Hostname: page-component-848d4c4894-hfldf Total loading time: 0 Render date: 2024-06-03T22:23:30.979Z Has data issue: false hasContentIssue false
  • English
  • Français

Neuronal receptors as targets for the action of amyloid-beta protein (Aβ) in the brain

Published online by Cambridge University Press:  20 January 2012

Aarti N. Patel  and
Jack H. Jhamandas
Aarti N. Patel
Affiliation:
Division of Neurology, Department of Medicine, Centre for Neuroscience, University of Alberta, Edmonton, Alberta, Canada
Jack H. Jhamandas*
Affiliation:
Division of Neurology, Department of Medicine, Centre for Neuroscience, University of Alberta, Edmonton, Alberta, Canada
*
*Corresponding author: Jack H. Jhamandas, Department of Medicine (Neurology), University of Alberta, 530 Heritage Medical Research Centre, Edmonton, Alberta, Canada T6 G 2S2. E-mail: jack.jhamandas@ualberta.ca
Get access Rights & Permissions [Opens in a new window]

Abstract

Accumulation of neurotoxic soluble amyloid-beta protein (Aβ) oligomers in the brains of patients with Alzheimer disease (AD) and their role in AD pathogenesis have emerged as topics of considerable interest in recent years. Soluble Aβ oligomers impair synaptic and neuronal function, leading to neurodegeneration that is clinically manifested by memory and cognitive dysfunction. The precise mechanisms whereby Aβ oligomers cause neurotoxicity remain unknown. Emerging insights into the mechanistic link between neuronal receptors and soluble Aβ oligomers highlight the potential role of these receptors in Aβ-mediated neurotoxicity in AD. The current review focuses on studies describing interactions between soluble Aβ oligomers and neuronal receptors, and their role in AD pathogenesis. Furthermore, these studies provide insight into potential therapies for AD using compounds directed at putative target receptors for the action of Aβ in the central nervous system. We focus on interactions of Aβ with subtypes of acetylcholine and glutamatergic receptors. Additionally, neuronal receptors such as insulin, amylin and receptor for advanced glycation end products could be potential targets for soluble Aβ-oligomer-mediated neurotoxicity. Aβ interactions with other receptors such as the p75 neurotrophin receptors, which are highly expressed on cholinergic basal forebrain neurons lost in AD, are also highlighted.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 14 , March 2012 , e2
Copyright
Copyright © Cambridge University Press 2012

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

References

1Li, S.F. et al. (2011) Requirement of alpha7 nicotinic acetylcholine receptors for amyloid beta protein-induced depression of hippocampal LTP in CA1 region of rats in vivo. Synapse 65, 1136-1143CrossRefGoogle ScholarPubMed
2Lacor, P.N. et al. (2007) Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. Journal of Neuroscience 27, 796-807CrossRefGoogle ScholarPubMed
3Selkoe, D.J. (2002) Alzheimer's disease is a synaptic failure. Science 298, 789-791CrossRefGoogle ScholarPubMed
4Citron, M. (2010) Alzheimer's disease: strategies for disease modification. Nature Reviews. Drug Discovery 9, 387-398CrossRefGoogle Scholar
5Wenk, G.L. (2003) Neuropathologic changes in Alzheimer's disease. Journal of Clinical Psychiatry 64 (Suppl 9), 7-10Google ScholarPubMed
6Glenner, G.G. and Wong, C.W. (1984) Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochemical and Biophysics Research Communications 120, 885-890CrossRefGoogle ScholarPubMed
7Gralle, M. and Ferreira, S.T. (2007) Structure and functions of the human amyloid precursor protein: the whole is more than the sum of its parts. Progress in Neurobiology 82, 11-32CrossRefGoogle Scholar
8Selkoe, D.J. (1998) The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer's disease. Trends in Cell Biology 8, 447-453CrossRefGoogle ScholarPubMed
9Selkoe, D.J. et al. (1996) The role of APP processing and trafficking pathways in the formation of amyloid beta-protein. Annals of the New York Academy of Sciences 777, 57-64CrossRefGoogle ScholarPubMed
10Lambert, M.P. et al. (1998) Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proceedings of the National Academy of Sciences of the United States of America 95, 6448-6453CrossRefGoogle ScholarPubMed
11Gong, Y. et al. (2003) Alzheimer's disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proceedings of the National Academy of Sciences of the United States of America 100, 10417-10422CrossRefGoogle ScholarPubMed
12Walsh, D.M. et al. (2002) Naturally secreted oligomers of amyloid [beta] protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535-539CrossRefGoogle ScholarPubMed
13Lambert, M.P. et al. (1998) Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins. Proceedings of the National Academy of Sciences of the United States of America 95, 6448-6453CrossRefGoogle ScholarPubMed
14Lesné, S. et al. (2006) A specific amyloid-[beta] protein assembly in the brain impairs memory. Nature 440, 352-357CrossRefGoogle ScholarPubMed
15Georganopoulou, D.G. et al. (2005) Nanoparticle-based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America 102, 2273-2276CrossRefGoogle ScholarPubMed
16Dineley, K.T. et al. (2001) Beta-amyloid activates the mitogen-activated protein kinase cascade via hippocampal alpha7 nicotinic acetylcholine receptors: in vitro and in vivo mechanisms related to Alzheimer's disease. Journal of Neuroscience 21, 4125-4133CrossRefGoogle ScholarPubMed
17Snyder, E.M. et al. (2005) Regulation of NMDA receptor trafficking by amyloid-[beta]. Nature Neuroscience 8, 1051-1058CrossRefGoogle ScholarPubMed
18Wang, H.Y. et al. (2000) beta-Amyloid(1-42) binds to alpha7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer's disease pathology. Journal of Biological Chemistry 275, 5626-5632CrossRefGoogle ScholarPubMed
19Zhao, W.-Q. et al. (2010) Inhibition of calcineurin-mediated endocytosis and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors prevents amyloid β oligomer-induced synaptic disruption. Journal of Biological Chemistry 285, 7619-7632 20CrossRefGoogle ScholarPubMed
20De Felice, F.G. et al. (2009) Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proceedings of the National Academy of Sciences of the United States of America 106, 1971-1976CrossRefGoogle ScholarPubMed
21Xie, L. et al. (2002) Alzheimer's beta-amyloid peptides compete for insulin binding to the insulin receptor. Journal of Neuroscience 22, RC221CrossRefGoogle ScholarPubMed
22Renner, M. et al. (2010) Deleterious effects of amyloid beta oligomers acting as an extracellular scaffold for mGluR5. Neuron 66, 739-754CrossRefGoogle ScholarPubMed
23Wang, Q. et al. (2004) Block of long-term potentiation by naturally secreted and synthetic amyloid beta-peptide in hippocampal slices is mediated via activation of the kinases c-Jun N-terminal kinase, cyclin-dependent kinase 5, and p38 mitogen-activated protein kinase as well as metabotropic glutamate receptor type 5. Journal of Neuroscience 24, 3370-3378CrossRefGoogle ScholarPubMed
24Iwatsubo, T. et al. (1994) Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron 13, 45-53CrossRefGoogle Scholar
25Fraering, P.C. (2007) Structural and functional determinants of gamma-secretase, an intramembrane protease implicated in Alzheimer's disease. Current Genomics 8, 531-549CrossRefGoogle ScholarPubMed
26Kuperstein, I. et al. (2010) Neurotoxicity of Alzheimer's disease Abeta peptides is induced by small changes in the Abeta42 to Abeta40 ratio. EMBO Journal 29, 3408-3420CrossRefGoogle ScholarPubMed
27Verdier, Y., Zarandi, M. and Penke, B. (2004) Amyloid beta-peptide interactions with neuronal and glial cell plasma membrane: binding sites and implications for Alzheimer's disease. Journal of Peptide Science 10, 229-248CrossRefGoogle ScholarPubMed
28Sze, C.I. et al. (1997) Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer disease. Journal of Neuropathology and Experimental Neurology 56, 933-944CrossRefGoogle ScholarPubMed
29Terry, R.D. et al. (1991) Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Annals of Neurology 30, 572-580CrossRefGoogle ScholarPubMed
30Shankar, G.M. et al. (2008) Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nature Medicine 14, 837-842CrossRefGoogle ScholarPubMed
31Townsend, M. et al. (2006) Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity: a potent role for trimers. Journal of Physiology 572, 477-492CrossRefGoogle ScholarPubMed
32Ondrejcak, T. et al. (2010) Alzheimer's disease amyloid beta-protein and synaptic function. Neuromolecular Medicine 12, 13-26CrossRefGoogle ScholarPubMed
33Lynch, M.A. (2004) Long-term potentiation and memory. Physiological Reviews 84, 87-136CrossRefGoogle ScholarPubMed
34Martin, S.J. and Morris, R.G. (2002) New life in an old idea: the synaptic plasticity and memory hypothesis revisited. Hippocampus 12, 609-636CrossRefGoogle Scholar
35Lee, H.G. et al. (2004) The role of metabotropic glutamate receptors in Alzheimer's disease. Acta Neurobiologiae Experimentalis 64, 89-98CrossRefGoogle ScholarPubMed
36Bennett, M.R. (2000) The concept of long term potentiation of transmission at synapses. Progress in Neurobiology 60, 109-137CrossRefGoogle ScholarPubMed
37Yamin, G. (2009) NMDA receptor-dependent signaling pathways that underlie amyloid beta-protein disruption of LTP in the hippocampus. Journal of Neuroscience Research 87, 1729-1736CrossRefGoogle ScholarPubMed
38Texido, L. et al. (2011) Amyloid beta peptide oligomers directly activate NMDA receptors. Cell Calcium 49, 184-190CrossRefGoogle ScholarPubMed
39Rammes, G. et al. (2011) Therapeutic significance of NR2B-containing NMDA receptors and mGluR5 metabotropic glutamate receptors in mediating the synaptotoxic effects of beta-amyloid oligomers on long-term potentiation (LTP) in murine hippocampal slices. Neuropharmacology 60, 982-990 21CrossRefGoogle ScholarPubMed
40Bordji, K., Becerril-Ortega, J. and Buisson, A. (2011) Synapses, NMDA receptor activity and neuronal Abeta production in Alzheimer's disease. Reviews in the Neurosciences 22, 285-294CrossRefGoogle ScholarPubMed
41Derkach, V.A. et al. (2007) Regulatory mechanisms of AMPA receptors in synaptic plasticity. Nature Reviews. Neuroscience 8, 101-113Google Scholar
42Lau, C.G. and Zukin, R.S. (2007) NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nature Reviews. Neuroscience 8, 413-426Google Scholar
43Paoletti, P. and Neyton, J. (2007) NMDA receptor subunits: function and pharmacology. Current Opinion in Pharmacology 7, 39-47CrossRefGoogle ScholarPubMed
44Wang, H.W. et al. (2002) Soluble oligomers of beta amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus. Brain Research 924, 133-140CrossRefGoogle Scholar
45Roselli, F. et al. (2005) Soluble beta-amyloid1-40 induces NMDA-dependent degradation of postsynaptic density-95 at glutamatergic synapses. Journal of Neuroscience 25, 11061-11070CrossRefGoogle ScholarPubMed
46Shankar, G.M. et al. (2007) Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. Journal of Neuroscience 27, 2866-2875CrossRefGoogle ScholarPubMed
47Deshpande, A. et al. (2009) A role for synaptic zinc in activity-dependent Abeta oligomer formation and accumulation at excitatory synapses. Journal of Neuroscience 29, 4004-4015CrossRefGoogle ScholarPubMed
48Rönicke, R. et al. (2011) Early neuronal dysfunction by amyloid [beta] oligomers depends on activation of NR2B-containing NMDA receptors. Neurobiology of Aging 32, 2219-2228CrossRefGoogle ScholarPubMed
49Decker, H. et al. (2010) Amyloid-beta peptide oligomers disrupt axonal transport through an NMDA receptor-dependent mechanism that is mediated by glycogen synthase kinase 3beta in primary cultured hippocampal neurons. Journal of Neuroscience 30, 9166-9171CrossRefGoogle ScholarPubMed
50De Felice, F.G. et al. (2007) Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. Journal of Biological Chemistry 282, 11590-11601CrossRefGoogle ScholarPubMed
51Alberdi, E. et al. (2010) Amyloid beta oligomers induce Ca2+ dysregulation and neuronal death through activation of ionotropic glutamate receptors. Cell Calcium 47, 264-272CrossRefGoogle ScholarPubMed
52Pelkey, K.A. et al. (2002) Tyrosine phosphatase STEP is a tonic brake on induction of long-term potentiation. Neuron 34, 127-138CrossRefGoogle ScholarPubMed
53Venkitaramani, D.V. et al. (2007) Beta-amyloid modulation of synaptic transmission and plasticity. Journal of Neuroscience 27, 11832-11837CrossRefGoogle ScholarPubMed
54Kurup, P. et al. (2010) Abeta-mediated NMDA receptor endocytosis in Alzheimer's disease involves ubiquitination of the tyrosine phosphatase STEP61. Journal of Neuroscience 30, 5948-5957CrossRefGoogle ScholarPubMed
55Zhang, Y. et al. (2010) Genetic reduction of striatal-enriched tyrosine phosphatase (STEP) reverses cognitive and cellular deficits in an Alzheimer's disease mouse model. Proceedings of the National Academy of Sciences of the United States of America 107, 19014-19019CrossRefGoogle Scholar
56Zieminska, E. and Lazarewicz, J.W. (2006) Excitotoxic neuronal injury in chronic homocysteine neurotoxicity studied in vitro: the role of NMDA and group I metabotropic glutamate receptors. Acta Neurobiologiae Experimentalis 66, 301-309CrossRefGoogle ScholarPubMed
57Chin, J.H. et al. (2007) Amyloid beta protein modulates glutamate-mediated neurotransmission in the rat basal forebrain: involvement of presynaptic neuronal nicotinic acetylcholine and metabotropic glutamate receptors. Journal of Neuroscience 27, 9262-9269CrossRefGoogle ScholarPubMed
58Albasanz, J.L. et al. (2005) Impaired metabotropic glutamate receptor/phospholipase C signaling pathway in the cerebral cortex in Alzheimer's disease and dementia with Lewy bodies correlates with stage of Alzheimer's-disease-related changes. Neurobiology of Disease 20, 685-693CrossRefGoogle ScholarPubMed
59Bortolotto, Z.A. et al. (2005) The regulation of hippocampal LTP by the molecular switch, a form of metaplasticity, requires mGlu5 receptors. Neuropharmacology 49(Suppl 1), 13-25 22CrossRefGoogle ScholarPubMed
60Jia, Z. et al. (1998) Selective abolition of the NMDA component of long-term potentiation in mice lacking mGluR5. Learning and Memory 5, 331-343CrossRefGoogle ScholarPubMed
61Bruno, V. et al. (2000) Selective blockade of metabotropic glutamate receptor subtype 5 is neuroprotective. Neuropharmacology 39, 2223-2230CrossRefGoogle ScholarPubMed
62Karanian, D.A. et al. (2006) 3-Nitropropionic acid toxicity in hippocampus: protection through N-methyl-D-aspartate receptor antagonism. Hippocampus 16, 834-842CrossRefGoogle ScholarPubMed
63Winblad, B. et al. (2007) Memantine in moderate to severe Alzheimer's disease: a meta-analysis of randomised clinical trials. Dementia and Geriatric Cognitive Disorders 24, 20-27CrossRefGoogle ScholarPubMed
64Schneider, L.S. et al. (2011) Lack of evidence for the efficacy of memantine in mild Alzheimer disease. Archives of Neurology 68, 991-998CrossRefGoogle ScholarPubMed
65Lindstrom, J.M. (2003) Nicotinic acetylcholine receptors of muscles and nerves: comparison of their structures, functional roles, and vulnerability to pathology. Annals of the New York Academy of Sciences 998, 41-52CrossRefGoogle ScholarPubMed
66Arneric, S.P., Holladay, M. and Williams, M. (2007) Neuronal nicotinic receptors: a perspective on two decades of drug discovery research. Biochemical Pharmacology 74, 1092-1101CrossRefGoogle ScholarPubMed
67D'Andrea, M.R. and Nagele, R.G. (2006) Targeting the alpha 7 nicotinic acetylcholine receptor to reduce amyloid accumulation in Alzheimer's disease pyramidal neurons. Current Pharmaceutical Design 12, 677-684CrossRefGoogle ScholarPubMed
68Gotti, C. et al. (2006) Selective nicotinic acetylcholine receptor subunit deficits identified in Alzheimer's disease, Parkinson's disease and dementia with Lewy bodies by immunoprecipitation. Neurobiology of Disease 23, 481-489CrossRefGoogle ScholarPubMed
69Martin-Ruiz, C.M. et al. (1999) Alpha4 but not alpha3 and alpha7 nicotinic acetylcholine receptor subunits are lost from the temporal cortex in Alzheimer's disease. Journal of Neurochemistry 73, 1635-1640CrossRefGoogle Scholar
70Sabbagh, M.N. et al. (2006) Pathologic and nicotinic receptor binding differences between mild cognitive impairment, Alzheimer disease, and normal aging. Archives of Neurology 63, 1771-1776CrossRefGoogle ScholarPubMed
71Wang, H.Y. et al. (2000) Amyloid peptide Abeta(1-42) binds selectively and with picomolar affinity to alpha7 nicotinic acetylcholine receptors. Journal of Neurochemistry 75, 1155-1161CrossRefGoogle ScholarPubMed
72Liu, Q., Kawai, H. and Berg, D.K. (2001) beta-Amyloid peptide blocks the response of alpha 7-containing nicotinic receptors on hippocampal neurons. Proceedings of the National Academy of Sciences of the United States of America 98, 4734-4739CrossRefGoogle ScholarPubMed
73Buckingham, S.D. et al. (2009) Nicotinic acetylcholine receptor signalling: roles in Alzheimer's disease and amyloid neuroprotection. Pharmacological Reviews 61, 39-61CrossRefGoogle ScholarPubMed
74Nagele, R.G. et al. (2002) Intracellular accumulation of beta-amyloid(1-42) in neurons is facilitated by the alpha 7 nicotinic acetylcholine receptor in Alzheimer's disease. Neuroscience 110, 199-211CrossRefGoogle ScholarPubMed
75Oddo, S. et al. (2005) Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America 102, 3046-3051CrossRefGoogle Scholar
76Small, D.H. et al. (2007) The beta-amyloid protein of Alzheimer's disease binds to membrane lipids but does not bind to the alpha7 nicotinic acetylcholine receptor. Journal of Neurochemistry 101, 1527-1538CrossRefGoogle ScholarPubMed
77Fodero, L.R. et al. (2004) Alpha7-nicotinic acetylcholine receptors mediate an Abeta(1-42)-induced increase in the level of acetylcholinesterase in primary cortical neurones. Journal of Neurochemistry 88, 1186-1193CrossRefGoogle ScholarPubMed
78Dineley, K.T. et al. (2002) beta-Amyloid peptide activates alpha 7 nicotinic acetylcholine receptors expressed in Xenopus oocytes. Journal of Biological Chemistry 277, 25056-25061CrossRefGoogle ScholarPubMed
79Lee, D.H. and Wang, H.Y. (2003) Differential physiologic responses of alpha7 nicotinic acetylcholine receptors to beta-amyloid1-40 and beta-amyloid1-42. Journal of Neurobiology 55, 25-30 23CrossRefGoogle ScholarPubMed
80Pettit, D.L., Shao, Z. and Yakel, J.L. (2001) beta-Amyloid(1-42) peptide directly modulates nicotinic receptors in the rat hippocampal slice. Journal of Neuroscience 21, RC120CrossRefGoogle ScholarPubMed
81Tozaki, H. et al. (2002) The inhibitory and facilitatory actions of amyloid-beta peptides on nicotinic ACh receptors and AMPA receptors. Biochemical and Biophysics Research Communications 294, 42-45CrossRefGoogle ScholarPubMed
82Tong, M. et al. (2011) Role of key aromatic residues in the ligand-binding domain of {alpha}7 nicotinic receptors in the agonist action of {beta}-amyloid. Journal of Biological Chemistry 286, 34373-34381CrossRefGoogle Scholar
83Hernandez, C.M. et al. (2010) Loss of alpha7 nicotinic receptors enhances beta-amyloid oligomer accumulation, exacerbating early-stage cognitive decline and septohippocampal pathology in a mouse model of Alzheimer's disease. Journal of Neuroscience 30, 2442-2453CrossRefGoogle Scholar
84Dziewczapolski, G. et al. (2009) Deletion of the alpha 7 nicotinic acetylcholine receptor gene improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer's disease. Journal of Neuroscience 29, 8805-8815CrossRefGoogle Scholar
85Mazurov, A., Hauser, T. and Miller, C.H. (2006) Selective alpha7 nicotinic acetylcholine receptor ligands. Current Medicinal Chemistry 13, 1567-1584CrossRefGoogle ScholarPubMed
86McLean, S.L. et al. (2011) Activation of alpha7 nicotinic receptors improves phencyclidine-induced deficits in cognitive tasks in rats: implications for therapy of cognitive dysfunction in schizophrenia. European Neuropsychopharmacology 21, 333-343CrossRefGoogle ScholarPubMed
87Liu, Q. et al. (2009) A novel nicotinic acetylcholine receptor subtype in basal forebrain cholinergic neurons with high sensitivity to amyloid peptides. Journal of Neuroscience 29, 918-929CrossRefGoogle ScholarPubMed
88Levey, A.I. et al. (1991) Identification and localization of muscarinic acetylcholine receptor proteins in brain with subtype-specific antibodies. Journal of Neuroscience 11, 3218-3226CrossRefGoogle ScholarPubMed
89Wei, J. et al. (1994) m1-m5 muscarinic receptor distribution in rat CNS by RT-PCR and HPLC. Journal of Neurochemistry 63, 815-821CrossRefGoogle ScholarPubMed
90Ferrari-DiLeo, G., Mash, D.C. and Flynn, D.D. (1995) Attenuation of muscarinic receptor-G-protein interaction in Alzheimer disease. Molecular and Chemical Neuropathology 24, 69-91CrossRefGoogle ScholarPubMed
91Tsang, S.W. et al. (2006) Impaired coupling of muscarinic M1 receptors to G-proteins in the neocortex is associated with severity of dementia in Alzheimer's disease. Neurobiology of Aging 27, 1216-1223CrossRefGoogle ScholarPubMed
92Warpman, U., Alafuzoff, I. and Nordberg, A. (1993) Coupling of muscarinic receptors to GTP proteins in postmortem human brain – alterations in Alzheimer's disease. Neuroscience Letters 150, 39-43CrossRefGoogle ScholarPubMed
93Flynn, D.D. et al. (1995) Differential regulation of molecular subtypes of muscarinic receptors in Alzheimer's disease. Journal of Neurochemistry 64, 1888-1891CrossRefGoogle ScholarPubMed
94Anagnostaras, S.G. et al. (2003) Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice. Nature Neuroscience 6, 51-58CrossRefGoogle ScholarPubMed
95Levey, A.I. (1996) Muscarinic acetylcholine receptor expression in memory circuits: implications for treatment of Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America 93, 13541-13546CrossRefGoogle ScholarPubMed
96Thathiah, A. and De Strooper, B. (2011) The role of G protein-coupled receptors in the pathology of Alzheimer's disease. Nature Reviews. Neuroscience 12, 73-87Google Scholar
97Buxbaum, J.D. et al. (1992) Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer beta/A4 amyloid protein precursor. Proceedings of the National Academy of Sciences of the United States of America 89, 10075-10078CrossRefGoogle ScholarPubMed
98Nitsch, R.M. et al. (1992) Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science 258, 304-307CrossRefGoogle ScholarPubMed
99Davis, A.A. et al. (2010) Deletion of M1 muscarinic acetylcholine receptors increases amyloid pathology in vitro and in vivo. Journal of Neuroscience 30, 4190-4196CrossRefGoogle ScholarPubMed
100Caccamo, A. et al. (2006) M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron 49, 671-682CrossRefGoogle ScholarPubMed
101Jones, C.K. et al. (2008) Novel selective allosteric activator of the M1 muscarinic acetylcholine receptor regulates amyloid processing and produces antipsychotic-like activity in rats. Journal of Neuroscience 28, 10422-10433CrossRefGoogle ScholarPubMed
102Shinoe, T. et al. (2005) Modulation of synaptic plasticity by physiological activation of M1 muscarinic acetylcholine receptors in the mouse hippocampus. Journal of Neuroscience 25, 11194-11200CrossRefGoogle ScholarPubMed
103Farber, S.A. et al. (1995) Regulated secretion of beta-amyloid precursor protein in rat brain. Journal of Neuroscience 15, 7442-7451CrossRefGoogle ScholarPubMed
104Fisher, A. (2008) Cholinergic treatments with emphasis on m1 muscarinic agonists as potential disease-modifying agents for Alzheimer's disease. Neurotherapeutics 5, 433-442CrossRefGoogle ScholarPubMed
105Bymaster, F.P. et al. (1998) Unexpected antipsychotic-like activity with the muscarinic receptor ligand (5R,6R)6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane. European Journal of Pharmacology 356, 109-119CrossRefGoogle ScholarPubMed
106Craft, S. (2007) Insulin resistance and Alzheimer's disease pathogenesis: potential mechanisms and implications for treatment. Current Alzheimer Research 4, 147-152CrossRefGoogle ScholarPubMed
107Hoyer, S. (2004) Glucose metabolism and insulin receptor signal transduction in Alzheimer disease. European Journal of Pharmacology 490, 115-125CrossRefGoogle ScholarPubMed
108Perry, T. et al. (2007) Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy. Experimental Neurology 203, 293-301CrossRefGoogle Scholar
109McClean, P.L. et al. (2011) The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease. Journal of Neuroscience 31, 6587-6594CrossRefGoogle Scholar
110Chakravarthy, B. et al. (2010) Amyloid-beta peptides stimulate the expression of the p75(NTR) neurotrophin receptor in SHSY5Y human neuroblastoma cells and AD transgenic mice. Journal of Alzheimers Disease 19, 915-925CrossRefGoogle ScholarPubMed
111Gispen, W.H. and Biessels, G.J. (2000) Cognition and synaptic plasticity in diabetes mellitus. Trends in Neurosciences 23, 542-549CrossRefGoogle ScholarPubMed
112Zhao, W. et al. (1999) Brain insulin receptors and spatial memory. Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. Journal of Biological Chemistry 274, 34893-34902CrossRefGoogle ScholarPubMed
113Zhao, W.Q. and Alkon, D.L. (2001) Role of insulin and insulin receptor in learning and memory. Molecular and Cellular Endocrinology 177, 125-134CrossRefGoogle ScholarPubMed
114Zhao, W.Q. et al. (2008) Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB Journal 22, 246-260CrossRefGoogle ScholarPubMed
115Moloney, A.M. et al. (2010) Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer's disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiology of Aging 31, 224-243CrossRefGoogle ScholarPubMed
116Townsend, M., Mehta, T. and Selkoe, D.J. (2007) Soluble Abeta inhibits specific signal transduction cascades common to the insulin receptor pathway. Journal of Biological Chemistry 282, 33305-33312CrossRefGoogle Scholar
117Lee, C.C. et al. (2009) Insulin rescues amyloid beta-induced impairment of hippocampal long-term potentiation. Neurobiology of Aging 30, 377-387CrossRefGoogle ScholarPubMed
118Risner, M.E. et al. (2006) Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease. Pharmacogenomics Journal 6, 246-254CrossRefGoogle Scholar
119Pedersen, W.A. et al. (2006) Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Experimental Neurology 199, 265-273CrossRefGoogle ScholarPubMed
120Lovshin, J.A. and Drucker, D.J. (2009) Incretin-based therapies for type 2 diabetes mellitus. Nature Reviews Endocrinology 5, 262-269CrossRefGoogle ScholarPubMed
121Gengler, S. et al. (2012) Val(8)GLP-1 rescues synaptic plasticity and reduces dense core plaques in APP/PS1 mice. Neurobiology of Aging 33, 265-276CrossRefGoogle ScholarPubMed
122Steen, E. et al. (2005) Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease – is this type 3 diabetes? Journal of Alzheimers Disease 7, 63-80CrossRefGoogle ScholarPubMed
123Carro, E. et al. (2005) Choroid plexus megalin is involved in neuroprotection by serum insulin-like growth factor I. Journal of Neuroscience 25, 10884-10893CrossRefGoogle ScholarPubMed
124Carro, E. et al. (2006) Therapeutic actions of insulin-like growth factor I on APP/PS2 mice with severe brain amyloidosis. Neurobiology of Aging 27, 1250-1257CrossRefGoogle ScholarPubMed
125Zhao, W.Q. et al. (2009) Insulin receptor dysfunction impairs cellular clearance of neurotoxic oligomeric a{beta}. Journal of Biological Chemistry 284, 18742-18753CrossRefGoogle ScholarPubMed
126Qiu, W.Q. and Folstein, M.F. (2006) Insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer's disease: review and hypothesis. Neurobiology of Aging 27, 190-198CrossRefGoogle ScholarPubMed
127Qiu, W.Q. et al. (1998) Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. Journal of Biological Chemistry 273, 32730-32738CrossRefGoogle ScholarPubMed
128Cooper, G.J. et al. (1987) Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients. Proceedings of the National Academy of Sciences of the United States of America 84, 8628-8632CrossRefGoogle ScholarPubMed
129Arispe, N., Pollard, H.B. and Rojas, E. (1993) Giant multilevel cation channels formed by Alzheimer disease amyloid beta-protein [A beta P-(1-40)] in bilayer membranes. Proceedings of the National Academy of Sciences of the United States of America 90, 10573-10577CrossRefGoogle Scholar
130Woods, S.C. et al. (2006) Pancreatic signals controlling food intake; insulin, glucagon and amylin. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 361, 1219-1235CrossRefGoogle Scholar
131Lutz, T.A. (2010) The role of amylin in the control of energy homeostasis. American Journal of Physiology. Regul Integr Comp Physiol 298, R1475-1484CrossRefGoogle Scholar
132May, P.C., Boggs, L.N. and Fuson, K.S. (1993) Neurotoxicity of human amylin in rat primary hippocampal cultures: similarity to Alzheimer's disease amyloid-beta neurotoxicity. Journal of Neurochemistry 61, 2330-2333CrossRefGoogle ScholarPubMed
133Tucker, H.M. et al. (1998) Human amylin induces ‘apoptotic’ pattern of gene expression concomitant with cortical neuronal apoptosis. Journal of Neurochemistry 71, 506-516CrossRefGoogle ScholarPubMed
134Lim, Y.A. et al. (2008) Human but not rat amylin shares neurotoxic properties with Abeta42 in long-term hippocampal and cortical cultures. FEBS Letters 582, 2188-2194CrossRefGoogle Scholar
135Lim, Y.A. et al. (2010) Abeta and human amylin share a common toxicity pathway via mitochondrial dysfunction. Proteomics 10, 1621-1633CrossRefGoogle Scholar
136Jhamandas, J.H. and MacTavish, D. (2004) Antagonist of the amylin receptor blocks beta-amyloid toxicity in rat cholinergic basal forebrain neurons. Journal of Neuroscience 24, 5579-5584CrossRefGoogle ScholarPubMed
137Jhamandas, J.H. et al. (2003) Human amylin actions on rat cholinergic basal forebrain neurons: antagonism of beta-amyloid effects. Journal of Neurophysiology 89, 2923-2930CrossRefGoogle ScholarPubMed
138Jhamandas, J.H. et al. (2011) Actions of beta-amyloid protein on human neurons are expressed through the amylin receptor. American Journal of Pathology 178, 140-149CrossRefGoogle ScholarPubMed
139Bierhaus, A. et al. (2005) Understanding RAGE, the receptor for advanced glycation end products. Journal of Molecular Medicine 83, 876-886CrossRefGoogle ScholarPubMed
140Schmidt, A.M. et al. (2001) The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses. Journal of Clinical Investigation 108, 949-955CrossRefGoogle ScholarPubMed
141Yan, S.D. et al. (1996) RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease. Nature 382, 685-691CrossRefGoogle ScholarPubMed
142Schmidt, A.M. et al. (2009) The role of RAGE in amyloid-beta peptide-mediated pathology in Alzheimer's disease. Current Opinion in Investigational Drugs 10, 672-680Google ScholarPubMed
143Yan, S.D. et al. (2009) RAGE and Alzheimer's disease: a progression factor for amyloid-beta-induced cellular perturbation? Journal of Alzheimers Disease 16, 833-843 26CrossRefGoogle ScholarPubMed
144Maczurek, A., Shanmugam, K. and Munch, G. (2008) Inflammation and the redox-sensitive AGE-RAGE pathway as a therapeutic target in Alzheimer's disease. Annals of the New York Academy of Sciences 1126, 147-151CrossRefGoogle ScholarPubMed
145Sousa, M.M. et al. (2000) Interaction of the receptor for advanced glycation end products (RAGE) with transthyretin triggers nuclear transcription factor kB (NF-kB) activation. Laboratory Investigation 80, 1101-1110CrossRefGoogle ScholarPubMed
146Origlia, N. et al. (2010) Microglial receptor for advanced glycation end product-dependent signal pathway drives beta-amyloid-induced synaptic depression and long-term depression impairment in entorhinal cortex. Journal of Neuroscience 30, 11414-11425CrossRefGoogle ScholarPubMed
147Han, S.H., Kim, Y.H. and Mook-Jung, I. (2011) RAGE: the beneficial and deleterious effects by diverse mechanisms of actions. Molecules and Cells 31, 91-97CrossRefGoogle ScholarPubMed
148Jeynes, B. and Provias, J. (2008) Evidence for altered LRP/RAGE expression in Alzheimer lesion pathogenesis. Current Alzheimer Research 5, 432-437CrossRefGoogle ScholarPubMed
149Deane, R. et al. (2003) RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nature Medicine 9, 907-913CrossRefGoogle ScholarPubMed
150Origlia, N. et al. (2008) Receptor for advanced glycation end product-dependent activation of p38 mitogen-activated protein kinase contributes to amyloid-beta-mediated cortical synaptic dysfunction. Journal of Neuroscience 28, 3521-3530CrossRefGoogle ScholarPubMed
151Chen, X. et al. (2007) RAGE: a potential target for Abeta-mediated cellular perturbation in Alzheimer's disease. Current Molecular Medicine 7, 735-742Google Scholar
152Deane, R., Wu, Z. and Zlokovic, B.V. (2004) RAGE (yin) versus LRP (yang) balance regulates alzheimer amyloid beta-peptide clearance through transport across the blood-brain barrier. Stroke 35, 2628-2631CrossRefGoogle ScholarPubMed
153Mackic, J.B. et al. (2002) Circulating amyloid-beta peptide crosses the blood-brain barrier in aged monkeys and contributes to Alzheimer's disease lesions. Vascular Pharmacology 38, 303-313CrossRefGoogle ScholarPubMed
154Martel, C.L. et al. (1996) Blood-brain barrier uptake of the 40 and 42 amino acid sequences of circulating Alzheimer's amyloid beta in guinea pigs. Neuroscience Letters 206, 157-160CrossRefGoogle ScholarPubMed
155Zhang, H. et al. (2008) Role of soluble receptor for advanced glycation end products on endotoxin-induced lung injury. American Journal of Respiratory and Critical Care Medicine 178, 356-362CrossRefGoogle ScholarPubMed
156Raucci, A. et al. (2008) A soluble form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane-bound form by the sheddase a disintegrin and metalloprotease 10 (ADAM10). FASEB Journal 22, 3716-3727CrossRefGoogle ScholarPubMed
157Emanuele, E. et al. (2005) Circulating levels of soluble receptor for advanced glycation end products in Alzheimer disease and vascular dementia. Archives of Neurology 62, 1734-1736CrossRefGoogle ScholarPubMed
158[No authors listed] TransTech PharmaTTP488, Alzheimer's Disease. www.ttpharma.com/pipeline_rage_antagonists.htmlGoogle Scholar
159Coulson, E.J. (2006) Does the p75 neurotrophin receptor mediate Abeta-induced toxicity in Alzheimer's disease? Journal of Neurochemistry 98, 654-660CrossRefGoogle ScholarPubMed
160Bothwell, M. (1991) Keeping track of neurotrophin receptors. Cell 65, 915-918CrossRefGoogle ScholarPubMed
161Chao, M.V. and Hempstead, B.L. (1995) p75 and Trk: a two-receptor system. Trends in Neurosciences 18, 321-326CrossRefGoogle Scholar
162Ibanez, C.F. et al. (1992) Disruption of the low affinity receptor-binding site in NGF allows neuronal survival and differentiation by binding to the trk gene product. Cell 69, 329-341CrossRefGoogle Scholar
163Ip, N.Y. et al. (1993) Similarities and differences in the way neurotrophins interact with the Trk receptors in neuronal and nonneuronal cells. Neuron 10, 137-149CrossRefGoogle ScholarPubMed
164Barker, P.A. (2004) p75NTR is positively promiscuous: novel partners and new insights. Neuron 42, 529-533 27CrossRefGoogle ScholarPubMed
165Nykjaer, A. et al. (2004) Sortilin is essential for proNGF-induced neuronal cell death. Nature 427, 843-848CrossRefGoogle ScholarPubMed
166Wang, K.C. et al. (2002) P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature 420, 74-78CrossRefGoogle ScholarPubMed
167Hu, X.Y. et al. (2002) Increased p75(NTR) expression in hippocampal neurons containing hyperphosphorylated tau in Alzheimer patients. Experimental Neurology 178, 104-111CrossRefGoogle ScholarPubMed
168Ginsberg, S.D. et al. (2006) Down regulation of trk but not p75NTR gene expression in single cholinergic basal forebrain neurons mark the progression of Alzheimer's disease. Journal of Neurochemistry 97, 475-487CrossRefGoogle Scholar
169Counts, S.E. and Mufson, E.J. (2005) The role of nerve growth factor receptors in cholinergic basal forebrain degeneration in prodromal Alzheimer disease. Journal of Neuropathology and Experimental Neurology 64, 263-272CrossRefGoogle ScholarPubMed
170Yaar, M. et al. (1997) Binding of beta-amyloid to the p75 neurotrophin receptor induces apoptosis. A possible mechanism for Alzheimer's disease. Journal of Clinical Investigation 100, 2333-2340CrossRefGoogle Scholar
171Knowles, J.K. et al. (2009) The p75 neurotrophin receptor promotes amyloid-beta(1-42)-induced neuritic dystrophy in vitro and in vivo. Journal of Neuroscience 29, 10627-10637CrossRefGoogle ScholarPubMed
172Sotthibundhu, A. et al. (2008) Beta-amyloid(1-42) induces neuronal death through the p75 neurotrophin receptor. Journal of Neuroscience 28, 3941-3946CrossRefGoogle ScholarPubMed
173Perini, G. et al. (2002) Role of p75 neurotrophin receptor in the neurotoxicity by beta-amyloid peptides and synergistic effect of inflammatory cytokines. Journal of Experimental Medicine 195, 907-918CrossRefGoogle ScholarPubMed
174Rabizadeh, S. et al. (1994) Expression of the low-affinity nerve growth factor receptor enhances beta-amyloid peptide toxicity. Proceedings of the National Academy of Sciences of the United States of America 91, 10703-10706CrossRefGoogle ScholarPubMed
175Costantini, C. et al. (2005) Characterization of the signaling pathway downstream p75 neurotrophin receptor involved in beta-amyloid peptide-dependent cell death. Journal of Molecular Neuroscience 25, 141-156CrossRefGoogle ScholarPubMed
176Mufson, E.J. et al. (2002) Loss of basal forebrain P75(NTR) immunoreactivity in subjects with mild cognitive impairment and Alzheimer's disease. Journal of Comparative Neurology 443, 136-153CrossRefGoogle ScholarPubMed
177Jaffar, S. et al. (2001) Neuropathology of mice carrying mutant APP(swe) and/or PS1(M146L) transgenes: alterations in the p75(NTR) cholinergic basal forebrain septohippocampal pathway. Experimental Neurology 170, 227-243CrossRefGoogle ScholarPubMed
178Bengoechea, T.G. et al. (2009) p75 reduces beta-amyloid-induced sympathetic innervation deficits in an Alzheimer's disease mouse model. Proceedings of the National Academy of Sciences of the United States of America 106, 7870-7875CrossRefGoogle Scholar
179Wang, Y.J. et al. (2011) 75NTR regulates Abeta deposition by increasing Abeta production but inhibiting Abeta aggregation with its extracellular domain. Journal of Neuroscience 31, 2292-2304CrossRefGoogle Scholar
180Hardy, J. and Selkoe, D.J. (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353-356CrossRefGoogle ScholarPubMed
181Morgan, D. et al. (2000) A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature 408, 982-985CrossRefGoogle Scholar
182Rinne, J.O. et al. (2010) 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurology 9, 363-372CrossRefGoogle ScholarPubMed
183Tomita, T. (2009) Secretase inhibitors and modulators for Alzheimer's disease treatment. Expert Review of Neurotherapeutics 9, 661-679CrossRefGoogle ScholarPubMed
184Augelli-Szafran, C.E. et al. (2010) Discovery of notch-sparing gamma-secretase inhibitors. Current Alzheimer Research 7, 207-209CrossRefGoogle ScholarPubMed

Further reading

The reader is referred to Refs 27, 32, 33, 35, 40 and 73 for reviews on Aβ protein and synaptic function, and amyloid interactions with specific types of neuronal receptors.