Brain Aging as a Cause of Alzheimer’s Disease

  • Toshiharu SuzukiEmail author
  • Ayano Kimura
  • Kyoko Chiba
  • Tadashi Nakaya
  • Saori Hata


Alzheimer’s disease (AD) is the most common form of senile dementia. Identification of genes causally associated with familial Alzheimer’s disease (FAD) advanced our understanding of the molecular mechanisms of AD pathogenesis. However, FAD is much less common than sporadic Alzheimer’s disease (SAD), which constitutes the majority of cases. Despite its similar pathology (albeit at a later age of onset), SAD is not linked to mutations in FAD-associated genes. In both FAD and SAD, the generation and oligomerization of amyloid β (Aβ) peptide play central roles in neurotoxicity, but it remains unclear how qualitative and quantitative alterations in Aβ occur in SAD patients in the absence of causative mutations. The predominant risk factor for SAD is aging, suggesting that some as-yet-unknown alterations in the aged brain augment the amyloidogenic metabolism of APP and promote the neural toxicity of Aβ oligomers. In this chapter, we discuss potential biochemical changes in amyloid β precursor protein (APP) and proteins related to APP metabolism and function in the aged brain. APP axonal transport, membrane microlocalization and metabolism, including generation of Aβ in neurons, are regulated by interactions with several cytoplasmic proteins and phosphorylation of the APP cytoplasmic region. Age-related decline or aberration in the regulation of APP transport, localization and metabolism may induce generation of altered Aβ. Here, we focus on APP phosphorylation at threonine 668 in the cytoplasmic domain and the roles of APP regulatory proteins, including X11-like (X11L), JIP1, kinesin-1, and Alcadein, on the regulation of APP metabolism and intracellular trafficking.


Brain aging Alzheimer’s disease APP Amyloid β peptide X11-like JIP1 Alcadein Protein phosphorylation Kinesin p3-Alc 



We are thankful to Prof. Nozomu Mori (Nagasaki University) and Prof. Inhee Mook-Jung (Seoul National University) for giving us this opportunity to write this review. This work was supported in part by Grant-in-Aid for Scientific Research 26293010 (to T.S.) and 24790062 (to S.H.) from MEXT, Japan, and in part by the Asian Core Program of the JSPS, Japan. S.H. was supported by the Bilateral Joint Research Projects of the JSPS.


  1. Ando K, Iijima KI, Elliott JI, Kirino Y, Suzuki T (2001) Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with FE65 affects the production of β-amyloid. J Biol Chem 276:40353–40361CrossRefPubMedGoogle Scholar
  2. Araki Y, Tomita S, Yamaguchi H, Miyagi N, Sumioka A, Kirino Y, Suzuki T (2003) Novel cadherin-related membrane proteins, Alcadeins, enhance the X11-like protein mediated stabilization of amyloid β-protein precursor metabolism. J Biol Chem 278:49448–49458CrossRefPubMedGoogle Scholar
  3. Araki Y, Miyagi N, Kato N, Yoshida T, Wada S, Nishimura M, Komano H, Yamamoto T, De Strooper B, Yamamoto K, Suzuki T (2004) Coordinated metabolism of Alcadein and amyloid β-protein precursor regulates FE65-dependent gene transactivation. J Biol Chem 279:24343–24354CrossRefPubMedGoogle Scholar
  4. Araki Y, Kawano T, Taru H, Saito Y, Wada S, Miyamoto K, Kobayashi H, Ishikawa HO, Ohsugi Y, Yamamoto T, Matsuno K, Kinjo M, Suzuki T (2007) The novel cargo Alcadein induces vesicle association of kinesin-1 motor components and activates axonal transport. EMBO J 26:1475–1486PubMedCentralCrossRefPubMedGoogle Scholar
  5. Beel A, Mobley CK, Kim HJ, Tian F, Hadziselimovic A, Jap B, Prestegard JH, Sanders CR (2008) Structural studies of the transmembrane C-terminal domain of the amyloid precursor protein (APP). Does APP functions as a cholesterol sensor? Biochemistry 47:9428–9446PubMedCentralCrossRefPubMedGoogle Scholar
  6. Chiba K, Araseki M, Nozawa K, Furukori K, Araki Y, Matsushima T, Nakaya T, Hata S, Saito Y, Uchida S, Okada Y, Nairn AC, Davis RJ, Yamamoto T, Kinjo M, Taru H, Suzuki T (2014) Quantitative analysis of APP axonal transport in neurons: role of JIP1 in enhanced APP anterograde transport. Mol Biol Cell 25:3569–3580PubMedCentralCrossRefPubMedGoogle Scholar
  7. Cole SL, Vassar R (2008) The role of amyloid precursor protein processing by BACE1, the β-secretase, in Alzheimer disease pathophysiology. J Biol Chem 283:29621–29625PubMedCentralCrossRefPubMedGoogle Scholar
  8. Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid β-peptide. Nat Rev Mol Cell Biol 8:101–112CrossRefPubMedGoogle Scholar
  9. Hancock WO (2014) Bidirectional cargo transport: moving beyond tug of war. Nat Rev Mol Cell Biol 9:615–628CrossRefGoogle Scholar
  10. Hata S, Fujishige S, Araki Y, Kato N, Araseki M, Nishimura M, Hartmann D, Saftig P, Fahrenholz F, Taniguchi M, Urakami K, Akatsu H, Martins RN, Yamamoto K, Maeda M, Yamamoto T, Nakaya T, Gandy S, Suzuki T (2009) Alcadein cleavages by APP α- and γ-secretases generate small peptides p3-Alcs indicating Alzheimer disease-related γ-secretase dysfunction. J Biol Chem 284:36024–36033PubMedCentralCrossRefPubMedGoogle Scholar
  11. Hata S, Fujishige S, Araki Y, Taniguchi M, Urakami K, Peskind E, Akatsu H, Araseki M, Yamamoto K, Martins NR, Maeda M, Nishimura M, Levey A, Chung KA, Montine T, Leverenz J, Fagan A, Goate A, Bateman R, Holtzman DM, Yamamoto T, Nakaya T, Gandy S, Suzuki T (2011) Alternative γ-secretase processing of γ-secretase substrates in common forms of mild cognitive impairment and Alzheimer disease: evidence for γ-secretase dysfunction. Ann Neurol 69:1026–1031PubMedCentralCrossRefPubMedGoogle Scholar
  12. Hata S, Taniguchi M, Piao Y, Ikeuchi T, Fagan AM, Holzman DM, Bateman R, Sohrabi HR, Martins RN, Gandy S, Urakami K, Suzuki T, J-ADNI (2012) Multiple γ-secretase product peptides are coordinately increased in concentration in the CSF of a subpopulation of sporadic Alzheimer's disease subjects. Mol Neurodegener 7:16PubMedCentralCrossRefPubMedGoogle Scholar
  13. Hirokawa N, Noda Y, Tanaka Y, Niwa S (2009) Kinesin superfamily motor proteins and intracellular transport. Nat Rev Mol Cell Biol 10:682–696CrossRefPubMedGoogle Scholar
  14. Horiuchi D, Barkus RV, Pilling AD, Gassman A, Saxton WM (2005) APLIP1, a kinesin binding JIP-1/JNK scaffold protein, influences the axonal transport of both vesicles and mitochondria in Drosophila. Curr Biol 15:2137–2141PubMedCentralCrossRefPubMedGoogle Scholar
  15. Iijima K, Ando K, Takeda S, Satoh Y, Seki T, Itohara S, Greengard P, Kirino Y, Nairn AC, Suzuki T (2000) Neuron-specific phosphorylation of Alzheimer’s b-amyloid precursor protein by cyclin-dependent kinase 5. J Neurochem 75:1085–1091CrossRefPubMedGoogle Scholar
  16. Kakuda N, Shoji M, Arai H, Furukawa K, Ikeuchi T, Akazawa K, Takami M, Hatsuta H, Murayama S, Hashimoto Y, Miyajima M, Arai H, Nagashima Y, Yamaguchi H, Kuwano R, Nagaike K, Ihara Y, for J-ADNI (2012) Altered γ-secretase activity in mild cognitive impairment and Alzheimer’s disease. EMBO Mol Med 4:344–352PubMedCentralCrossRefPubMedGoogle Scholar
  17. Kamal A, Stokin GB, Yang Z, Xia CH, Goldstein LS (2000) Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-1. Neuron 28:449–459CrossRefPubMedGoogle Scholar
  18. Kamogawa K, Kohara K, Tabara Y, Takita R, Miki T, Konno T, Hata S, Suzuki T (2012) Utility of plasma levels of soluble p3-Alcadeinα as a biomarker for sporadic Alzheimer’s disease. J Alzheimers Dis 31:421–428PubMedGoogle Scholar
  19. Kanekiyo T, Xu H, Bu G (2014) ApoE and Ab in Alzheimer’s disease: accidental encounters or partners. Neuron 81:740–754PubMedCentralCrossRefPubMedGoogle Scholar
  20. Kawano T, Araseki M, Araki Y, Kinjo M, Yamamoto T, Suzuki T (2012) A small peptide sequence is sufficient for initiating kinesin-1 activation through part of TPR region of KLC1. Traffic 13:834–848CrossRefPubMedGoogle Scholar
  21. Kok E, Haikonen S, Luoto T, Huhtala H, Goebeler S, Haapasalo H, Karhunen PJ (2009) Appolipoprotein E-dependent accumulation of Alzheimer disease-related lesions begins in middle age. Ann Neurol 65:650–657CrossRefPubMedGoogle Scholar
  22. Konecta A, Frischknecht R, Kinter J, Ludwig A, Steuble M, Meskenaite V, Indermuhle M, Engel M, Cen C, Mateos JM, Sreit P, Sonderegger P (2006) Calsyntenin-1 docks vescular cargo to kinesin-1. Mol Biol Cell 17:3651–3663CrossRefGoogle Scholar
  23. Konnno T, Hata S, Hamada Y, Horikoshi Y, Nakaya T, Saito Y, Yamamoto T, Yamamoto T, Maeda M, Gandy S, Akatsu H, Suzuki T, for J-ADNI (2011) Coordinate increase of γ-secretase reaction products in the plasma of some female Japanese sporadic Alzheimer’s disease patients: quantitative analysis with a new ELISA system. Mol Neurodegener 6:76CrossRefGoogle Scholar
  24. Matsushima T, Saito Y, Elliott JI, Iijim-Ando K, Nishimura M, Kimura N, Hata S, Yamamoto T, Nakaya T, Suzuki T (2012) Membrane-microdomain localization of amyloid β-precursor protein (APP) C-terminal fragments is regulated by phosphorylation of the cytoplasmic Thr668 residue. J Biol Chem 287:19715–19724PubMedCentralCrossRefPubMedGoogle Scholar
  25. Mawuenyaga KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, Yarasheski KE, Bateman RJ (2010) Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science 330:1774CrossRefGoogle Scholar
  26. Millecamps S, Julien J-P (2013) Axonal transport deficits and neurodegenerative disease. Nat Rev Neurosci 14:161–176CrossRefPubMedGoogle Scholar
  27. Morel M, Heraud C, Nicaise C, Suain V, Brion JP (2012) Levels of kinesin light chain and dynein intermediate chain are reduced in the frontal cortex in Alzheimer’s disease: implications for axoplasmic transport. Acta Neuropathol 123:71–84CrossRefPubMedGoogle Scholar
  28. Morihara T, Hayashi N, Yokokoji M, Akatsu H, Silverman MA, Kimura N, Sato M, Saito Y, Suzuki T, Yanagida K, Kodama TS, Tanaka T, Okochi M, Tagami S, Kazui H, Kubo T, Hashimoto R, Itoh N, Nishitomi K, Yamaguchi-Kabata Y, Tsunoda T, Takamura H, Katayama T, Kimura R, Kamino K, Hashizume Y, Takeda M (2014) Transcriptome analysis of distinct mouse strains reveals kinesin light chain-1 splicing as an amyloid-β accumulation modifier. Proc Natl Acad Sci USA 111:2638–2643PubMedCentralCrossRefPubMedGoogle Scholar
  29. Oikawa N, Kimura N, Yanagisawa K (2010) Alzheimer-type tau pathology in advanced age nonhuman primate brains harboring substantial amyloid deposition. Brain Res 1315:137–149CrossRefPubMedGoogle Scholar
  30. Omori C, Kaneko M, Nakajima E, Akatsu H, Waragai M, Maeda M, Morishima-Kawashima M, Saito Y, Nakaya T, Taru H, Yamamoto T, Asada T, Hata S, Suzuki T, for J-ADNI (2014) Increased levels of plasma p3-Alcα35, a major fragment of alcaseinα by γ-secretase cleavage, in Alzheimer disease. J Alzheimers Dis 39:861–870PubMedGoogle Scholar
  31. Piao Y, Kimura A, Urano S, Saito Y, Taru H, Yamamoto T, Hata S, Suzuki T (2013) Mechanism of intramembrane cleavage of Alcadeins by γ-secretase. PLoS One 8:e62431PubMedCentralCrossRefPubMedGoogle Scholar
  32. Ramelot TA, Nicholson LK (2001) Phosphorylation-induced structural changes in the amyloid precursor protein cytoplasmic tail detected by NMR. J Mol Biol 307:871–884CrossRefPubMedGoogle Scholar
  33. Rhinn H, Fujita R, Qiang L, Cheng R, Lee JH, Abeliovich A (2013) Integrative genomics identifies APOEe4 effectors in Alzheimer’s disease. Nature 500:45–50CrossRefPubMedGoogle Scholar
  34. Riddle DR, Christie G, Hussain I, Dingwall C (2001) Compartmentalization of beta-secretase (Asp2) into low-buoyant density, noncaveolar lipid rafts. Curr Biol 11:1288–1293CrossRefGoogle Scholar
  35. Saito Y, Sano Y, Vassar R, Gandy S, Nakaya T, Yamamoto T, Suzuki T (2008) X11 proteins regulate the translocation of amyloid β-protein precursor (APP) into detergent-resistant membrane and suppress the amyloidogenic cleavage of APP by β-site-cleaving enzyme in brain. J Biol Chem 283:35763–35771PubMedCentralCrossRefPubMedGoogle Scholar
  36. Stokin GG, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, Raman R, Davies P, Masliah E, Williams DS, Goldstein LS (2005) Axonopathy and transport deficities early in the pathogenesis of Alzheimer’s disease. Science 307:1282–1288CrossRefPubMedGoogle Scholar
  37. Suzuki T, Nakaya T (2008) Regulation of amyloid β-protein precursor by phosphorylation and protein interactions. J Biol Chem 283:29633–29637PubMedCentralCrossRefPubMedGoogle Scholar
  38. Suzuki T, Araki Y, Yamamoto T, Nakaya T (2006) Trafficking of Alzheimer’s disease-related membrane proteins and its participation in disease pathogenesis. J Biochem 139:949–955CrossRefPubMedGoogle Scholar
  39. Takami M, Nagashima Y, Sano Y, Ishihara S, Morishima-Kawashima M, Funamoto S, Ihara Y (2009) Gamma-secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J Neurosci 29:13042–13052CrossRefPubMedGoogle Scholar
  40. Takei N, Sobu Y, Kimura A, Urano S, Piao Y, Araki Y, Taru H, Yamamoto T, Hata S, Nakaya T, Suzuki T (2015) Cytoplasmic fragment of Alcadeinα generated by regulated intramembrane proteolysis enhances APP transport into the late-secretory pathway and facilitates APP cleavage. J Biol Chem 290:987–995CrossRefPubMedGoogle Scholar
  41. Taru H, Suzuki T (2009) Regulation of physiological function and metabolism of AβPP by AβPP binding proteins. J Alzheimer Dis 18:253–265Google Scholar
  42. Taru T, Iijima K, Hase M, Kirino Y, Yagi Y, Suzuki T (2002) Interaction of Alzheimer’s β-amyloid precursor family proteins with scaffold proteins of the JNK signaling cascade. J Biol Chem 277:20070–20078CrossRefPubMedGoogle Scholar
  43. Thies W, Bleiler L, Alzheimer’s Association (2013) Alzheimer’s disease facts and figures. Alzheimers Dement 9:208–245CrossRefGoogle Scholar
  44. Thinakaran G, Koo EH (2008) Amyloid precursor protein trafficking, processing, and function. J Biol Chem 283:29615–29619PubMedCentralCrossRefPubMedGoogle Scholar
  45. Vale RD, Reese TS, Sheetz MP (1985) Identification of a novel force-generating protein, kinesin, involved in microtubule-based motility. Cell 42:39–50PubMedCentralCrossRefPubMedGoogle Scholar
  46. Verhey KJ, Hammond JW (2009) Traffic control: regulation of kinesin motors. Nat Rev Mol Cell Biol 10:765–777CrossRefPubMedGoogle Scholar
  47. Verhey KJ, Meyer D, Deehan R, Blenis J, Schnapp BJ, Rapoport TA, Margolis B (2001) Cargo of kinesin identified as JIP scaffolding proteins and associated signaling molecules. J Cell Biol 152:959–970PubMedCentralCrossRefPubMedGoogle Scholar
  48. Vogt L, Schrimpf SP, Meskenaite V, Frischknecht R, Kinter J, Leone DP, Ziegler U, Sonderegger P (2001) Calsyntenin-1, a proteolytically processed postsynaptic membrane protein with a cytoplasmic calcium-binding domain. Mol Cell Neurosci 17:151–166CrossRefPubMedGoogle Scholar
  49. World Health Organization and Alzheimer’s Disease International (2012) Mental health. Dementia: a public health priority. WHO Press, Geneva. ISBN:978 92 4 156445 8Google Scholar
  50. Yagi Y, Tomita S, Nakamura M, Suzuki T (2000) Overexpression of human amyloid precursor protein in Drosophila. Mol Cell Biol Res Commun 4:43–49CrossRefPubMedGoogle Scholar

Copyright information

© Springer Japan 2015

Authors and Affiliations

  • Toshiharu Suzuki
    • 1
    Email author
  • Ayano Kimura
    • 1
  • Kyoko Chiba
    • 1
  • Tadashi Nakaya
    • 1
  • Saori Hata
    • 1
  1. 1.Laboratory of Neuroscience, Graduate School of Pharmaceutical SciencesHokkaido UniversitySapporoJapan

Personalised recommendations