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β-Amyloid precursor protein (APP) and the human diseases

1 Department of Medicine, Biochemical Genetics and Metabolism, The Mitochondrial and Metabolic Disease Center, School of Medicine, University of California, San Diego, Building CTF, Room C-103, 214 Dickinson Street, San Diego, CA 92103-8467, USA
2 Department of Pediatrics, University of California, San Diego, School of Medicine, San Diego, La Jolla, CA 92093-0830, USA

Special Issues: Alzheimer’s Disease

Several pathophysiological functions of the human β-amyloid precursor protein (APP) have been recently proposed in different human diseases such as neurodevelopmental and neurodegenerative disorders including rare diseases such as autism, fragile X syndrome, amyotrophic lateral sclerosis, multiple sclerosis, Lesch-Nyhan disease; common and complex disorders such as Alzheimer’s disease; metabolic disorders such as diabetes; and also cancer. APP as well as all of its proteolytic fragments including the amyloid-β (Aβ) peptide, are part of normal physiology. The targeting of the components of APP proteolytic processing as a pharmacologic strategy will not be without consequences. Recent research results highlight the impact of alternative splicing (AS) process on human disease, and may provide new directions for the research on the impact of the human APP on human diseases. The identification of molecules capable of correcting and/or inhibiting pathological splicing events is therefore an important issue for future therapeutic approaches. To this end, the defective APP-mRNA isoform responsible for the disease in cells and tissues appears as an ideal target for epigenetic therapeutic intervention and antisense drugs are potential treatment.
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Keywords human β-amyloid precursor protein; epigenetics; epistasis; alternative splicing; neurodevelopmental and neurodegenerative disorders; rare diseases and common and complex disorders; antisense drugs

Citation: Khue Vu Nguyen. β-Amyloid precursor protein (APP) and the human diseases. AIMS Neuroscience, 2019, 6(4): 273-281. doi: 10.3934/Neuroscience.2019.4.273


  • 1. Nguyen KV (2018) Alzheimer's disease. AIMS Neuroscience 5: 74–80.    
  • 2. Zheng H, Koo EH (2006) The amyloid precursor protein: beyond amyloid. Mol Neurodegener 1: 5.    
  • 3. Nguyen KV (2015) The human β-amyloid precursor protein: biomolecular and epigenetic aspects. BioMol Concepts 6: 11–32.
  • 4. Di Luca M, Colciaghi F, Pastorino L, et al. (2000) Platelets as a peripheral district where to study pathogenetic mechanisms of Alzheimer disease: The case of amyloid precursor protein. Eur J Pharmacol 405: 277–283.    
  • 5. Ray B, Long JM, Sokol DK, et al. (2011) Increased secreted amyloid precursor protein-α(sAPPα) in severe autism: proposal of a specific, anabolic pathway and putative biomarker. PLoS One 6: e20405.    
  • 6. Sokol DK, Maloney B, Long JM, et al. (2011) Autism, Alzheimer's disease, and fragile X, APP, FMRP, and mGluR5 are molecular links. Neurology 76: 1344–1352.    
  • 7. Lahiri DK, Sokol DK, Erickson C, et al. (2013) Autism as early neurodevelopmental disorders: evidence for an sAPPα-mediated anabolic pathway. Front Cell Neurosci 7: 1–13.
  • 8. Hagerman RJ, Berry-Kravis E, Kaufmann WE, et al. (2009) Advance in the treatment of fragile X syndrome. Pediatrics 123: 378–390.    
  • 9. Bryson JB, Hobbs C, Parsons MJ, et al. (2012) Amyloid precursor protein (APP) contributes to pathology in the SOD1G93A mouse model of amyotrophic lateral sclerosis. Hum Mol Genet 21: 3871–3882.    
  • 10. Gehrmann J, Banati RB, Cuzner ML, et al. (1995) Amyloid precursor protein (APP) expression in multiple sclerosis lesions. Glia 15: 141–151.    
  • 11. Grant JL, Ghosn EE, Axtell RC, et al. (2012) Reversal of paralysis and reduced inflammation from peripheral administration of β-amyloid in TH1and TH17 versions of experimental autoimmune encephalomyelitis. Sci Transl Med 4: 145ra 105.
  • 12. Hohlfeld R, Wekerle H (2012) β-Amyloid: enemy or remedy. Sci Transl Med 4: 145fs24.
  • 13. Chandra A (2015) Role of amyloid from a multiple sclerosis. Perspective: a literature review. Neuroimmunomodulation 22: 343–346.
  • 14. Matias-Guiu JA, Oreja-Guevara C, Cabrera-Martin MN, et al. (2016) Amyloid proteins and their role in multiple sclerosis. Considerations in the use of amyloid-PET imaging. Front Neurol 7: 53.
  • 15. Imamura A, Yamanouchi H, Kurokawa T, et al. (1992) Elevated fibrinopeptide A (FPA) in patients with Lesch-Nyhan syndrome. Brain Dev 14: 424–425.    
  • 16. Irbaz bin R, Muhammmad H, Huthayfa A (2014) Recurrent thrombosis in a patient with Lesch-Nyhan syndrome. Am J Med 127: e12.
  • 17. Canobbio I, Visconte C, Momi S, et al. (2017) Platelet amyloid precursor protein is a modulator of venous thromboembolism in mice. Blood 130: 527–536.    
  • 18. Nguyen KV (2014) Epigenetic regulation in amyloid precursor protein and the Lesch-Nyhan syndrome. Biochem Biophys Res Commun 446: 1091–1095.    
  • 19. Nguyen KV (2015) Epigenetic regulation in amyloid precursor protein with genomic rearrangements and the Lesch-Nyhan syndrome. Nucleosides Nucleotides Nucleic Acids 34: 674–690.    
  • 20. Nguyen KV, Nyhan WL (2017) Quantification of various APP-mRNA isoforms and epistasis in Lesch-Nyhan disease. Neurosci Lett 643: 52–58.    
  • 21. Hardy JA, Higgin GA (1992) Alzheimer's disease: the amyloid cascade hypothesis. Science 256: 184–185.    
  • 22. Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessonsrom the Alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol 8: 102–112.
  • 23. Bettens K, Sleegers K, Van Broeckhoven C (2010) Current status on Alzheimer's disease molecular genetics: from past, to present, to future. Hum Mol Genet 19: R4–R11.    
  • 24. Hampel H, Frank R, Broich K, et al. (2010) Biomarkers for Alzheimer's disease: academic, industry and regulatory perspectives. Nat Rev 9: 560–574.
  • 25. Jiang T, Yu JT, Zhu XC, et al. (2013) TREM2 in Alzheimer's disease. Mol Neurobiol 48: 180– 185.    
  • 26. Ulrich JD, UllandTK, Colonna M, et al. (2017) Elucidating the role of TREM2 in Alzheimer's disease. Neuron 94: 237–248.    
  • 27. Klafki HW (2006) Therapeutic approaches to Alzheimer's disease. Brain 129: 2840–2855.    
  • 28. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297: 353–356.    
  • 29. Chetelat G (2013) Aβ-independent processes-rethinking preclinical AD. Nat Rev Neurol 9: 123–124.    
  • 30. Wang SC, Oelze B, Schumacher A (2008) Age-specific epigenetic drift in late-onset Alzheimer's disease. PLoS One 3: e2698.    
  • 31. Combarros O, Cortina-Borja M, Smith AD, et al. (2009) Epistasis in sporadic Alzheimer's disease. Neurobiol Aging 30: 1333–1349.    
  • 32. Czeczor JK, McGee SL (2017) Emerging roles for the amyloid precursor protein and derived peptides in the regulation of cellular and systemic metabolism. J Neuroendocrinol 29: 1–8.
  • 33. Aulston B, Schapansky J, HuangYW, et al. (2018) Secreted amyloid precursor protein alpha activates neuronal insulin receptor and prevents diabetes-induced encephalopathy. Exp Neurol 303: 29–37.    
  • 34. Moreno-Gonzalez I, Edwards III G, Salvadores N, et al. (2017) Molecular interaction between type 2 diabetes and Alzheimer's disease through cross-seeding of protein misfolding. Mol Psychiatry 22: 1327–1334.    
  • 35. Saitoh T, Sundsmo M, Roch JM, et al. (1989) Secreted form of amyloid beta protein precursor is involved in the growth regulation of fibroblast. Cell 58: 615–622.    
  • 36. Thinakaran G, Koo EH (2008) Amyloid precursor protein trafficking, processing, and function. J Biol Chem 283: 29615–29619.    
  • 37. Zheng H, Koo EH (2011) Biology and pathology of the amyloid precursor protein. Mol Neurodegener 6: 27.    
  • 38. Roe CM, Fitzpatrick AL, Xiong C, et al. (2010) Cancer linked to Alzheimer disease but not vascular dementia. Neurology 74: 106–112.    
  • 39. Hansel DE, Rahman A, Wehner S, et al. (2003) Increase expression and processing of the Alzheimer amyloid precursor protein in pancreatic cancer may influence cellular proliferation. Cancer Res 63: 7032–7037.
  • 40. Takayama KI, Tsutsumi S, Suzuki T, et al. (2009) Amyloid precursor protein is a primary androgen target gene that promotes prostate cancer growth. Cancer Res 69: 137–142.    
  • 41. Venkataramani V, Rossner C, Iffland L, et al. (2010) Histone deacetylase inhibitor valproic acid inhibits cancer cell proliferation via dow-regulation of the Alzheimer amyloid precursor protein. J Biol Chem 285: 10678–10689.    
  • 42. Venkataramani V, Thiele K, Behnes CL, et al. (2012) Amyloid precursor protein is a biomarker for transformed human pluripotent stem cells. Am J Pathol 180: 1636–1652.    
  • 43. Takagi K, Ito S, Miyazaki T, et al. (2013) Amyloid precursor protein in human breast cancer: an androgen-induced gene associated with cell proliferation. Cancer Res 104: 1532–1538.
  • 44. MiyazakiT, Ikeda K, Horie-Inoue K, et al. (2014) Amyloid precursor protein regulates migration and metalloproteinase gene expression in prostate cancer cells. Biochem Biophys Res Commun 452: 828–833.    
  • 45. Lim S, Yoo BK, Kim HS, et al. (2014) Amyloid-β precursor protein promotes cell proliferation and motility of advanced breast cancer. BMC Cancer 14: 928.    
  • 46. Pandey P, Sliker B, Peters HL, et al. (2016) Amyloid precursor protein and amyloid-precursor-like protein 2 in cancer. Oncotarget 7: 19430–19444.
  • 47. Cordell HJ (2002) Epistasis: what it means, what it doesn't mean, and statistical method to detect it in humans. Hum Mol Genet 11: 2463–2468.    
  • 48. Moore JH (2003) The ubiquitous nature of epistasis in determining susceptibility to common human diseases. Hum Hered 56: 73–82.    
  • 49. Riordan JD, Nadeau JH (2017) From peas to disease: modifier genes, network resilience, and the genetics of health. Am J Hum Genet 101: 177–191.    
  • 50. Pan Q, Shai O, Lee LJ, et al. (2008) Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet 40: 1413–1415.    
  • 51. Faustino NA, Cooper TA (2003) Pre-mRNA splicing and human disease. Genes Dev 17: 419–437.    
  • 52. Nguyen KV (2019) Potential epigenomic co-management in rare diseases and epigenetic therapy. Nucleosides Nucleotides Nucleic Acids 38: 752–780.    
  • 53. Saonere JA (2011) Antisense therapy, a magic bullet for the treatment of various diseases: present and future prospects. J Med Genet Genom 3: 77–83.


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