http://dx.doi.org/10.1519/JSC.0000000000000828] [PMID: 25915527]
[59]
Malcolm J, Sherriff A, Lappin DF, et al. Salivary antimicrobial proteins associate with age-related changes in streptococcal composition in dental plaque. Mol Oral Microbiol 2014; 29(6): 284-93.
[http://dx.doi.org/10.1111/omi.12058] [PMID: 24890264]
[60]
Jourdain ML, Velard F, Pierrard L, Sergheraert J, Gangloff SC, Braux J. Cationic antimicrobial peptides and periodontal physiopathology: A systematic review. J Periodontal Res 2019; 54(6): 589-600.
[http://dx.doi.org/10.1111/jre.12676] [PMID: 31215656]
[61]
Manocha GD, Floden AM, Miller NM, et al. Temporal progression of Alzheimer’s disease in brains and intestines of transgenic mice. Neurobiol Aging 2019; 81: 166-76.
[http://dx.doi.org/10.1016/j.neurobiolaging.2019.05.025] [PMID: 31284126]
[62]
Sanz M, Beighton D, Curtis MA, et al. Role of microbial biofilms in the maintenance of oral health and in the development of dental caries and periodontal diseases. Consensus report of group 1 of the Joint EFP/ORCA workshop on the boundaries between caries and periodontal disease. J Clin Periodontol 2017; 44(18): S5-S11.
[http://dx.doi.org/10.1111/jcpe.12682] [PMID: 28266109]
[63]
Sakurai K, Wang D, Suzuki J, et al. High incidence of actinobacillus actinomycetemcomitans infection in acute coronary syndrome. Int Heart J 2007; 48(6): 663-75.
[http://dx.doi.org/10.1536/ihj.48.663] [PMID: 18160759]
[64]
Fine DH, Furgang D, Goldman D. Saliva from subjects harboring Actinobacillus actinomycetemcomitans kills Streptococcus mutans in vitro. J Periodontol 2007; 78(3): 518-26.
[http://dx.doi.org/10.1902/jop.2007.060229] [PMID: 17335376]
[65]
Litvak Y, Byndloss MX, Bäumler AJ. Colonocyte metabolism shapes the gut microbiota. Science 2018; 362(6418)eaat9076
[http://dx.doi.org/10.1126/science.aat9076] [PMID: 30498100]
[66]
Ilievski V, Zuchowska PK, Green SJ, et al. Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration and amyloid beta production in wild type mice. PLoS One 2018; 13(10)e0204941
[http://dx.doi.org/10.1371/journal.pone.0204941] [PMID: 30281647]

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