Tau Phosphorylation and Amyloid-β Deposition in the Presence of Formaldehyde

  • Jing Lu
  • Rongqiao HeEmail author


Alzheimer’s disease (AD) is a devastating neurodegenerative disorder with a relentless progression. It is associated with amyloid-β (Aβ) peptide deposition in senile plaques and hyperphosphorylated Tau protein in neurofibrillary tangles in the AD patients’ brain. Aβ accumulation occurs in early preclinical stage as a trigger factor for AD pathogenesis followed by silence of synapses and Tau hyperphosphorylation. However, what triggers Aβ deposition and Tau hyperphosphorylation is still under investigation. As an endogenous small-molecule metabolite, formaldehyde is produced by multiple cellular processes, including lipid oxidation, protein denaturation, sugar decomposition, methanol degradation, oxidative stress, DNA demethylation, and semicarbazide-sensitive amine oxidase (SSAO) catalyzation (see Chap.  2). Recent studies demonstrated that formaldehyde plays a pivotal role in the development of age-related neurodegenerative diseases by inducing the cellular component malfunction, such as Tau hyperphosphorylation, Aβ aggregation, and cell apoptosis. However, the underlying molecular mechanisms remain largely elusive. This chapter briefly introduces recent progresses on production and accumulation of formaldehyde with aging and the signaling pathways of formaldehyde, leading to dysfunction of nuclear Tau protein, aggregation of Aβ, as well as dysfunction of ApoE in vitro and in vivo. Formaldehyde acts as an effective trigger of Tau protein hyperphosphorylation in cell lines, primary cultured neurons, mouse brains, as well as monkey brains. During formaldehyde-induced Tau hyperphosphorylation, activation of Tau phosphorylation kinases glycogen synthase kinase 3 beta (GSK-3β) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) as well as suppression of protein phosphatase 2A (PP2A) were shown to be highlighted pathways. Long-term incubation of N2a cells with formaldehyde at the pathological concentration referred to AD patients resulted in formaldehyde accumulation also inducing Tau hyperphosphorylation and morphological changes of neuronal processes and neurites. Both Tau hyperphosphorylation and Aβ deposition were found in the hippocampus and cerebral cortex of rhesus monkeys through a long-term feeding with low concentration of methanol in drinking water or cerebral ventricle injection, and those monkeys suffered from decline of cognitive abilities as well. Formaldehyde is shown to be a strong trigger of Aβ deposition and Tau phosphorylation, so that the dysmetabolism of endogenous formaldehyde should occur in the early stage of AD as formaldehyde disturbs nervous system in different pathways and in diverse manners.


Formaldehyde Methanol Tau hyperphosphorylation Neurofibrillary tangles Tauopathy Amyloid-β Senile plaque Cognitive impairment APOE4 Neurite Neuronal processes Cell death Mouse model Nonhuman primate Dephosphorylation Pathology 



This project was supported by grants from the National Key Research and Development Program of China (2016YFC1306300), the National Basic Research Program of China (973 Program) (2012CB911004), the Natural Scientific Foundation of China (NSFC 31270868), Foundation of Chinese Academy of Sciences CAS-20140909, and the Queensland-Chinese Academy of Sciences Biotechnology Fund (GJHZ201302).

Competing Financial Interests

The authors declare no competing financial interests.


  1. Abraha A, Ghoshal N, Gamblin TC, Cryns V, Berry RW, Kuret J, Binder LI (2000) C-terminal inhibition of tau assembly in vitro and in Alzheimer’s disease. J Cell Sci 113(Pt 21):3737–3745PubMedGoogle Scholar
  2. Allison SL, Fagan AM, Morris JC, Head D (2016) Spatial navigation in preclinical Alzheimer’s disease. J Alzheimer’s Dis JAD 52:77–90PubMedCrossRefGoogle Scholar
  3. Alonso AD, Beharry C, Corbo CP, Cohen LS (2016) Molecular mechanism of prion-like tau-induced neurodegeneration. Alzheimer’s Dementia J Alzheimer’s Assoc 12:1090–1097CrossRefGoogle Scholar
  4. Alvarez G, Munoz-Montano JR, Satrustegui J, Avila J, Bogonez E, Diaz-Nido J (1999) Lithium protects cultured neurons against beta-amyloid-induced neurodegeneration. FEBS Lett 453:260–264PubMedCrossRefGoogle Scholar
  5. Alzheimer A (1907) Über eine eigenartige Erkrankung der Hirnrinde [about a peculiar disease of the cerebral cortex]. Allgemeine Zeitschrift fur Psychiatrie und Psychisch-Gerichtlich Medizin 64:146–148Google Scholar
  6. Alzheimer’s A (2015) 2015 Alzheimer’s disease facts and figures. Alzheimer’s Demen 11:332–384CrossRefGoogle Scholar
  7. Arnsten AF, Cai JX, Goldman-Rakic PS (1988) The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes. J Neurosci 8:4287–4298PubMedGoogle Scholar
  8. Avila J (2006) Tau phosphorylation and aggregation in Alzheimer’s disease pathology. FEBS Lett 580:2922–2927PubMedCrossRefGoogle Scholar
  9. Ballard C, Khan Z, Clack H, Corbett A (2011) Nonpharmacological treatment of Alzheimer disease. Can J Psychiatr 56:589–595CrossRefGoogle Scholar
  10. Barron M, Gartlon J, Dawson LA, Atkinson PJ, Pardon MC (2016) A state of delirium: deciphering the effect of inflammation on tau pathology in Alzheimer’s disease. Exp Gerontol 94:103–107Google Scholar
  11. Bird TD (1993) Early-onset familial Alzheimer disease. In: GeneReviews(R) editors: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Fong CT, Mefford HC, Smith RJH et al. (eds) Seattle (WA)Google Scholar
  12. Blennow K (2005) CSF biomarkers for Alzheimer’s disease: use in early diagnosis and evaluation of drug treatment. Expert Rev Mol Diagn 5:661–672PubMedCrossRefGoogle Scholar
  13. Bruckner J, Warren D (2001) Toxic effects of solvents and vapors in Casarett & Doull’s toxicology. The basic science of poisons, 6th edn. Klaassen CD, McGraw-Hill, Kansas, USA, pp 894–895Google Scholar
  14. Bufill E, Blesa R, Augusti J (2013) Alzheimer’s disease: an evolutionary approach. J Anthropol Sci 91:135–157PubMedGoogle Scholar
  15. Caceres A, Kosik KS (1990) Inhibition of neurite polarity by tau antisense oligonucleotides in primary cerebellar neurons. Nature 343:461–463PubMedCrossRefGoogle Scholar
  16. Cai T, Che H, Yao T, Chen Y, Huang C, Zhang W, Du K, Zhang J, Cao Y, Chen J et al (2011) Manganese induces tau hyperphosphorylation through the activation of ERK MAPK pathway in PC12 cells. Toxicol Sci 119:169–177PubMedCrossRefGoogle Scholar
  17. Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, Fagan AM, Morris JC, Mawuenyega KG, Cruchaga C et al (2011) Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance. Sci Transl Med 3:89ra57PubMedPubMedCentralCrossRefGoogle Scholar
  18. Chan SF, Sucher NJ (2001) An NMDA receptor signaling complex with protein phosphatase 2A. J Neurosci 21:7985–7992PubMedGoogle Scholar
  19. Chen XX, Su T (2015) Microcirculation dysfunction in age-related cognitive impairment. Prog Biochem Biophys 42(12):1077–1083Google Scholar
  20. Chen YH, Luo JY, Li W, He RQ (1999) Effect of acetaldehyde on phosphorylation of human neuronal tau. J Biochem Mol Biol & Biophys 3:197–202Google Scholar
  21. Chen K, Kazachkov M, Yu PH (2007) Effect of aldehydes derived from oxidative deamination and oxidative stress on beta-amyloid aggregation; pathological implications to Alzheimer’s disease. J Neural Trans (Vienna, Austria: 1996) 114:835–839Google Scholar
  22. Chen N, Dai LF, Jiang WY, Wu Y (2012a) Pathogenic role of UPR (unfolded protein response) among hereditary Leukoencephalopathy and neurodegenerative disorders after endoplasmic reticulum stress. Prog Biochem Biophys 39:764–770CrossRefGoogle Scholar
  23. Chen NN, Luo DJ, Yao XQ, Yu C, Wang Y, Wang Q, Wang JZ, Liu GP (2012b) Pesticides induce spatial memory deficits with synaptic impairments and an imbalanced tau phosphorylation in rats. J Alzheimer’s Dis 30:585–594Google Scholar
  24. Coultrap SJ, Bayer KU (2012) CaMKII regulation in information processing and storage. Trends Neurosci 35:607–618PubMedPubMedCentralCrossRefGoogle Scholar
  25. Cui Y, Su T, Zhang SD, Huang P, He YG, Liu Y, Zhang C, Ritch R, He RQ (2016) Elevated urine formaldehyde in elderly patients with primary open angle glaucoma. Int J Ophthalmol 9:411–416PubMedPubMedCentralGoogle Scholar
  26. Drubin DG, Kirschner MW (1986) Tau protein function in living cells. J Cell Biol 103:2739–2746PubMedCrossRefGoogle Scholar
  27. Engelborghs S, De Deyn PP (2001) Biological and genetic markers of sporadic Alzheimer’s disease. Acta Med Okayama 55:55–63PubMedGoogle Scholar
  28. Evans AM, Fameli N, Ogunbayo OA, Duan J, Navarro-Dorado J (2016) From contraction to gene expression: nanojunctions of the sarco/endoplasmic reticulum deliver site- and function-specific calcium signals. Sci China Life Sci 59(8):749–763PubMedCrossRefGoogle Scholar
  29. Fu HJ, Rodriguez GA, Herman M, Emrani S, Nahmani E, Barrett G, Figueroa HY, Goldberg E, Hussaini SA, Duff KE (2017) Tau pathology induces excitatory neuron loss, grid cell dysfunction, and spatial memory deficits reminiscent of early Alzheimer’s disease. Neuron 93(3):533–541PubMedCrossRefGoogle Scholar
  30. Fyhn M, Molden S, Witter MP, Moser EI, Moser MB (2004) Spatial representation in the entorhinal cortex. Science 305:1258–1264PubMedCrossRefGoogle Scholar
  31. Ghosh A, Giese KP (2015) Calcium/calmodulin-dependent kinase II and Alzheimer’s disease. Mol Brain 8(78). doi: 10.1186/s13041-015-0166-2
  32. Goedert M, Wischik CM, Crowther RA et al (1988) Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc Natl Acad Sci U S A 85(11):4051–4055PubMedPubMedCentralCrossRefGoogle Scholar
  33. Gong CX, Singh TJ, Grundke-Iqbal I, Iqbal K (1993) Phosphoprotein phosphatase activities in Alzheimer disease brain. J Neurochem 61:921–927PubMedCrossRefGoogle Scholar
  34. Gong CX, Liu F, Grundke-Iqbal I, Iqbal K (2005) Post-translational modifications of tau protein in Alzheimer’s disease. J Neural Trans (Vienna, Austria: 1996) 112:813–838Google Scholar
  35. Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM (1986) Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem 261:6084–6089PubMedGoogle Scholar
  36. Hafting T, Fyhn M, Molden S, Moser MB, Moser EI (2005) Microstructure of a spatial map in the entorhinal cortex. Nature 436:801–806PubMedCrossRefGoogle Scholar
  37. Harrington CR, Mukaetova-Ladinska EB, Hills R et al (1991) Measurement of distinct immunochemical presentations of tau protein in Alzheimer disease. Proc Natl Acad Sci U S A 88(13):5842–5846PubMedPubMedCentralCrossRefGoogle Scholar
  38. He R (2016) Abnormal lysosome, formaldehyde Dysmetabolism and age-related cognitive impairment. Prog Biochem Biophys 43(12):1197Google Scholar
  39. He R, Luo J, Li W (1998) Effect of ethanol on the aggregation of human neuronal tau protein. Protein Pept Lett 5(5):279–285Google Scholar
  40. He R, Lu J, Miao JY (2010) Formaldehyde stress. Sci China Life Sci 53(12):1399–1404PubMedCrossRefGoogle Scholar
  41. He X, Li Z, Rizak JD, Wu S, Wang Z, He R, Su M, Qin D, Wang J, Hu X (2016) Resveratrol attenuates formaldehyde induced hyperphosphorylation of Tau protein and cytotoxicity in N2a cells. Front Neurosci 10(598). doi: 10.3389/fnins.2016.00598
  42. Hu X, Wang T, Jin F (2016) Alzheimer’s disease and gut microbiota. Sci China Life Sci 59(10):1006–1023PubMedCrossRefGoogle Scholar
  43. Hua Q, He RQ (2002) Effect of phosphorylation and aggregation on tau binding to DNA. Protein Pept Lett 9(4):349–357PubMedCrossRefGoogle Scholar
  44. Hua Q, He RQ (2003) Tau could protect DNA double helix structure. Biochim Biophys Acta 1645(2):205–211PubMedCrossRefGoogle Scholar
  45. Hua Q, He RQ, Haque N, Qu MH, del Carmen Alonso A, Grundke-Iqbal I, Iqbal K (2003) Microtubule associated protein tau binds to double-stranded but not single-stranded DNA. Cell Mol Life Sci CMLS 60(2):413–421PubMedCrossRefGoogle Scholar
  46. Huang W, Qiu C, von Strauss E, Winblad B, Fratiglioni L (2004) APOE genotype, family history of dementia, and Alzheimer disease risk: a 6-year follow-up study. Arch Neurol 61(12):1930–1934PubMedCrossRefGoogle Scholar
  47. Jembrek MJ, Babic M, Pivac N, Hof PR, Simic G (2013) Hyperphosphorylation of tau by gsk-3 beta in alzheimer’s disease: the interaction of a beta and sphingolipid mediators as a therapeutic target. Transl Neurosci 4(4):466–476CrossRefGoogle Scholar
  48. Jian X, Zhu MX (2016) Regulation of lysosomal ion homeostasis by channels and transporters. Sci China Life Sci 59(8):777–791CrossRefGoogle Scholar
  49. Kar A, Kuo D, He R, Zhou J, Wu JY (2005) Tau alternative splicing and frontotemporal dementia. Alzheimer Dis Assoc Disord 19(Suppl 1):S29–S36PubMedPubMedCentralCrossRefGoogle Scholar
  50. Kesavapany S, Li BS, Amin N, Zheng YL, Grant P, Pant HC (2004) Neuronal cyclin-dependent kinase 5: role in nervous system function and its specific inhibition by the Cdk5 inhibitory peptide. Biochim Biophys Acta 1697(1–2):143–153PubMedCrossRefGoogle Scholar
  51. Kilburn KH (1994) Neurobehavioral impairment and seizures from formaldehyde. Arch Environ Health 49(1):37–44PubMedCrossRefGoogle Scholar
  52. Kim B, Backus C, Oh S, Hayes JM, Feldman EL (2009) Increased tau phosphorylation and cleavage in mouse models of type 1 and type 2 diabetes. Endocrinology 150(12):5294–5301PubMedPubMedCentralCrossRefGoogle Scholar
  53. Kim DH, Huh JW, Jang M, Suh JH, Kim TW, Park JS, Yoon SY (2012) Sitagliptin increases tau phosphorylation in the hippocampus of rats with type 2 diabetes and in primary neuron cultures. Neurobiol Dis 46(1):52–58PubMedCrossRefGoogle Scholar
  54. Kopke E, Tung YC, Shaikh S et al (1993) Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. J Biol Chem 268(32):24374–24384PubMedGoogle Scholar
  55. Ksiezak-Reding H, Liu WK, Yen SH (1992) Phosphate analysis and dephosphorylation of modified tau associated with paired helical filaments. Brain Res 597(2):209–219PubMedCrossRefGoogle Scholar
  56. Li T, Paudel HK (2006) Glycogen synthase kinase 3beta phosphorylates Alzheimer’s disease-specific Ser396 of microtubule-associated protein tau by a sequential mechanism. Biochemistry 45(10):3125–3133PubMedCrossRefGoogle Scholar
  57. Li XH, Lv BL, Xie JZ, Liu J, Zhou XW, Wang JZ (2012) AGEs induce Alzheimer-like tau pathology and memory deficit via RAGE-mediated GSK-3 activation. Neurobiol Aging 33(7):1400–1410PubMedCrossRefGoogle Scholar
  58. Lindwall G, Cole RD (1984) Phosphorylation affects the ability of tau protein to promote microtubule assembly. J Biol Chem 259(8):5301–5305PubMedGoogle Scholar
  59. Lithfous S, Dufour A, Despres O (2013) Spatial navigation in normal aging and the prodromal stage of Alzheimer’s disease: insights from imaging and behavioral studies. Ageing Res Rev 12(1):201–213PubMedCrossRefGoogle Scholar
  60. Liu F, Liang Z, Wegiel J, Hwang YW, Iqbal K, Grundke-Iqbal I, Ramakrishna N, Gong CX (2008) Overexpression of Dyrk1A contributes to neurofibrillary degeneration in down syndrome. FASEB J 22(9):3224–3233PubMedPubMedCentralCrossRefGoogle Scholar
  61. Liu K, He Y, Yu L, Chen Y, He R (2017) Markedly elevated formaldehyde in the cecum of APP/PS1 mouse. Microbiol China 44(8):1761–1766Google Scholar
  62. Loomis PA, Howard TH, Castleberry RP, Binder LI (1990) Identification of nuclear tau isoforms in human neuroblastoma cells. Proc Natl Acad Sci U S A 87(21):8422–8426PubMedPubMedCentralCrossRefGoogle Scholar
  63. Lu Z, Li CM, Qiao Y, Yan Y, Yang X (2008) Effect of inhaled formaldehyde on learning and memory of mice. Indoor Air 18(2):77–83PubMedCrossRefGoogle Scholar
  64. Lu J, Miao JY, Pan R, He RQ (2011) Formaldehyde-mediated hyperphosphorylation disturbs the interaction between tau protein and DNA. Prog Biochem Biophys 38(12):1113–1120CrossRefGoogle Scholar
  65. Lu J, Miao J, Su T, Liu Y, He R (2013a) Formaldehyde induces hyperphosphorylation and polymerization of tau protein both in vitro and in vivo. Biochim Biophys Acta 1830(8):4102–4116PubMedCrossRefGoogle Scholar
  66. Lu Y, He HJ, Zhou J, Miao JY, Lu J, He YG, Pan R, Wei Y, Liu Y, He RQ (2013b) Hyperphosphorylation results in tau dysfunction in DNA folding and protection. J Alzheimers Dis 37(3):551–563PubMedGoogle Scholar
  67. Lu J, Li T, He R, Bartlett PF, Gotz J (2014) Visualizing the microtubule-associated protein tau in the nucleus. Sci China Life Sci 57(4):422–431PubMedCrossRefGoogle Scholar
  68. Luo J, He R (1999) Effect of acetaldehyde on aggregation of neuronal tau. Protein Pept Lett 6(2):105–110Google Scholar
  69. MacAllister SL, Choi J, Dedina L, O’Brien PJ (2011) Metabolic mechanisms of methanol/formaldehyde in isolated rat hepatocytes: carbonyl-metabolizing enzymes versus oxidative stress. Chem Biol Interact 191(1–3):308–314PubMedCrossRefGoogle Scholar
  70. Miao J, Lu J, Zhang Z, Tong Z, He R (2013) The effect of formaldehyde on cell cycle is in a concentration-dependent manner. Prog Biochem Biophys 40(7):641–651Google Scholar
  71. Michel G, Mercken M, Murayama M, Noguchi K, Ishiguro K, Imahori K, Takashima A (1998) Characterization of tau phosphorylation in glycogen synthase kinase-3beta and cyclin dependent kinase-5 activator (p23) transfected cells. Biochim Biophys Acta 1380(2):177–182PubMedCrossRefGoogle Scholar
  72. Monte WC (2012) While science sleeps (SC, USA: Charleston)Google Scholar
  73. Mudher A, Lovestone S (2002) Alzheimer’s disease-do tauists and baptists finally shake hands? Trends Neurosci 25(1):22–26PubMedCrossRefGoogle Scholar
  74. Nie CL, Wei Y, Chen XY, Liu YY, Dui W, Liu Y, Davies MC, Tendler SJB, He RG (2007) Formaldehyde at low concentration induces protein tau into globular amyloid-like aggregates in vitro and in vivo. PLoS One 2(7). doi: 10.1371/journal.pone.0000629
  75. Nobutoki T, Ihara T (2015) Early disruption of neurovascular units and microcirculatory dysfunction in the spinal cord in spinal muscular atrophy type I. Med Hypotheses 85(6):842–845PubMedCrossRefGoogle Scholar
  76. Oliveira JM, Henriques AG, Martins F, Rebelo S, Silva OABDE (2015) Amyloid-beta modulates both a beta PP and tau phosphorylation. J Alzheimers Dis 45(2):495–507PubMedGoogle Scholar
  77. Olsson A, Vanderstichele H, Andreasen N, De Meyer G, Wallin A, Holmberg B, Rosengren L, Vanmechelen E, Blennow K (2005) Simultaneous measurement of beta-amyloid(1-42), total tau, and phosphorylated tau (Thr181) in cerebrospinal fluid by the xMAP technology. Clin Chem 51(2):336–345PubMedCrossRefGoogle Scholar
  78. Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH (1999) Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402(6762):615–622PubMedCrossRefGoogle Scholar
  79. Planel E, Tatebayashi Y, Miyasaka T, Liu L, Wang L, Herman M, Yu WH, Luchsinger JA, Wadzinski B, Duff KE et al (2007) Insulin dysfunction induces in vivo tau hyperphosphorylation through distinct mechanisms. J Neurosci 27(50):13635–13648PubMedCrossRefGoogle Scholar
  80. Qu Z, Jiao Z, Sun X, Zhao Y, Ren J, Xu G (2011) Effects of streptozotocin-induced diabetes on tau phosphorylation in the rat brain. Brain Res 1383(300–6):300–306PubMedCrossRefGoogle Scholar
  81. Rahman A, Ting K, Cullen KM, Braidy N, Brew BJ, Guillemin GJ (2009) The Excitotoxin Quinolinic acid induces tau phosphorylation in human neurons. PLoS One 4(7). doi: 10.1371/journal.pone.0006344
  82. Rhein V, Song X, Wiesner A, Ittner LM, Baysang G, Meier F, Ozmen L, Bluethmann H, Drose S, Brandt U et al (2009) Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice. Proc Natl Acad Sci U S A 106(47):20057–20062PubMedPubMedCentralCrossRefGoogle Scholar
  83. Rizak JD, Ma Y, Hu X (2014) Is formaldehyde the missing link in AD pathology? The differential aggregation of amyloid-beta with APOE isoforms in vitro. Curr Alzheimer Res 11(5):461–468PubMedCrossRefGoogle Scholar
  84. Run X, Liang Z, Zhang L, Iqbal K, Grundke-Iqbal I, Gong CX (2009) Anesthesia induces phosphorylation of tau. J Alzheimer’s Dis 16(3):619–626CrossRefGoogle Scholar
  85. Sanhueza M, Lisman J (2013) The CaMKII/NMDAR complex as a molecular memory. Mol Brain 6(10). doi: 10.1186/1756-6606-6-10
  86. Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W et al (1996) Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med 2(8):864–870PubMedCrossRefGoogle Scholar
  87. Serrano J, Fernandez AP, Martinez-Murillo R, Martinez A (2010) High sensitivity to carcinogens in the brain of a mouse model of Alzheimer’s disease. Oncogene 29(15):2165–2171PubMedCrossRefGoogle Scholar
  88. Shcherbakova LN, Tel’pukhov VI, Trenin SO, Bashilov IA, Lapkina TI (1986) Permeability of the blood-brain barrier to intra-arterial formaldehyde. Biull Eksp Biol Med 102(11):573–575PubMedGoogle Scholar
  89. Shu R, Wong W, Ma QH, Yang ZZ, Zhu H, Liu FJ, Wang P, Ma J, Yan S, Polo JM, et al (2015) APP intracellular domain acts as a transcriptional regulator of miR-663 suppressing neuronal differentiation. Cell Death Dis 19(6). doi: 10.1038/cddis.2015.10
  90. Sontag JM, Sontag E (2014) Protein phosphatase 2A dysfunction in Alzheimer’s disease. Front Mol Neurosci 7(16). doi: 10.3389/fnmol.2014.00016
  91. Stoothoff WH, Johnson GV (2005) Tau phosphorylation: physiological and pathological consequences. Biochim Biophys Acta 1739(2–3):280–297PubMedCrossRefGoogle Scholar
  92. Su T, Monte WC, Hu X, He Y, He R (2016) Formaldehyde as a trigger for protein aggregation and potential target for mitigation of age-related, progressive cognitive impairment. Curr Top Med Chem 16(5):472–484PubMedCrossRefGoogle Scholar
  93. Sultan A, Nesslany F, Violet M, Begard S, Loyens A, Talahari S, Mansuroglu Z, Marzin D, Sergeant N, Humez S et al (2011) Nuclear tau, a key player in neuronal DNA protection. J Biol Chem 286(6):4566–4575PubMedCrossRefGoogle Scholar
  94. Sun P, Chen JY, Li J, Sun MR, Mo WC, Liu KL, Meng YY, Liu Y, Wang F, He RQ et al (2013) The protective effect of geniposide on human neuroblastoma cells in the presence of formaldehyde. BMC Complement Altern Med 13(152). doi: 10.1186/1472-6882-13-152
  95. Tang XQ, Zhuang YY, Zhang P, Fang HR, Zhou CF, Gu HF, Zhang H, Wang CY (2013) Formaldehyde impairs learning and memory involving the disturbance of hydrogen sulfide generation in the hippocampus of rats. J Mol Neurosci 49(1):140–149PubMedCrossRefGoogle Scholar
  96. Tong Z, Zhang J, Luo W, Wang W, Li F, Li H, Luo H, Lu J, Zhou J, Wan Y et al (2011) Urine formaldehyde level is inversely correlated to mini mental state examination scores in senile dementia. Neurobiol Aging 32(1):31–41PubMedCrossRefGoogle Scholar
  97. Tong Z, Han C, Luo W, Li H, Luo H, Qiang M, Su T, Wu B, Liu Y, Yang X et al (2013) Aging-associated excess formaldehyde leads to spatial memory deficits. Sci Rep 3(1807). doi: 10.1038/srep01807
  98. Tong Z, Han C, Qiang M, Wang W, Lv J, Zhang S, Luo W, Li H, Luo H, Zhou J et al (2015) Age-related formaldehyde interferes with DNA methyltransferase function, causing memory loss in Alzheimer’s disease. Neurobiol Aging 36(1):100–110PubMedCrossRefGoogle Scholar
  99. Tsai LH, Delalle I, Caviness VS Jr, Chae T, Harlow E (1994) p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature 371(6496):419–423PubMedCrossRefGoogle Scholar
  100. Tsuji S (2010) Genetics of neurodegenerative diseases: insights from high-throughput resequencing. Hum Mol Genet 19(R1):R65–R70PubMedPubMedCentralCrossRefGoogle Scholar
  101. Verghese PB, Castellano JM, Holtzman DM (2011) Apolipoprotein E in Alzheimer’s disease and other neurological disorders. Lancet Neurol 10(3):241–252PubMedPubMedCentralCrossRefGoogle Scholar
  102. Wallin A, Nordlund A, Jonsson M, Blennow K, Zetterberg H, Ohrfelt A, Stalhammar J, Eckerstrom M, Carlsson M, Olsson E et al (2016a) Alzheimer’s disease--subcortical vascular disease spectrum in a hospital-based setting: overview of results from the Gothenburg MCI and dementia studies. J Cereb Blood Flow Metab 36(1):95–113PubMedPubMedCentralCrossRefGoogle Scholar
  103. Wallin A, Nordlund A, Jonsson M, Lind K, Edman A, Gothlin M, Stalhammar J, Eckerstrom M, Kern S, Borjesson-Hanson A, Carlsson M, Olsson E, Zetterberg H, Blennow K, Svensson J, Öhrfelt A, Bjerke M, Rolstad S, Eckerström C (2016b) The Gothenburg MCI study: design and distribution of Alzheimer’s disease and subcortical vascular disease diagnoses from baseline to 6-year follow-up. J Cereb Blood Flow Metab 36(1):114–131PubMedPubMedCentralCrossRefGoogle Scholar
  104. Wang Y, Loomis PA, Zinkowski RP, Binder LI (1993) A novel tau transcript in cultured human neuroblastoma cells expressing nuclear tau. J Cell Biol 121(2):257–267PubMedCrossRefGoogle Scholar
  105. Wang JH, Rizak JD, Chen YM, Li L, Hu XT, Ma YY (2013a) Interactive effects of morphine and dopaminergic compounds on spatial working memory in rhesus monkeys. Neurosci Bull 29(1):37–46PubMedPubMedCentralCrossRefGoogle Scholar
  106. Wang JZ, Xia YY, Grundke-Iqbal I, Iqbal K (2013b) Abnormal hyperphosphorylation of tau: sites, regulation, and molecular mechanism of neurofibrillary degeneration. J Alzheimer’s Dis 33(Suppl 1):S123–S139Google Scholar
  107. Wang J, Zhou J, Mo W, He Y, Wei Y, He R, Yi F (2017) Pathological level of formaldehyde decreases cell viability and adhesive morphology in murine neuroblastoma cells. Prog Biochem Biophys 44(7):601–614Google Scholar
  108. Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW (1975) A protein factor essential for microtubule assembly. Proc Natl Acad Sci U S A 72(5):1858–1862PubMedPubMedCentralCrossRefGoogle Scholar
  109. Whittington RA, Virag L, Marcouiller F, Papon MA, El Khoury NB, Julien C, Morin F, Emala CW, Planel E (2011) Propofol directly increases tau phosphorylation. PLoS One 6(1):e16648. doi: 10.1371/journal.pone.0016648 PubMedPubMedCentralCrossRefGoogle Scholar
  110. Wu L, Rosa-Neto P, Hsiung GY, Sadovnick AD, Masellis M, Black SE, Jia J, Gauthier S (2012) Early-onset familial Alzheimer’s disease (EOFAD). Can J Neurol Sci Le journal canadien des sciences neurologiques 39(4):436–445CrossRefGoogle Scholar
  111. Wu B, Wei Y, Wang Y, Su T, Zhou L, Liu Y, He R (2015) Gavage of D-Ribose induces Abeta-like deposits, Tau hyperphosphorylation as well as memory loss and anxiety-like behavior in mice. Oncotarget 6(33):34128–34142PubMedPubMedCentralGoogle Scholar
  112. Yanagisawa M, Planel E, Ishiguro K, Fujita SC (1999) Starvation induces tau hyperphosphorylation in mouse brain: implications for Alzheimer’s disease. FEBS Lett 461(3):329–333PubMedCrossRefGoogle Scholar
  113. Yang M, Lu J, Miao J, Rizak J, Yang J, Zhai R, Zhou J, Qu J, Wang J, Yang S et al (2014a) Alzheimer’s disease and methanol toxicity (part 1): chronic methanol feeding led to memory impairments and tau hyperphosphorylation in mice. J Alzheimer’s Dis JAD 41(4):1117–1129PubMedGoogle Scholar
  114. Yang M, Miao J, Rizak J, Zhai R, Wang Z, Huma T, Li T, Zheng N, Wu S, Zheng Y et al (2014b) Alzheimer’s disease and methanol toxicity (part 2): lessons from four rhesus macaques (Macaca mulatta) chronically fed methanol. J Alzheimer’s Dis 41(4):1131–1147Google Scholar
  115. Youmans KL, Tai LM, Nwabuisi-Heath E, Jungbauer L, Kanekiyo T, Gan M, Kim J, Eimer WA, Estus S, Rebeck GW et al (2012) APOE4-specific changes in Abeta accumulation in a new transgenic mouse model of Alzheimer disease. J Biol Chem 287(50):41774–41786PubMedPubMedCentralCrossRefGoogle Scholar
  116. Yu PH (2001) Involvement of cerebrovascular semicarbazide-sensitive amine oxidase in the pathogenesis of Alzheimer’s disease and vascular dementia. Med Hypotheses 57(2):175–179PubMedCrossRefGoogle Scholar
  117. Yu J, Su T, Zhou T, He Y, Lu J, Li J, He R (2014) Uric formaldehyde levels are negatively correlated with cognitive abilities in healthy older adults. Neurosci Bull 30(2):172–184PubMedPubMedCentralCrossRefGoogle Scholar
  118. Zhao B, Wan L (2012) Metal metabolic homeostasis disruption and early initiation of mechanism for Alzheimer′s disease. Prog Biochem Biophys 39(8):756–763CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2017

Authors and Affiliations

  1. 1.Monash Institute of Cognitive and Clinical NeurosciencesMonash UniversityMelbourneAustralia
  2. 2.State Key Laboratory of Brain and Cognitive ScienceInstitute of Biophysics, Chinese Academy of SciencesBeijingChina
  3. 3.University of Chinese Academy of SciencesBeijingChina

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