Accessible Requires Authentication Published by De Gruyter July 10, 2014

Deciphering an interplay of proteins associated with amyloid β 1-42 peptide and molecular mechanisms of Alzheimer’s disease

Luis Fernando Hernández-Zimbrón and Selva Rivas-Arancibia


Extracellular and intracellular accumulation of amyloid beta 1-42 peptide in different states of aggregation has been involved in the development and progression of Alzheimer’s disease. However, the precise mechanisms involved in amyloid beta peptide neurotoxicity have not been fully understood. There exists a wide variety of studies demonstrating the binding of amyloid beta peptide to a great variety of macromolecules and that such associations affect the cellular functions. This type of association involves proteins and receptors anchored to the plasma membrane of neurons or immune cells of the central nervous system as well as intracellular proteins that can alter intracellular transport, activate signaling pathways or affect proper mitochondrial function. In this review, we present some examples of such associations and the role played by these interactions, which are generally involved in the pathological progression of Alzheimer’s disease.

Corresponding author: Luis Fernando Hernández-Zimbrón, Faculty of Medicine, Physiology Department, National Autonomous University of Mexico, CP 04510, Mexico City, Mexico, e-mail:


Funding was provided by DGAPA-UNAM (IN221114); LFHZ is a recipient of a postdoctoral scholarship from Programa de Becas Posdoctorales, DGAPA-UNAM, México. The authors thank Varsha Velumani and Subramaniam Velumani for comments and English translation and Gevorkian G for valuable comments.


Bamberger, M.E., Harris, M.E., McDonald, D.R., Husemann, J., and Landreth, G.E. (2003). A cell surface receptor complex for fibrillar β-amyloid mediates microglial activation. J. Neurosci. 23, 2665–2674. Search in Google Scholar

Bi, X., Gall, C.M., Zhou, J., and Lynch, G. (2002). Uptake and pathogenic effects of amyloid β peptide 1-42 are enhanced by integrin antagonists and blocked by NMDA receptor antagonists. Neuroscience 112, 827–840. Search in Google Scholar

Bobba, A., Amadoro, G., Valenti, D., Corsetti, V., Lassandro, R., and Atlante, A. (2013). Mitochondrial respiratory chain complexes I and IV are impaired by β-amyloid via direct interaction and through complex I-dependent ROS production, respectively. Mitochondrion 13, 298–311. Search in Google Scholar

Bora, R.P. and Prabhakar, R. (2010). Elucidation of interactions of Alzheimer amyloid β peptides (Aβ40 and Aβ42) with insulin degrading enzyme: a molecular dynamics study. Biochem. 49, 3947–3956. Search in Google Scholar

Bothwell, M. (1996). p75NTR: a receptor after all. Science 272, 506–507. Search in Google Scholar

Cabrol, C., Huzarska, M.A., Dinolfo, D., Rodriguez, M.C., Reinstatler, L., Ni, J., Yeh, L.A., Cuny, G.D., Stein, R.L., Selkoe, D.J., et al. (2009). Small-molecule activators of insulin-degrading enzyme discovered through high-throughput compound screening. PLoS One 4, No. e5274. Search in Google Scholar

Casley, C.S., Land, J.M., Sharpe, M.A., Clark, J.B., Duchen, M.R., and Canevari, L. (2002). β-Amyloid fragment 25–35 causes mitochondrial dysfunction in primary cortical neurons. Neurobiol. Dis. 10, 258–267. Search in Google Scholar

Chavis, P. and Westbrook, G. (2001). Integrins mediate functional pre- and postsynaptic maturation at a hippocampal synapse. Nature 411, 317–321. Search in Google Scholar

Chen, K., Iribarren, P., Hu, J., Chen, J., Gong, W., Cho, E.H., Lockett, S., Dunlop, N.M., and Wang, J.M. (2006). Activation of Toll-like receptor 2 on microglia promotes cell uptake of Alzheimer disease-associated amyloid β peptide. J. Biol. Chem. 281, 3651–3659. Search in Google Scholar

Christie, R.H., Freeman, M., and Hyman, B.T. (1996). Expression of the macrophage scavenger receptor, a multifunctional lipoprotein receptor, in microglia associated with senile plaques in Alzheimer’s disease. Am. J. Pathol. 148, 399. Search in Google Scholar

Connor, B., Young, D., Yan, Q., Faull, R.L.M., Synek, B., and Dragunow, M. (1997). Brain-derived neurotrophic factor is reduced in Alzheimer’s disease. Mol. Brain Res. 49, 71–81. Search in Google Scholar

Coraci, I.S., Husemann, J., Berman, J.W., Hulette, C., Dufour, J.H., Campanella, G.K., and El Khoury, J.B. (2002). CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer’s disease brains and can mediate production of reactive oxygen species in response to β-amyloid fibrils. Am. J. Pathol. 160, 101–112. Search in Google Scholar

Cramer, P.E., Cirrito, J.R., Wesson, D.W., Lee, C.D., Karlo, J.C., Zinn, A.E., and Landreth, G.E. (2012). ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Science 335, 1503–1506. Search in Google Scholar

Dineley, K.T., Bell, K.A., Bui, D., and Sweatt, J.D. (2002). Beta-amyloid peptide activates α7 nicotinic acetylcholine receptors expressed in Xenopus oocytes. J. Biol. Chem. 277, 25056–25061. Search in Google Scholar

Du Yan, S., Chen, X., Fu, J., Chen, M., Zhu, H., Roher, A., Slattery, T., Zhao, L., Nagashima, M., Morser, J., et al. (1996). RAGE and amyloid-β peptide neurotoxicity in Alzheimer’s disease. Nature 382, 685–691. Search in Google Scholar

Duckworth, W.C., Bennett, R.G., and Hamel, F.G. (1998). Insulin degradation: progress and potential 1. Endocr. Rev. 19, 608–624. Search in Google Scholar

Dunah, A.W., Wyszynski, M., Martin, D.M., Sheng, M., and Standaert, D.G. (2000). α-Actinin-2 in rat striatum: localization and interaction with NMDA glutamate receptor subunits. Mol. Brain. Res. 79, 77–87. Search in Google Scholar

Dziewczapolski, G., Glogowski, C.M., Masliah, E., and Heinemann, S.F. (2009). Deletion of the α7 nicotinic acetylcholine receptor gene improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer’s disease. J. Neurosci. 29, 8805–8815. Search in Google Scholar

Eisenberg, D. and Jucker, M. (2012). The amyloid state of proteins in human diseases. Cell. 148, 1188–1203. Search in Google Scholar

Ernfors, P. and Bramham, C.R. (2003). The coupling of a trkB tyrosine residue to LTP. Trends Neurosci. 26, 171–173. Search in Google Scholar

Garzon, D.J. and Fahnestock, M. (2007). Oligomeric amyloid decreases basal levels of brainderived neurotrophic factor (BDNF) mRNA via specific downregulation of BDNF transcripts IV and V in differentiated human neuroblastoma cells. J. Neurosci. 27, 2628–2635. Search in Google Scholar

Geula, C. (1998). Abnormalities of neural circuitry in Alzheimer’s disease hippocampus and cortical cholinergic innervation. Neurology 51, S18–S29. Search in Google Scholar

Gevorkian, G., Gonzalez-Noriega, A., Acero, G., Ordoñez, J., Michalak, C., Munguia, M.E., and Manoutcharian, K. (2008). Amyloid-β peptide binds to microtubule-associated protein 1B (MAP1B). Neurochem. Int. 52, 1030–1036. Search in Google Scholar

Ghosh, C., Mukherjee, S., and Dey, S.G. (2013). Direct electron transfer between Cyt c and heme-Aβ relevant to Alzheimer’s disease. Chem. Commun. 49, 5754–5756. Search in Google Scholar

Gouras, G.K., Tsai, J., Naslund, J., Vincent, B., Edgar, M., Checler, F., Greenfield, J.P., Haroutunian, V., Buxbaum, J.D., Xu, H., et al. (2000). Intraneuronal Ab42 accumulation in human brain. Am. J. Pathol. 156, 15–20. Search in Google Scholar

He, X.Y., Schulz, H., and Yang, S.Y. (1998). A human brain L-3-hydroxyacylcoenzymeA dehydrogenase is identical to an amyloid β-peptide-binding protein involved in Alzheimer’s disease. J. Biol. Chem. 273, 10741–10746. Search in Google Scholar

Hernández-Zimbrón, L.F., Luna-Muñoz, J., Mena, R., Vazquez-Ramirez, R., Kubli-Garfias, C., Cribbs, D.H., Manoutcharian, K., and Gevorkian, G. (2012). Amyloid-β peptide binds to cytochrome C and oxidase subunit 1. PLoS One 7, e42344. Search in Google Scholar

Hirai, K., Aliev, G., Nunomura, A., Fujioka, H., Russell, R.L., Atwood, C.S., and Smith, M.A. (2001). Mitochondrial abnormalities in Alzheimer’s disease. J. Neurosci. 21, 3017–3023. Search in Google Scholar

Hoos, M.D., Ahmed, M., Smith, S.O., and Van Nostrand, W.E. (2007). Inhibition of familial cerebral amyloid angiopathy mutant amyloid β-protein fibril assembly by myelin basic protein. J. Biol. Chem. 282, 9952–9961. Search in Google Scholar

In’t Veld, B.A., Ruitenberg, A., Hofman, A., Launer, L.J., van Duijn, C.M., Stijnen, T., and Stricker, B.H. (2001). Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. New Engl. J. Med. 345, 1515–1521. Search in Google Scholar

Inestrosa, N.C., Alvarez, A., Pérez, C., Moreno, R., Vicente, M., Linker, C., Casanueva, O., Soto, C., and Garrido J. (1996). Acetylcholinesterase accelerates assembly of amyloid-β-peptides into Alzheimer’s fibrils: possible role of the peripheral site of the enzyme. Neuron 16, 881–891. Search in Google Scholar

Iqbal, K., del C Alonso, A., Chen, S., Chohan, M.O., El-Akkad, E., Gong, C.X., and Grundke-Iqbal, I. (2005). Tau pathology in Alzheimer disease and other tauopathies. BBA-Mol. Basis Dis. 1739, 198–210. Search in Google Scholar

Iribarren, P., Chen, K., Hu, J., Gong, W., Cho, E.H., Lockett, S., and Wang, J.M. (2005). CpG-containing oligodeoxynucleotide promotes microglial cell uptake of amyloid β 1-42 peptide by up-regulating the expression of the G-protein-coupled receptor mFPR2. FASEB. J. 19, 2032–2034. Search in Google Scholar

Jakovcevski, I., Filipovic, R., Mo, Z., Rakic, S., and Zecevic, N. (2009). Oligodendrocyte development and the onset of myelination in the human fetal brain. Front. Neuroanat. 3, 1–15. Search in Google Scholar

Jeynes, B. and Provias, J. (2008). Evidence for altered LRP/RAGE expression in Alzheimer lesion pathogenesis. Curr. Alzheimer Res. 5, 432–437. Search in Google Scholar

Jiang, Q., Lee, C.Y., Mandrekar, S., Wilkinson, B., Cramer, P., Zelcer, N., and Landreth, G.E. (2008). ApoE promotes the proteolytic degradation of Aβ. Neuron 58, 681–693. Search in Google Scholar

Kawai, T. and Akira, S. (2007). TLR signaling. Semin. Immunol. 19, 24–32. Search in Google Scholar

Khan, G., Tong, M., Jhun, M., Arora, K., and Nichols, Y.R. (2010). β-Amyloid activates presynaptic α7 nicotinic acetylcholine receptors reconstituted into a model nerve cell system: involvement of lipid rafts. Eur. J. Neurosci. 31, 788–796. Search in Google Scholar

Kim, M., Hersh, L.B., Leissring, M.A., Ingelsson, M., Matsui, T., Farris, W., Lu, A., Hyman, B.T., Selkoe, D.J., Betram, L., et al. (2007). Decreased catalytic activity of the insulin-degrading enzyme in chromosome 10-linked Alzheimer disease families. J. Biol. Chem. 282, 7825–7832. Search in Google Scholar

Koo, E.H., Lansbury, P.T., and Kelly, J.W. (1999). Amyloid diseases: abnormal protein aggregation in neurodegeneration. Proc. Natl. Acad. Sci. USA 96, 9989–9990. Search in Google Scholar

Kuner, P., Schubenel, R., Hertel, C. (1998). Amyloid binds to p75NTR and activates NFkB in human neuroblastoma cells, J. Neurosci. Res. 54, 798–804. Search in Google Scholar

Kwong, J.Q., Henning, M.S., Starkov, A.A., and Manfredi, G. (2007). The mitochondrial respiratory chain is a modulator of apoptosis. J. Cell Biol. 179, 1163–1177. Search in Google Scholar

La Ferla, F., Green, K., and Oddo, S. (2007). Intracellular amyloid-β in Alzheimer’s disease. Nat. Rev. Neu. 8, 499–509. Search in Google Scholar

Lee, D.H. and Wang, H.Y. (2003). Differential physiologic responses of alpha7 nicotinic acetylcholine receptors to beta-amyloid1-40 and β-amyloid1-42. J. Neurobiol. 55, 25–30. Search in Google Scholar

Lee, V.M., Goedert, M., and Trojanowski, J.Q. (2001). Neurodegenerative tauopathies. Annu. Rev. Neurosci. 24, 1121–1159. Search in Google Scholar

Liang, W.S., Reiman, E.M., Valla, J., Dunckley, T., Beach, T.G., Grover, A., and Stephan, D.A. (2008). Alzheimer’s disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons. Proc. Natl. Acad. Sci. USA 105, 4441–4446. Search in Google Scholar

Li, Y., Liu, L., Barger, S.W., and Griffin, W.S.T. (2003). Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. J. Neurosci. 23, 1605–1611. Search in Google Scholar

Lin, B., Arai, A.C., Lynch, G., and Gall, C.M. (2003). Integrins regulate NMDA receptor-mediated synaptic currents. J. Neurophysiol. 89, 2874–2878. Search in Google Scholar

Liu, Q., Kawai, H., and Berg, D.K. (2001). β-Amyloid peptide blocks the response of a7-containing nicotinic receptors on hippocampal neurons. Proc. Natl. Acad. Sci. USA 98, 4734–4739. Search in Google Scholar

Lorenzo, A., Yuan, M., Zhang, Z., Paganetti, P.A., Sturchler-Pierrat, C., Staufenbiel, M., and Yankner, B.A. (2000). Amyloid β interacts with the amyloid precursor protein: a potential toxic mechanism in Alzheimer’s disease. Nat. Neurosci. 3, 460–464. Search in Google Scholar

Lustbader, J.W., Cirilli, M., and Lin, C. (2004). ABAD directly links amyloid beta to mitochondrial toxicity in Alzheimer’s disease. Science 304, 448–452. Search in Google Scholar

Malherbe, P., Richards, J.G., Gaillard, H., Thompson, A., Diener, C., Schuler, A., and Huber, G. (1999). cDNA cloning of a novel secreted isoform of the human receptor for advanced glycation end products and characterization of cells co-expressing cell-surface scavenger receptors and Swedish mutant amyloid precursor protein. Mol. Brain Res. 71, 159–170. Search in Google Scholar

Morris, M.C., Evans, D.A., Bienias, J.L., Tangney, C.C., Bennett, D.A., Wilson, R.S., and Schneider, J. (2003). Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch. Neurol. Chicago 60, 940–946. Search in Google Scholar

McGeer, P.L., Rogers, J., and McGeer, E.G. (2006). Inflammation, anti-inflammatory agents and Alzheimer disease: the last 12 years. J. Alzheimers Dis. 9, 271–276. Search in Google Scholar

Mucke, L., Masliah, E., Yu, G.Q., Mallory, M., Rockenstein, E.M., Tatsuno, G., Hu, K., Kholodenko, D., Johnson-Wood, K., and McConlogue, L. (2000). High-level neuronal expression of Aβ1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J. Neurosci. 20, 4050–4058. Search in Google Scholar

Mungarro-Menchaca, X., Ferrera, P., Morán, J., and Arias, C. (2002). β-Amyloid peptide induces ultrastructural changes in synaptosomes and potentiates mitochondrial dysfunction in the presence of ryanodine. J Neurosci. Res. 68, 89–96. Search in Google Scholar

Munguia, M.E., Govezensky, T., Martinez, R., Manoutcharian, K., and Gevorkian, G. (2006). Identification of amyloid-beta 1-42 binding protein fragments by screening of a human brain cDNA library. Neurosci. Lett. 397, 79–82. Search in Google Scholar

Nagahara, A.H., Merrill, D.A., Coppola, G., Tsukada, S., Schroeder, B.E., Shaked, G.M., Wang, L., Blesch, A., Kim, A., Conner, J.M., et al. (2009). Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nat. Med. 15, 331–337. Search in Google Scholar

Neant-Fery, M., Garcia-Ordoñez, R.D., Logan, T.P., Selkoe, D.J., Li, L., Reinstatler, L., and Leissring, M.A. (2008). Molecular basis for the thiol sensitivity of insulin-degrading enzyme. Proc. Natl. Acad. Sci. USA 105, 9582–9587. Search in Google Scholar

Oz, M., Lorke, D.E., Yang, K.H., and Petroianu, G. (2013). On the interaction of β-amyloid peptides and α7-nicotinic acetylcholine receptors in Alzheimer’s disease. Curr. Alzheimer Res. 10, 618–630. Search in Google Scholar

Pahnke, J., Fröhlich, C., Krohn, M., Schumacher, T., and Paarmann K. (2013). Impaired mitochondrial energy production and ABC transporter function – A crucial interconnection in dementing proteopathies of the brain. Mech. Ageing Dev. 134, 506. Search in Google Scholar

Panegyres, P.K. (2001). The functions of the amyloid precursor protein gene. Rev. Neurosci. 12, 1–40. Search in Google Scholar

Peng, X., Katz, M., Gerzanich, V., Anand, R., and Lindstrom, J. (1994). Human α 7 acetylcholine receptor: cloning of the α 7 subunit from the SH-SY5Y cell line and determination of pharmacological properties of native receptors and functional α 7 homomers expressed in Xenopus oocytes. Mol. Pharmacol. 45, 546–554. Search in Google Scholar

Pérez, M., Cuadros, R., Benítez, M.J., and Jiménez, J.S. (2004). Interaction of Alzheimer’s disease amyloid ß peptide fragment 25-35 with tau protein, and with a tau peptide containing the microtubule binding domain. J. Alzheimers Dis. 6, 461–467. Search in Google Scholar

Pike, C.J., Walencewicz, A.J., Glabe, C.G., and Cotman, C.W. (1991). In vitro aging of beta-amyloid protein causes peptide aggregation and neurotoxicity. Brain Res. 563, 311–314. Search in Google Scholar

Poon, W.W., Blurton-Jones, M., Tu, C.H., Feinberg, L.M., Chabrier, M.A., Harris, J.W., and Cotman, C.W. (2011). β-Amyloid impairs axonal BDNF retrograde trafficking. Neurobiol. Aging 32, 821–833. Search in Google Scholar

Puzzo, D., Privitera, L., Leznik, E., Fà, M., Staniszewski, A., Palmeri, A., and Arancio, O. (2008). Picomolar amyloid-β positively modulates synaptic plasticity and memory in hippocampus. J. Neurosci. 28, 14537–14545. Search in Google Scholar

Reddy, P.H. and Beal, M.F. (2008). Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer’s disease. Trends Mol. Med. 14, 45–53. Search in Google Scholar

Rees, T., Hammond, P.I., Soreq, H., Younkin, S., and Brimijoin, S. (2003). Acetylcholinesterase promotes beta-amyloid plaques in cerebral cortex. Neurobiol. Aging 24, 777–787. Search in Google Scholar

Sanan, D.A., Weisgraber, K.H., Russell, S.J., Mahley, R.W., Huang, D., Saunders, A., and Roses, A.D. (1994). Apolipoprotein E associates with β amyloid peptide of Alzheimer’s disease to form novel monofibrils. Isoform apoE4 associates more efficiently than apoE3. J. Clin. Invest. 94, 860. Search in Google Scholar

Scheff, S.W., Price, D.A., Schmitt, F.A., DeKosky, S.T., and Mufson, E.J. (2007). Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment. Neurology 68, 1501–1508. Search in Google Scholar

Selkoe, D.J. (1999). Translating cell biology into therapeutic advances in Alzheimer’s diseases. Nature 399, A23–A31. Search in Google Scholar

Selkoe, D.J. (2001). Alzheimer’s disease: genes, proteins, and therapy. Physiol. Rev. 81, 741. Search in Google Scholar

Small, D.H. and McLean, C.A. (1999). Alzheimer’s disease and the amyloid β protein: what is the role of amyloid? J. Neurochem. 73, 443–449. Search in Google Scholar

Smith G. (2007). The redox chemistry of the Alzheimer’s disease amyloid peptide. Biochim. Biophys. Acta 1768, 1976–1990. Search in Google Scholar

Stewart, W.F., Kawas, C., Corrada, M., and Metter, E.J. (1997). Risk of Alzheimer’s disease and duration of NSAID use. Neurology 48, 626–632. Search in Google Scholar

Swerdlow, R.H., Burns, J.M., and Khan, S.M. (2010). The Alzheimer’s disease mitochondrial cascade hypothesis. J. Alzheimers Dis. 20, 265–279. Search in Google Scholar

Talaga, P. and Quere, L. (2002). The plasma membrane: a target and hurdle for the development of Anti-Aβ drugs? Curr. Drug Target C.N.S. Neurol. Disord. 1, 567–574. Search in Google Scholar

Thathiah, A. and De Strooper, B. (2009). G Protein-coupled receptors, cholinergic dysfunction, and A {beta} toxicity in Alzheimer’s Disease. Sci. Signal. 2, re8. Search in Google Scholar

Wang, H.Y., Lee, D.H., D’Andrea, M.R., Peterson, P.A., Shank, R.P., and Reitz, A.B. (2000). β-Amyloid1-42 binds to α7 nicotinic acetylcholine receptor with high affinity. J. Biol. Chem. 275, 5626–5632. Search in Google Scholar

Wang, H.Y., Li, W., Benedetti, N.J., and Lee, D.H. (2003). Alpha 7 nicotinic acetylcholine receptors mediate β-amyloid peptide-induced tau protein phosphorylation. J. Biol. Chem. 278, 31547–31553. Search in Google Scholar

Wang, H.Y., Stucky, A., Liu, J., Shen, C., Trocme-Thibierge, C., and Morain, P. (2009). Dissociating β-amyloid from α7 nicotinic acetylcholine receptor by a novel therapeutic agent, S 24795, normalizes α7 nicotinic acetylcholine and NMDA receptor function in Alzheimer’s disease brain. J. Neurosci. 29, 10961–10973. Search in Google Scholar

Yaar, M., Zhai, S., Pilch, P.F., Doyle, S.M., Eisenhauer, P.B., Fine, R.E., and Gilchrest, B.A. (1997). Binding of β-amyloid to the p75 neurotrophin receptor induces apoptosis. A possible mechanism for Alzheimer’s disease. J. Clin. Invest. 100, 2333. Search in Google Scholar

Yaar, M., Zhai, S., Fine, R.E., Eisenhauer, P.B., Arble, B.L., Stewart, K.B., and Gilchrest, B.A. (2002). Amyloid β binds trimers as well as monomers of the 75-kDa neurotrophin receptor and activates receptor signaling. J. Biol. Chem. 277, 7720–7725. Search in Google Scholar

Yan, S.D. and Stern, D.M. (2005). Mitochondrial dysfunction and Alzheimer’s disease: role of amyloid β peptide alcohol dehydrogenase (ABAD). Int. J. Exp. Pathol. 86, 161–171. Search in Google Scholar

Received: 2014-3-21
Accepted: 2014-6-1
Published Online: 2014-7-10
Published in Print: 2014-12-1

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