Skip to main content
SpringerLink
Log in

What is the dominant aβ species in human brain tissue? A review

  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

Epub ahead of print: December 2004 Interest in the beta amyloid (Aβ) peptides continues to grow due to their known accumulation in the brains of patients with Alzheimer’s disease and recent tantalising evidence that reducing such accumulations can reverse disease-associated functional deficits. Aβ peptides are naturally produced in every cell by proteolytic cleavage of the amyloid precursor protein with two main alloforms (40 or 42 amino acids) both of which are disease associated. The identification that genetic mutations causing Alzheimer’s disease impact on Aβ production and clearance have allowed for the manipulation of these pathways in cellular and animal models. These studies show that the amount and type of Aβ in the brain has significant consequences on neural function. However, there have been significant difficulties in the conversion of these findings into successful treatments in humans. In this review we concentrate on data from human studies to determine any comparative differences in Aβ production and clearance that may assist with better treatment design and delivery. Aβ40 is the dominant peptide species in human cerebrospinal fluid accounting for approximately 90% of total Aβ under normal conditions. However, similar studies using disease free human brain tissue do not correlate with these findings. In these studies, concentrations of Aβ40 are low with Aβ42 often identified as the dominant species. The data suggest preferential brain tissue utilisation and/or clearance of Aβ40 compared with Aβ42, findings which may have been predicted by their physiochemical differences. In Alzheimer’s disease this equilibrium is disrupted significantly increasing Aβ peptide levels in brain tissue. The disease-specific increase in Aβ40 brain tissue levels in Alzheimer’s disease appears to be an important though overlooked pathological change compared with the welldocumented Aβ42 change observed both in the aged and in Alzheimer’s disease. These findings are discussed in association with Aβ peptide function and a model of toxicity developed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Andreasen N, C Hesse, P Davidsson, L Minthon, A Wallin, B Winblad, H Vanderstichele, E Vanmechelen and K Blennow (1999a) Cerebrospinal fluid beta-amyloid(1-42) in Alzheimer disease: differences between early- and late-onset Alzheimer disease and stability during the course of disease.Arch. Neurol. 56, 673–680.

    Article  PubMed  CAS  Google Scholar 

  • Andreasen N, L Minthon, E Vanmechelen, H Vanderstichele, P Davidsson, B Winblad and K Blennow (1999b) Cerebrospinal fluid tau and Abeta42 as predictors of development of Alzheimer’s disease in patients with mild cognitive impairment.Neurosci. Lett. 273, 5–8.

    Article  PubMed  CAS  Google Scholar 

  • Avdulov NA, SV Chochina, U Igbavboa, CS Warden, AV Vassiliev and WG Wood (1997) Lipid binding to amyloid beta-peptide aggregates: preferential binding of cholesterol as compared with phosphatidylcholine and fatty acids.J. Neurochem. 69, 1746–1752.

    Article  PubMed  CAS  Google Scholar 

  • Banks WA, SM Ronbinson, S Verma and JE Morley (2003) Efflux of human and mouse amyloid β proteins 1-40 and 1-42 from brain: impairment in a mouse model of Alzheimer’s disease.Neuroscience 121, 487–492.

    Article  PubMed  CAS  Google Scholar 

  • Bard F, C Cannon, R Barbour, RL Burke, D Games, H Grajeda, T Guido, K Hu, J Huang, K Johnson-Wood, K Khan, D Kholodenko, M Lee, I Lieberburg, R Motter, M Nguyen, F Soriano, N Vasquez, K Weiss, B Welch, P Seubert, D Schenk and T Yednock (2000) Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease.Nat. Med. 6, 916–919.

    Article  PubMed  CAS  Google Scholar 

  • Beffert U, JS Cohn, C Petit-Turcotte, M Tremblay, N Aumont, C Ramassamy, J Davignon and J Poirier (1999) Apolipoprotein E and beta-amyloid levels in the hippocampus and frontal cortex of Alzheimer’s disease subjects are disease-related and apolipoprotein E genotype dependent.Brain Res. 843, 87–94.

    Article  PubMed  CAS  Google Scholar 

  • Bitan G, MD Kirkitadze, A Lomakin, SS Vollers, GB Benedek and DB Teplow (2003a) Amyloid beta -protein (Abeta) assembly: Abeta 40 and Abeta 42 oligomerize through distinct pathways.Proc. Natl. Acad. Sci. USA 100, 330–335.

    Article  PubMed  CAS  Google Scholar 

  • Bitan G, SS Vollers and DB Teplow (2003b) Elucidation of primary structure elements controlling early amyloid beta-protein oligomerization.J. Biol. Chem. 278, 34882–34889.

    Article  PubMed  CAS  Google Scholar 

  • Borchelt DR, T Ratovitski, J van Lare, MK Lee, V Gonzales, NA Jenkins, NG Copeland, DL Price and SS Sisodia (1997) Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins.Neuron 19, 939–945.

    Article  PubMed  CAS  Google Scholar 

  • Borroni B, F Colciaghi, C Caltagirone, L Rozzini, L Broglio, F Cattabeni, M Di Luca and A Padovani (2003) Platelet amyloid precursor protein abnormalities in mild cognitive impairment predict conversion to dementia of Alzheimer type: a 2-year follow-up study.Arch. Neurol. 60, 1740–1744.

    Article  PubMed  Google Scholar 

  • Brown MS, J Ye, RB Rawson and JL Goldstein (2000) Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans.Cell 100, 391–398.

    Article  PubMed  CAS  Google Scholar 

  • Butterfield DA and AI Bush (2004) Alzheimer’s amyloid β-peptide (1-42): involvement of methionine residue 35 in the oxidative stress and neurotoxicity properties of this peptide.Neurobiol. Aging 25, 563–568.

    Article  PubMed  CAS  Google Scholar 

  • Calero M, A Rostagno, E Matsubara, B Zlokovic, B Frangione and J Ghiso (2000) Apolipoprotein J (clusterin) and Alzheimer’s disease.Microsc. Res. Tech. 50, 305–315.

    Article  PubMed  CAS  Google Scholar 

  • Chesneau V, K Vekrellis, MR Rosner and DJ Selkoe (2000) Purified recombinant insulin-degrading enzyme degrades amyloid betaprotein but does not promote its oligomerization.Biochem. J. 351, 509–516.

    Article  PubMed  CAS  Google Scholar 

  • Coles M, W Bicknell, AA Watson, DP Fairlie and DJ Craik (1998) Solution structure of amyloid beta-peptide(1-40) in a watermicelle environment. Is the membrane-spanning domain where we think it is?Biochemistry 37, 11064–11077.

    Article  PubMed  CAS  Google Scholar 

  • Cook DG, MS Forman, JC Sung, S Leight, DL Kolson, T Iwatsubo, VM Lee and RW Doms (1997) Alzheimer’s Abeta(1-42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells.Nat. Med. 3, 1021–1023.

    Article  PubMed  CAS  Google Scholar 

  • Crawford F, Z Suo, C Fang and M Mullan (1998) Characteristics of thein vitro vasoactivity of beta-amyloid peptides.Exp. Neurol. 150, 159–168.

    Article  PubMed  CAS  Google Scholar 

  • Crescenzi O, S Tomaselli, R Guerrini, S Salvadori, AM D’Ursi, PA Temussi and D Picone (2002) Solution structure of the Alzheimer amyloid beta-peptide (1-42) in an apolar microenvironment. Similarity with a virus fusion domain.Eur. J. Biochem. 269, 5642–5648.

    Article  PubMed  CAS  Google Scholar 

  • Cuajungco MP, LE Goldstein, A Nunomura, MA Smith, JT Lim, CS Atwood, X Huang, YW Farrag, G Perry and AI Bush (2000) Evidence that the beta-amyloid plaques of Alzheimer’s disease represent the redox-silencing and entombment of Abeta by zinc.J. Biol. Chem. 275, 19439–19442.

    Article  PubMed  CAS  Google Scholar 

  • Das P and TE Golde (2002) Open peer commentary regarding Abeta immunization and CNS inflammation by Pasinettiet al., Neurobiol. Aging 23, 671–4; discussion 683-684.

    Article  PubMed  Google Scholar 

  • De Ferrari GV and NC Inestrosa (2000) Wnt signaling function in Alzheimer’s disease.Brain Res. Brain Res. Rev. 33, 1–12.

    PubMed  Google Scholar 

  • DeMattos RB, KR Bales, DJ Cummins, JC Dodart, SM Paul and DM Holtzman (2001) Peripheral anti-Abeta antibody alters CNS and plasma Abeta clearance and decreases brain Abeta burden in a mouse model of Alzheimer’s disease.Proc. Natl. Acad. Sci. USA 98, 8850–8855.

    Article  Google Scholar 

  • DeMattos RB, KR Bales, DJ Cummins, SM Paul and DM Holtzman (2002) Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer’s disease.Science 295, 2264–2267.

    Article  Google Scholar 

  • Esler WP, WT Kimberly, BL Ostaszewski, W Ye, TS Diehl, DJ Selkoe and MS Wolfe (2002) Activity-dependent isolation of the presenilin- gamma-secretase complex reveals nicastrin and a gamma substrate.Proc. Natl. Acad. Sci. USA 99, 2720–2725.

    Article  PubMed  CAS  Google Scholar 

  • Francis R, G McGrath, J Zhang, DA Ruddy, M Sym, J Apfeld, M Nicoll, M Maxwell, B Hai, MC Ellis, AL Parks, W Xu, J Li, M Gurney, RL Myers, CS Himes, R Hiebsch, C Ruble, JS Nye and D Curtis (2002) aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation.Dev. Cell 3, 85–97.

    Article  PubMed  CAS  Google Scholar 

  • Fukumoto H, A Asami-Odaka, N Suzukiand T Iwatsubo (1996) Association of Abeta 40-positive senile plaques with microglial cells in the brains of patients with Alzheimer’s disease and in non-demented aged individuals.Neurodegeneration 5, 13–17.

    Article  PubMed  CAS  Google Scholar 

  • Funato H, M Yoshimura, K Kusui, A Tamaoka, K Ishikawa, N Ohkoshi, K Namekata, R Okeda and Y Ihara (1998) Quantitation of amyloid beta-protein (Abeta) in the cortex during aging and in Alzheimer’s disease.Am. J. Pathol. 152, 1633–1640.

    PubMed  CAS  Google Scholar 

  • Games D, D Adams, R Alessandrini, R Barbour, P Berthelette, C Blackwell, T Carr, J Clemens, T Donaldson, F Gillespie, T Guido, S Hagopian, K Johnson-Wood, K Khan, M Lee, P Leibowitz, I Lieberburg, S Little, E Masliah, L McConlogue, M Montoya-Zavala, L Mucke, L Paganini, E Penniman, M Power, D Schenk, P Seubert, B Snyder, F Soriano, H Tan, J Vitale, S Wadsworth, B Wolozin and J Zhao (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein.Nature 373, 523–527.

    Article  PubMed  CAS  Google Scholar 

  • Glenner GG and CW Wong (1984) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein.Biochem. Biophys. Res. Commun. 120, 885–890.

    Article  PubMed  CAS  Google Scholar 

  • Goate A, MC Chartier-Harlin, M Mullan, J Brown, F Crawford, L Fidani, L Giuffra, A Haynes, N Irving, L James, R Mant, P Newton, K Rooke, P Roques, C Talbot, M Pericak-Vance, A Roses, R Williamson, M Rossor, M Owen and J Hardy (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease.Nature 349, 704–706.

    Article  PubMed  CAS  Google Scholar 

  • Gotz J, JR Streffer, D David, A Schild, F Hoerndli, L Pennanen, P Kurosinski and F Chen (2004) Transgenic animal models of Alzheimer’s disease and related disorders: histopathology, behavior and therapy.Mol. Psychiatry 9, 664–683.

    PubMed  CAS  Google Scholar 

  • Goutte C, M Tsunozaki, VA Hale and JR Priess (2002) APH-1 is a multipass membrane protein essential for the Notch signaling pathway inCaenorhabditis elegans embryos.Proc. Natl. Acad. Sci. USA 99, 775–779.

    Article  PubMed  CAS  Google Scholar 

  • Gravina SA, L Ho, CB Eckman, KE Long, L Otvos, Jr., LH Younkin, N Suzuki and SG Younkin (1995) Amyloid beta protein (Abeta) in Alzheimer’s disease brain. Biochemical and immunocytochemical analysis with antibodies specific for forms ending at Abeta 40 or Abeta 42(43).J. Biol. Chem. 270, 7013–7016.

    Article  PubMed  CAS  Google Scholar 

  • Gu Y, N Sanjo, F Chen, H Hasegawa, A Petit, X Ruan, W Li, C Shier, T Kawarai, G Schmitt-Ulms, D Westaway, P St George-Hyslop and PE Fraser (2004) The presenilin proteins are components of multiple membrane-bound complexes which have different biological activities.J. Biol. Chem. 279, 31329–31336.

    Article  PubMed  CAS  Google Scholar 

  • Haass C, MG Schlossmacher, AY Hung, C Vigo-Pelfrey, A Mellon, BL Ostaszewski, I Lieberburg, EH Koo, D Schenk, DB Teplow and DJ Selkoe (1992) Amyloid beta-peptide is produced by cultured cells during normal metabolism.Nature 359, 322–325.

    Article  PubMed  CAS  Google Scholar 

  • Haass C, AY Hung, MG Schlossmacher, DB Teplow and DJ Selkoe (1993) Beta-amyloid peptide and a 3-kDa fragment are derived by distinct cellular mechanisms.J. Biol. Chem. 268, 3021–3024.

    PubMed  CAS  Google Scholar 

  • Hampel H, A Mitchell, K Blennow, RA Frank, S Brettschneider, L Weller and HJ Moller (2004) Core biological marker candidates of Alzheimer’s disease — perspectives for diagnosis, prediction of outcome and reflection of biological activity.J. Neural Transm. 111, 247–272.

    Article  PubMed  CAS  Google Scholar 

  • Hardy JA and GA Higgins (1992) Alzheimer’s disease: the amyloid cascade hypothesis.Science 256, 184–185.

    Article  PubMed  CAS  Google Scholar 

  • Hartley DM, DM Walsh, CP Ye, T Diehl, S Vasquez, PM Vassilev, DB Teplow and DJ Selkoe (1999) Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons.J. Neurosci. 19, 8876–8884.

    PubMed  CAS  Google Scholar 

  • Hartmann T, SC Bieger, B Bruhl, PJ Tienari, N Ida, D Allsop, GW Roberts, CL Masters, CG Dotti, K Unsicker and K Beyreuther (1997) Distinct sites of intracellular production for Alzheimer’s disease Abeta40/42 amyloid peptides.Nat. Med. 3, 1016–1020.

    Article  PubMed  CAS  Google Scholar 

  • Hershkowitz M and A Adunsky (1996) Binding of platelet-activating factor to platelets of Alzheimer’s disease and multiinfarct dementia patients.Neurobiol. Aging 17, 865–868.

    Article  PubMed  CAS  Google Scholar 

  • Hoglund K, O Wiklund, H Vanderstichele, O Eikenberg, E Vanmechelen and K Blennow (2004) Plasma levels of beta-amyloid(1-40), beta-amyloid(1-42), and total beta-amyloid remain unaffected in adult patients with hypercholesterolemia after treatment with statins.Arch. Neurol. 61, 333–337.

    Article  PubMed  Google Scholar 

  • Hosoda R, TC Saido, L Otvos Jr, T Arai, DM Mann, VM Lee, JQ Trojanowski and T Iwatsubo (1998) Quantification of modified amyloid beta peptides in Alzheimer disease and Down syndrome brains.J. Neuropathol. Exp. Neurol. 57, 1089–1095.

    Article  PubMed  CAS  Google Scholar 

  • Houlden H, M Baker, E McGowan, P Lewis, M Hutton, R Crook, NW Wood, S Kumar-Singh, J Geddes, M Swash, F Scaravilli, JL Holton, T Lashley, T Tomita, T Hashimoto, A Verkkoniemi, H Kalimo, M Somer, A Paetau, JJ Martin, C Van Broeckhoven, T Golde, J Hardy, M Haltia and T Revesz (2000) Variant Alzheimer’s disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations.Ann. Neurol. 48, 806–808.

    Article  PubMed  CAS  Google Scholar 

  • Hsiao K, P Chapman, S Nilsen, C Eckman, Y Harigaya, S Younkin, F Yang and G Cole (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice.Science 274, 99–102.

    Article  PubMed  CAS  Google Scholar 

  • Ida N, T Hartmann, J Pantel, J Schroder, R Zerfass, H Forstl, R Sandbrink, CL Masters and K Beyreuther (1996) Analysis of heterogeneous A4 peptides in human cerebrospinal fluid and blood by a newly developed sensitive Western blot assay.J. Biol. Chem. 271, 22908–22914.

    Article  PubMed  CAS  Google Scholar 

  • Ingelsson M, H Fukumoto, KL Newell, JH Growdon, ET Hedley-Whyte, MP Frosch, MS Albert, BT Hyman and MC Irizarry (2004) Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain.Neurology 62, 925–931.

    PubMed  CAS  Google Scholar 

  • Iwata N, S Tsubuki, Y Takaki, K Watanabe, M Sekiguchi, E Hosoki, M Kawashima-Morishima, HJ Lee, E Hama, Y Sekine-Aizawa and TC Saido (2000) Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition.Nat. Med. 6, 143–150.

    Article  PubMed  CAS  Google Scholar 

  • Iwata N, S Tsubuki, Y Takaki, K Shirotani, B Lu, NP Gerard, C Gerard, E Hama, HJ Lee and TC Saido (2001) Metabolic regulation of brain Abeta by neprilysin.Science 292, 1550–1552.

    Article  PubMed  CAS  Google Scholar 

  • Iwatsubo T, A Odaka, N Suzuki, H Mizusawa, N Nukina and Y Ihara (1994) Visualization of Abeta 42(43) and Abeta 40 in senile plaques with end-specific Abeta monoclonals: evidence that an initially deposited species is Abeta 42(43).Neuron 13, 45–53.

    Article  PubMed  CAS  Google Scholar 

  • Iwatsubo T, DM Mann, A Odaka, N Suzuki and Y Ihara (1995) Amyloid beta protein (Abeta) deposition: Abeta 42(43) precedes Abeta 40 in Down syndrome.Ann. Neurol. 37, 294–299.

    Article  PubMed  CAS  Google Scholar 

  • Jarrett JT, EP Berger and PT Lansbury Jr (1993) The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease.Biochemistry 32, 4693–4697.

    Article  PubMed  CAS  Google Scholar 

  • Kakimura J, Y Kitamura, T Taniguchi, S Shimohama and PJ Gebicke-Haerter (2001) Bip/GRP78-induced production of cytokines and uptake of amyloid-beta(1-42) peptide in microglia.Biochem. Biophys. Res. Commun. 281, 6–10.

    Article  PubMed  CAS  Google Scholar 

  • Kamenetz F, T Tomita, H Hsieh, G Seabrook, D Borchelt, T Iwatsubo, S Sisodia and R Malinow (2003) APP processing and synaptic function.Neuron 37, 925–937.

    Article  PubMed  CAS  Google Scholar 

  • Kanai M, E Matsubara, K Isoe, K Urakami, K Nakashima, H Arai, H Sasaki, K Abe, T Iwatsubo, T Kosaka, M Watanabe, Y Tomidokoro, M Shizuka, K Mizushima, T Nakamura, Y Igeta, Y Ikeda, M Amari, T Kawarabayashi, K Ishiguro, Y Harigaya, K Wakabayashi, K Okamoto, S Hirai and M Shoji (1998) Longitudinal study of cerebrospinal fluid levels of tau, Abetal-40, and Abeta 1-42(43) in Alzheimer’s disease: a study in Japan.Ann. Neurol. 44, 17–26.

    Article  PubMed  CAS  Google Scholar 

  • Kanemaru K, N Kameda an H Yamanouchi (2000) Decreased CSF amyloid beta42 and normal tau levels in dementia with Lewy bodies.Neurology 54, 1875–1876.

    PubMed  CAS  Google Scholar 

  • Kawarabayashi T, LH Younkin, TC Saido, M Shoji, KH Ashe and SG Younkin (2001) Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer’s disease.J. Neurosci. 21, 372–381.

    PubMed  CAS  Google Scholar 

  • Kirkitadze MD, MM Condron and DB Teplow (2001) Identification and characterization of key kinetic intermediates in amyloid beta-protein fibrillogenesis.J. Mol. Biol. 312, 1103–1119.

    Article  PubMed  CAS  Google Scholar 

  • Klein WL, GA Krafft and CE Finch (2001) Targeting small Abeta oligomers: the solution to an Alzheimer’s disease conundrum?Trends Neurosci. 24, 219–224.

    Article  PubMed  CAS  Google Scholar 

  • Kuo YM, MR Emmerling, C Vigo-Pelfrey, TC Kasunic, JB Kirkpatrick, GH Murdoch, MJ Ball and AE Roher (1996) Watersoluble Abeta (N-40, N-42) oligomers in normal and Alzheimer disease brains.J. Biol. Chem. 271, 4077–4081.

    Article  PubMed  CAS  Google Scholar 

  • Kuo YM, MR Emmerling, CL Bisgaier, AD Essenburg, HC Lampert, D Drumm and AE Roher (1998) Elevated low-density lipoprotein in Alzheimer’s disease correlates with brain abeta 1-42 levels.Biochem. Biophys. Res. Commun. 252, 711–715.

    Article  PubMed  CAS  Google Scholar 

  • Kuo YM, MR Emmerling, HC Lampert, SR Hempelman, TA Kokjohn, AS Woods, RJ Cotter and AE Roher (1999) High levels of circulating Abeta42 are sequestered by plasma proteins in Alzheimer’s disease.Biochem. Biophys. Res. Commun. 257, 787–791.

    Article  PubMed  CAS  Google Scholar 

  • Lauer D, A Reichenbach and G Birkenmeier (2001) Alpha 2-macroglobulin-mediated degradation of amyloid beta 1-42: a mechanism to enhance amyloid beta catabolism.Exp. Neurol. 167, 385–392.

    Article  PubMed  CAS  Google Scholar 

  • Li QX, SJ Fuller, K Beyreuther and CL Masters (1999) The amyloid precursor protein of Alzheimer disease in human brain and blood.J. Leukoc. Biol. 66, 567–574.

    PubMed  CAS  Google Scholar 

  • Li R, K Lindholm, LB Yang, X Yue, M Citron, R Yan, T Beach, L Sue, M Sabbagh, H Cai, P Wong, D Price and Y Shen (2004) Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer’s disease patients.Proc. Natl. Acad. Sci. USA 101, 3632–3637.

    Article  PubMed  CAS  Google Scholar 

  • Lue LF, YM Kuo, AE Roher, L Brachova, Y Shen, L Sue, T Beach, H Kurth, RE Rydel and J Rogers (1999) Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease.Am. J. Pathol. 155, 853–862.

    PubMed  CAS  Google Scholar 

  • Lustbader JW, M Cirilli, C Lin, HW Xu, K Takuma, N Wang, C Caspersen, X Chen, S Pollak, M Chaney, F Trinchese, S Liu, F Gunn-Moore, LF Lue, DG Walker, P Kuppusamy, ZL Zewier, O Arancio, D Stern, SS Yan and H Wu (2004) ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease.Science 304, 448–452.

    Article  PubMed  CAS  Google Scholar 

  • Mackic J,J Ghiso, B Frangione, L Kirkman, J Bading and B Zlokovic (2002) Differential cerebrovascular sequestration and enhanced blood-brain barrier permeability to circulating Alzheimer’s amyloid-β peptide in aged Rhesus vs. aged Squirrel monkey.Vascular Pharmacol. 18, 303–313.

    Article  Google Scholar 

  • Mager PP (1998) Molecular simulation of the primary and secondary structures of the Abeta(1-42)-peptide of Alzheimer’s disease.Med. Res. Rev. 18, 403–430.

    Article  PubMed  CAS  Google Scholar 

  • Malouf AT (1992) Effect of beta amyloid peptides on neurons in hippocampal slice cultures.Neurobiol. Aging 13, 543–551.

    Article  PubMed  CAS  Google Scholar 

  • Mann DM, T Iwatsubo, H Fukumoto, Y Ihara, A Odaka and N Suzuki (1995) Microglial cells and amyloid beta protein (Abeta) deposition; association with Abeta 40-containing plaques.Acta Neuropathol. 90, 472–477.

    Article  PubMed  CAS  Google Scholar 

  • Mann DM, T Iwatsubo, SM Pickering-Brown, F Owen, TC Saido and RH Perry (1997) Preferential deposition of amyloid beta protein (Abeta) in the form Abeta40 in Alzheimer’s disease is associated with a gene dosage effect of the apolipoprotein E E4 allele.Neurosci. Lett. 221, 81–84.

    Article  PubMed  CAS  Google Scholar 

  • Mayeux R, MX Tang, DM Jacobs, J Manly, K Bell, C Merchant, SA Small, Y Stern, HM Wisniewski and PD Mehta (1999) Plasma amyloid beta-peptide 1-42 and incipient Alzheimer’s disease.Ann. Neurol. 46, 412–416.

    Article  PubMed  CAS  Google Scholar 

  • Mehta PD, T Pirttila, SP Mehta, EA Sersen, PS Aisen and HM Wisniewski (2000) Plasma and cerebrospinal fluid levels of amyloid beta proteins 1-40 and 1-42 in Alzheimer disease.Arch. Neurol. 57, 100–105.

    Article  PubMed  CAS  Google Scholar 

  • Michikawa M, JS Gong, QW Fan, N Sawamuraand K Yanagisawa (2001) A novel action of Alzheimer’s amyloid beta-protein (Abeta): oligomeric Abeta promotes lipid release.J. Neurosci. 21, 7226–7235.

    PubMed  CAS  Google Scholar 

  • Miklossy J, K Taddei, D Suva, G Verdile, J Fonte, C Fisher, A Gnjec, J Ghika, F Suard, PD Mehta, CA McLean, CL Masters, WS Brooks and RN Martins (2003) Two novel presenilinmutations (Y256S and Q222H) are associated with early-onset Alzheimer’s disease.Neurobiol. Aging 24, 655–662.

    Article  PubMed  CAS  Google Scholar 

  • Misonou H, M Morishima-Kawashima and Y Ihara (2000) Oxidative stress induces intracellular accumulation of amyloid beta-protein (Abeta) in human neuroblastoma cells.Biochemistry 39, 6951–6959.

    Article  PubMed  CAS  Google Scholar 

  • Morishima-Kawashima M, N Oshima, H Ogata, H Yamaguchi, M Yoshimura, S Sugihara and Y Ihara (2000) Effect of apolipoprotein E allele epsilon4 on the initial phase of amyloid beta-protein accumulation in the human brain.Am. J. Pathol. 157, 2093–2099.

    PubMed  CAS  Google Scholar 

  • Motter nR, C Vigo-Pelfrey, D Kholodenko, R Barbour, K Johnson-Wood, D Galasko, L Chang, B Miller, C Clark and R Green (1995) Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer’s disease.Ann. Neurol. 38, 643–648.

    Article  PubMed  CAS  Google Scholar 

  • Mukherjee A, E Song, M Kihiko-Ehmann, JP Goodman, Jr., JS Pyrek, S Estus and LB Hersh (2000) Insulysin hydrolyzes amyloid beta peptides to products that are neither neurotoxic nor deposit on amyloid plaques.J. Neurosci. 20, 8745–8749.

    PubMed  CAS  Google Scholar 

  • Nakamura T, M Shoji, Y Harigaya, M Watanabe, K Hosoda, TT Cheung, LM Shaffer, TE Golde, LH Younkin, SG Younkin and S Hirai (1994) Amyloid beta protein levels in cerebrospinal fluid are elevated in early-onset Alzheimer’s disease.Ann. Neurol. 36, 903–911.

    Article  PubMed  CAS  Google Scholar 

  • Naslund J, A Schierhorn, U Hellman, L Lannfelt, AD Roses, LO Tjernberg, J Silberring, SE Gandy, B Winblad, P Greengardet al. (1994) Relative abundance of Alzheimer Abeta amyloid peptide variants in Alzheimer disease and normal aging.Proc. Natl. Acad. Sci. USA 91, 8378–8382.

    Article  PubMed  CAS  Google Scholar 

  • Naslund J, V Haroutunian, R Mohs, KL Davis, P Davies, P Greengard and JD Buxbaum (2000) Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline.JAMA 283, 1571–1577.

    Article  PubMed  CAS  Google Scholar 

  • Nilsberth C, A Westlind-Danielsson, CB Eckman, MM Condron, K Axelman, C Forsell, C Stenh, J Luthman, DB Teplow, SG Younkin, J Naslund and L Lannfelt (2001) The ’Arctic’ APP mutation (E693G) causes Alzheimer’s disease by enhanced Abeta protofibril formation.Nat. Neurosci. 4, 887–893.

    Article  PubMed  CAS  Google Scholar 

  • Nunan J and DH Small (2000) Regulation of APP cleavage by alpha-, beta- and gamma-secretases.FEBS Lett. 483, 6–10.

    Article  PubMed  CAS  Google Scholar 

  • Otto M, H Esselmann, W Schulz-Shaeffer, M Neumann, A Schroter, P Ratzka, L Cepek, I Zerr, P Steinacker, O Windl, J Kornhuber, HA Kretzschmar, S Poser and J Wiltfang (2000) Decreased beta-amyloid 1-42 in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease.Neurology 54, 1099–1102.

    PubMed  CAS  Google Scholar 

  • Paola D, C Domenicotti, M Nitti, A Vitali, R Borghi, D Cottalasso, D Zaccheo, P Odetti, P Strocchi, UM Marinari, M Tabaton and MA Pronzato (2000) Oxidative stress induces increase in intracellular amyloid beta-protein production and selective activation of betaI and betaII PKCs in NT2 cells.Biochem. Biophys. Res. Commun. 268, 642–646.

    Article  PubMed  CAS  Google Scholar 

  • Pike CJ, AJ Walencewicz, CG Glabe and CW Cotman (1991) Aggregation-related toxicity of synthetic beta-amyloid protein in hippocampal cultures.Eur. J. Pharmacol. 207, 367–368.

    Article  PubMed  CAS  Google Scholar 

  • Plant LD, JP Boyle, IF Smith, C Peers and HA Pearson (2003) The production of amyloid β peptide is a critical requirement for the viability of central neurons.J. Neurosci. 23, 5531–5535.

    PubMed  CAS  Google Scholar 

  • Qiu WQ, DM Walsh, Z Ye, K Vekrellis, J Zhang, MB Podlisny, MR Rosner, A Safavi, LB Hersh and DJ Selkoe (1998) Insulindegrading enzyme regulates extracellular levels of amyloid betaprotein by degradation.J. Biol. Chem. 273, 32730–32738.

    Article  PubMed  CAS  Google Scholar 

  • Qiu Z, DK Strickland, BT Hyman and GW Rebeck (1999) Alpha2-macroglobulin enhances the clearance of endogenous soluble beta-amyloid peptide via low-density lipoprotein receptor-related protein in cortical neurons.J. Neurochem. 73, 1393–1398.

    Article  PubMed  CAS  Google Scholar 

  • Ramsden M, LD Plant, NJ Webster, PF Vaughan, Z Henderson and HA Pearson (2001) Differential effects of unaggregated and aggregated amyloid beta protein (1-40) on K(+) channel currents in primary cultures of rat cerebellar granule and cortical neurones.J. Neurochem. 79, 699–712.

    Article  PubMed  CAS  Google Scholar 

  • Rhodin JA, TN Thomas, L Clark, A Garces and M Bryant (2003)In vivo cerebrovascular actions of amyloid beta-peptides and the protective effect of conjugated estrogens.J. Alzheimers Dis. 5, 275–286.

    PubMed  CAS  Google Scholar 

  • Roher AE, JD Lowenson, S Clarke, AS Woods, RJ Cotter, E Gowing and MJ Ball (1993) Beta-amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease.Proc. Natl. Acad. Sci. USA 90, 10836–10840.

    Article  PubMed  CAS  Google Scholar 

  • Samuels SC, JM Silverman, DB Marin, ER Peskind, SG Younki, DA Greenberg, E Schnur, J Santoro and KL Davis (1999) CSF beta-amyloid, cognition, and APOE genotype in Alzheimer’s disease.Neurology 52, 547–551.

    PubMed  CAS  Google Scholar 

  • Schenk D, R Barbour, W Dunn, G Gordon, H Grajeda, T Guido, K Hu, J Huang, K Johnson-Wood, K Khan, D Kholodenko, M Lee, Z Liao, I Lieberburg, R Motter, L Mutter, F Soriano, G Shopp, N Vasquez, C Vandevert, S Walker, M Wogulis, T Yednock, D Games and P Seubert (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse.Nature 400, 173–177.

    Article  PubMed  CAS  Google Scholar 

  • Scheuner D, C Eckman, M Jensen, X Song, M Citron, N Suzuki, TD Bird, J Hardy, M Hutton, W Kukull, E Larson, E Levy-Lahad, M Viitanen, E Peskind, P Poorkaj, G Schellenberg, R Tanzi, W Wasco, L Lannfelt, D Selkoe and S Younkin (1996) Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increasedin vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease.Nat. Med. 2, 864–870.

    Article  PubMed  CAS  Google Scholar 

  • Selkoe DJ (2001a) Alzheimer’s disease: genes, proteins, and therapy.Physiol. Rev. 81, 741–766.

    PubMed  CAS  Google Scholar 

  • Selkoe DJ (2001b) Clearing the brain’s amyloid cobwebs.Neuron 32, 177–180.

    Article  PubMed  CAS  Google Scholar 

  • Shaffer LM, MD Dority, R Gupta-Bansal, RC Frederickson, SG Younkin and KR Brunden (1995) Amyloid beta protein (Abeta) removal by neuroglial cells in culture.Neurobiol. Aging 16, 737–745.

    Article  PubMed  CAS  Google Scholar 

  • Shinkai Y, M Yoshimura, M Morishima-Kawashima, Y Ito, H Shimada, K Yanagisawa and Y Ihara (1997) Amyloid beta-protein deposition in the leptomeninges and cerebral cortex.Ann. Neurol. 42, 899–908.

    Article  PubMed  CAS  Google Scholar 

  • Shoji M (2002) Cerebrospinal fluid Abeta40 and Abeta42: natural course and clinical usefulness.Front. Biosci. 7, d997-d1006.

    Article  PubMed  CAS  Google Scholar 

  • Shoji M, E Matsubara, M Kanai, M Watanabe, T Nakamura, Y Tomidokoro, M Shizuka, K Wakabayashi, Y Igeta, Y Ikeda, K Mizushima, M Amari, K Ishiguro, T Kawarabayashi, Y Harigaya, K Okamoto and S Hirai (1998) Combination assay of CSF tau, Abeta 1-40 and Abeta 1-42(43) as a biochemical marker of Alzheimer’s disease.J. Neurol. Sci. 158, 134–140.

    Article  PubMed  CAS  Google Scholar 

  • Shoji M, M Kanai, E Matsubara, M Ikeda, Y Harigaya, K Okamoto and S Hirai (2000) Taps to Alzheimer’s patients: a continuous Japanese study of cerebrospinal fluid biomarkers.Ann. Neurol. 48, 402.

    Article  PubMed  CAS  Google Scholar 

  • Suzuki N, TT Cheung, XD Cai, A Odaka, L Otvos, Jr., C Eckman, TE Golde and SG Younkin (1994) An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants.Science 264, 1336–1340.

    Article  PubMed  CAS  Google Scholar 

  • Tamaoka A, T Kondo, A Odaka, N Sahara, N Sawamura, K Ozawa, N Suzuki, S Shoji and H Mori (1994a) Biochemical evidence for the long-tail form (Abeta 1-42/43) of amyloid beta protein as a seed molecule in cerebral deposits of Alzheimer’s disease.Biochem. Biophys. Res. Commun. 205, 834–842.

    Article  PubMed  CAS  Google Scholar 

  • Tamaoka A, A Odaka, Y Ishibashi, M Usami, N Sahara, N Suzuki, N Nukina, H Mizusawa, S Shoji and I Kanazawa (1994b) APP717 missense mutation affects the ratio of amyloid beta protein species (Abeta 1-42/43 and Abeta 1-40) in familial Alzheimer’s disease brain.J. Biol. Chem. 269, 32721–32724.

    PubMed  CAS  Google Scholar 

  • Tamaoka A, N Sawamura, A Odaka, N Suzuki, H Mizusawa, S Shoji and H Mori (1995) Amyloid beta protein 1-42/43 (Abeta 1-42/43) in cerebellar diffuse plaques: enzyme-linked immunosorbent assay and immunocytochemical study.Brain Res. 679, 151–156.

    Article  PubMed  CAS  Google Scholar 

  • Tamaoka A, T Fukushima, N Sawamura, K Ishikawa, E Oguni, Y Komatsuzaki and S Shoji (1996) Amyloid beta protein in plasma from patients with sporadic Alzheimer’s disease.J. Neurol. Sci 141, 65–68.

    Article  PubMed  CAS  Google Scholar 

  • Tamaoka A, N Sawamura, T Fukushima, S Shoji, E Matsubara, M Shoji, S Hirai, Y Furiya, R Endoh and H Mori (1997) Amyloid beta protein 42(43) in cerebrospinal fluid of patients with Alzheimer’s disease.J. Neurol. Sci. 148, 41–45.

    Article  PubMed  CAS  Google Scholar 

  • Tamaoka A, PE Fraser, K Ishii, N Sahara, K Ozawa, M Ikeda, AM Saunders, Y Komatsuzaki, R Sherrington, G Levesque, G Yu, E Rogaeva, S Shoji, LE Nee, DA Pollen, L Hendriks, JJ Martin, C Van Broeckhoven, AD Roses, LA Farrer, PH St George-Hyslop and H Mori (1998) Amyloid-beta-protein isoforms in brain of subjects with PS 1-linked, beta APP-linked and sporadic Alzheimer disease.Mol. Brain Res. 56, 178–185.

    Article  PubMed  CAS  Google Scholar 

  • Tapiola T, T Pirttila, PD Mehta, I Alafuzofff, M Lehtovirta and H Soininen (2000a) Relationship between apoE genotype and CSF beta-amyloid (1-42) and tau in patients with probable and definite Alzheimer’s disease.Neurobiol. Aging 21, 735–740.

    Article  PubMed  CAS  Google Scholar 

  • Tapiola T, T Pirttila, M Mikkonen, PD Mehta, I Alafuzoff, K Koivisto and H Soininen (2000b) Three-year follow-up of cerebrospinal fluid tau, beta-amyloid 42 and 40 concentrations in Alzheimer’s disease.Neurosci. Lett. 280, 119–122.

    Article  PubMed  CAS  Google Scholar 

  • Temussi PA, L Masino and A Pastore (2003) From Alzheimer to Huntington: why is a structural understanding so difficult?EMBOJ. 22, 355–361.

    Article  CAS  Google Scholar 

  • Turner PR, K O’Connor, WP Tate and WC Abraham (2003) Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory.Prog. Neurobiol. 70, 1–32.

    Article  PubMed  CAS  Google Scholar 

  • Turner RS, N Suzuki, AS Chyung, SG Younkin and VM Lee (1996) Amyloids beta40 and beta42 are generated intracellularly in cultured human neurons and their secretion increases with maturation.J. Biol. Chem. 271, 8966–8970.

    Article  PubMed  CAS  Google Scholar 

  • Ulery PG, J Beers, I Mikhailenko, RE Tanzi, GW Rebeck, BT Hyman and DK Strickland (2000) Modulation of beta-amyloid precursor protein processing by the low density lipoprotein receptor-related protein (LRP). Evidence that LRP contributes to the pathogenesis of Alzheimer’s disease.J. Biol. Chem. 275, 7410–7415.

    Article  PubMed  CAS  Google Scholar 

  • Van Broeckhoven C, J Haan, E Bakker, JA Hardy, W Van Hul, A Wehnert, M Vegter-Van der Vlis and RA Roos (1990) Amyloid beta protein precursor gene and hereditary cerebral hemorrhage with amyloidosis (Dutch).Science 248, 1120–1122. Vassar R, BD Bennett, S Babu-Khan, S Kahn, EA Mendiaz, P Denis,

    Article  PubMed  Google Scholar 

  • DB Teplow, S Ross, P Amarante, R Loeloff, Y Luo, S Fisher, J Fuller, S Edenson, J Lile, MA Jarosinski, AL Biere, E Curran, T Burgess, JC Louis, F Collins, J Treanor, G Rogers and M Citron (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE.Science 286, 735–741.

    Article  PubMed  Google Scholar 

  • Verdile G, A Gnjec, J Miklossy, J Fonte, G Veurink, K Bates, B Kakulas, PD Mehta, EA Milward, N Tan, R Lareau, D Lim, A Dharmarajan and RN Martins (2004) Protein markers for Alzheimer disease in the frontal cortex and cerebellum.Neurology 63, 1385–1392.

    PubMed  CAS  Google Scholar 

  • Walsh DM, A Lomakin, GB Benedek, MM Condron and DB Teplow (1997) Amyloid beta-protein fibrillogenesis. Detection of a protofibrillar intermediate.J. Biol. Chem. 272, 22364–22372.

    Article  PubMed  CAS  Google Scholar 

  • Walsh DM, I Klyubin, JV Fadeeva, WK Cullen, R Anwyl, MS Wolfe, MJ Rowan and DJ Selkoe (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiationin vivo.Nature 416, 535–539.

    Article  PubMed  CAS  Google Scholar 

  • Wang J, DW Dickson, JQ Trojanowski and VM Lee (1999) The levels of soluble versus insoluble brain Abeta distinguish Alzheimer’s disease from normal and pathologic aging.Exp. Neurol. 158, 328–337.

    Article  PubMed  CAS  Google Scholar 

  • Weiner HL, CA Lemere, R Maron, ET Spooner, TJ Grenfell, C Mori, S Issazadeh, WW Hancock and DJ Selkoe (2000) Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer’s disease.Ann. Neurol. 48, 567–579.

    Article  PubMed  CAS  Google Scholar 

  • Weller RO (1998) Pathology of cerebrospinal fluid and interstitial fluid of the CNS: significance for Alzheimer disease, prion disorders and multiple sclerosis.J. Neuropathol. Exp. Neurol. 57, 885–894.

    Article  PubMed  CAS  Google Scholar 

  • Wild-Bode C, T Yamazaki, A Capell, U Leimer, H Steiner, Y Ihara and C Haass (1997) Intracellular generation and accumulation of amyloid beta-peptide terminating at amino acid 42.J. Biol. Chem. 272, 16085–16088.

    Article  PubMed  CAS  Google Scholar 

  • Yankner BA, LK Duffy and DA Kirschner (1990) Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides.Science 250, 279–282.

    Article  PubMed  CAS  Google Scholar 

  • Yasojima K, EG McGeer and PL McGeer (2001) Relationship between beta amyloid peptide generating molecules and neprilysin in Alzheimer disease and normal brain.Brain Res. 919, 115–121.

    Article  PubMed  CAS  Google Scholar 

  • Yatin SM, S Varadarajan, CD Link and DA Butterfield (1999)In vitro andin vivo oxidative stress associated with Alzheimer’s amyloid beta-peptide (1-42).Neurobiol. Aging 20, 325–330; discussion 339–342.

    Article  PubMed  CAS  Google Scholar 

  • Yu G, M Nishimura, S Arawaka, D Levitan, L Zhang, A Tandon, YQ Song, E Rogaeva, F Chen, T Kawarai, A Supala, L Levesque, H Yu, DS Yang, E Holmes, P Milman, Y Liang, DM Zhang, DH Xu, C Sato, E Rogaev, M Smith, C Janus, Y Zhang, R Aebersold, LS Farrer, S Sorbi, A Bruni, P Fraser and P St George-Hyslop (2000) Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing.Nature 407, 48–54.

    Article  PubMed  CAS  Google Scholar 

  • Zhang L, B Zhao, DT Yew, JW Kusiak and GS Roth (1997) Processing of Alzheimer’s amyloid precursor protein during H2O2-induced apoptosis in human neuronal cells.Biochem. Biophys. Res. Commun. 235, 845–848.

    Article  PubMed  CAS  Google Scholar 

  • Zlokovic BV (2004) Clearing amyloid through the blood-brain barrier.J. Neurochem. 89, 807–811.

    Article  PubMed  CAS  Google Scholar 

  • Zlokovic BV (1996) Cerebrovascular transport of Alzheimer’s amyloid beta and apolipoproteins J and E: possible anti-amyloidogenic role of the blood-brain barrier.Life Sci. 59, 1483–1497.

    Article  PubMed  CAS  Google Scholar 

  • Zou K, J-S Gong, K Yanagisawa and M Michikawa (2002) A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metal-induced oxidative damage.J. Neurosci. 22, 4833–4841.

    PubMed  CAS  Google Scholar 

  • Zou K, D Kim, A Kakio, K Byun, J-S Gong, J Kim, M Kim, N Sawamura, S-i Nishimoto, K Matsuzaki, B Lee, K Yanagisawa and M Michikawa (2003) Amyloid beta-protein 1-40 protects neurons from damage induced by Abeta 1-42 in culture and in rat brain.J. Neurochem. 87, 609–619.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Prince of Wales Medical Research Institute and the University of New South Wales, Sydney, Australia

    Gillian C. Gregory & Glenda M. Halliday

Authors
  1. Gillian C. Gregory
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Glenda M. Halliday
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Glenda M. Halliday.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gregory, G.C., Halliday, G.M. What is the dominant aβ species in human brain tissue? A review. neurotox res 7, 29–41 (2005). https://doi.org/10.1007/BF03033774

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03033774

Keywords

Search

Navigation