AAD  Vol.2 No.4 , December 2013
Accelerating Alzheimer’s pathogenesis by GRK5 deficiency via cholinergic dysfunction
Abstract: G protein-coupled receptors (GPCRs) mediate a wide variety of physiological function. GPCR signaling is negatively regulated by the receptor desensitization, a procedure initiated by a group of kinases, including GPCR kinases (GRKs). Studies using genetargeted mice revealed that deficiency of a particular GRK member led to dysfunction of a highly selective group of GPCRs. In particular, for example, GRK5 deficiency specifically disrupts M2/M4-mediated muscarinic cholinergic function. Emerging evidence indicates that ?-amyloid accumulation may lead to GRK5 deficiency, while the latter impairs desensitization of M2/M4 receptors. Within memory circuits, M2 is primarily presynaptic autoreceptor serving as a negative feedback to inhibit acetylcholine release. The impaired desensitization of M2 receptor by GRK5 deficiency leads to hyperactive M2, which eventually suppresses acetylcholine release and results in an overall cholinergic hypofunctioning. Since the cholinergic hypofunctioning is known to cause ?-amyloid accumulation, the GRK5 deficiency appears to connect the cholinergic hypofunctioning and ?-amyloid accumulation together into a self-amplifying cycle, which accelerates both changes. Given that the ? -amyloid accumulation and the cholinergic hypofucntioning are the hallmark changes in the ?-amyloid hypothesis and the cholinergic hypothesis, respectively, the GRK5 deficiency appears to bring the two major hypotheses in Alzheimer’s disease together, whereas the GRK5 deficiency is the pivotal link. Therefore, any strategies that can break this cycle would be therapeutically beneficial for Alzheimer’s patients.
Cite this paper: Suo, W. (2013) Accelerating Alzheimer’s pathogenesis by GRK5 deficiency via cholinergic dysfunction. Advances in Alzheimer's Disease, 2, 148-160. doi: 10.4236/aad.2013.24020.

[1]   Duyckaerts, C., Delatour, B. and Potier, M.C. (2009) Classification and basic pathology of Alzheimer disease. Acta neuro-pathologica, 118, 5-36.

[2]   Nelson, P.T., Braak, H. and Markesbery, W.R. (2009) Neuropathology and cognitive impairment in Alzheimer disease: A complex but coherent relationship. Journal of Neuropathology and Experimental Neurology, 68, 1-14.

[3]   Jellinger, K.A. and Bancher, C. (1998) Neuropathology of Alzheimer’s disease: A critical update. Journal of neural transmission. Supplementum, 54, 77-95.

[4]   Mahler, M.E. and Cummings, J.L. (1990) Alzheimer disease and the dementia of Parkinson disease: Comparative investigations. Alzheimer Disease and Associated Disorders, 4, 133-149.

[5]   Bartus, R.T., Dean 3rd, R.L., Beer, B. and Lippa, A.S. (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science, 217, 408-414.

[6]   Hardy, J. and Selkoe, D.J. (2002) The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science, 297, 353-356.

[7]   Zatta, P.F. (1995) Aluminum binds to the hyperphosphorylated tau in Alzheimer’s disease: A hypothesis. Medical Hypotheses, 44, 169-172.

[8]   Hoyer, S. (2000) Brain glucose and energy metabolism abnormalities in sporadic Alzheimer disease. Causes and consequences: An Update. Experimental Gerontology, 35, 1363-1372.

[9]   Aisen, P.S. (1996) Inflammation and Alzheimer disease. Molecular and Chemical Neuropathology, 28, 83-88.

[10]   McGeer, E.G. and McGeer, P.L. (1999) Brain inflammation in Alzheimer disease and the therapeutic implications. Current Pharmaceutical Design, 5, 821-836.

[11]   Blennow, K., Wallin, A., Uhlemann, C. and Gottfries, C.G. (1991) White-matter lesions on CT in Alzheimer patients: Relation to clinical symptomatology and vascular factors. Acta Neurologica Scandinavica, 83, 187-193.

[12]   Smith, M.A., Richey, P.L., Kalaria, R.N. and Perry, G. (1996) Elastase is associated with the neurofibrillary pathology of Alzheimer disease: A putative link between proteolytic imbalance and oxidative stress. Restorative Neurology and Neuroscience, 9, 213-217.

[13]   Pappolla, M.A., Sos, M., Omar, R.A. and Sambamurti, K. (1996) The heat shock/oxidative stress connection. Relevance to Alzheimer disease. Molecular and Chemical Neuropathology, 28, 21-34.

[14]   Hoyer, S. (1998) Is sporadic Alzheimer disease the brain type of non-insulin dependent diabetes mellitus? A challenging hypothesis. Journal of Neural Transmission, 105, 415-422.

[15]   Supnet, C. and Bezprozvanny, I. (2010) The dysregulation of intracellular calcium in Alzheimer disease. Cell Calcium, 47, 183-189.

[16]   Sallese, M., Mariggio, S., Collodel, G., Moretti, E., Piomboni, P., Baccetti, B. and De Blasi, A. (1997) G protein-coupled receptor kinase GRK4. Molecular analysis of the four isoforms and ultrastructural localization in spermatozoa and germinal cells. The Journal of Biological Chemistry, 272, 10188-10195.

[17]   Virlon, B., Firsov, D., Cheval, L., Reiter, E., Troispoux, C., Guillou, F. and Elalouf, J.M. (1998) Rat G protein-coupled receptor kinase GRK4: Identification, functional expression, and differential tissue distribution of two splice variants. Endocrinology, 139, 2784-2795.

[18]   Sallese, M., Salvatore, L., D’Urbano, E., Sala, G., Storto, M., Launey, T., Nicoletti, F., Knopfel, T. and De Blasi, A. (2000) The G-protein-coupled receptor kinase GRK4 mediates homologous desensitization of metabotropic glutamate receptor 1. The FASEB Journal, 14, 2569-2580.

[19]   Pitcher, J.A., Freedman, N.J. and Lefkowitz, R.J. (1998) G protein-coupled receptor kinases. Annual Review of Biochemistry, 67, 653-692.

[20]   Kohout, T.A. and Lefkowitz, R.J. (2003) Regulation of G protein-coupled receptor kinases and arrestins during receptor desensitization. Molecular Pharmacology, 63, 9-18.

[21]   Ribas, C., Penela, P., Murga, C., Salcedo, A., Garcia-Hoz, C., Jurado-Pueyo, M., Aymerich, I. and Mayor Jr., F. (2007) The G protein-coupled receptor kinase (GRK) interactome: Role of GRKs in GPCR regulation and signalling. Biochimica et Biophysica Acta, 1768, 913-922.

[22]   Reiter, E. and Lefkowitz, R.J. (2006) GRKs and beta-arrestins: Roles in receptor silencing, trafficking and signaling. Trends in Endocrinology and Metabolism: TEM, 17, 159-165.

[23]   Kunapuli, P. and Benovic, J.L. (1993) Cloning and expression of GRK5: A member of the G protein-coupled receptor kinase family. Proceedings of the National Academy of Sciences of the United States of America, 90, 5588-5592.

[24]   Premont, R.T., Koch, W.J., Inglese, J. and Lefkowitz, R.J. (1994) Identification, purification, and characterization of GRK5, a member of the family of G protein-coupled receptor kinases. The Journal of Biological Chemistry, 269, 6832-6841.

[25]   Erdtmann-Vourliotis, M., Mayer, P., Ammon, S., Riechert, U. and Hollt, V. (2001) Distribution of G-protein-coupled receptor kinase (GRK) isoforms 2, 3, 5 and 6 mRNA in the rat brain, brain research. Molecular Brain Research, 95, 129-137.

[26]   Wu, C.C., Tsai, F.M., Shyu, R.Y., Tsai, Y.M., Wang, C.H. and Jiang, S.Y. (2011) G protein-coupled receptor kinase 5 mediates Tazarotene-induced gene 1-induced growth suppression of human colon cancer cells. BMC Cancer, 11, 175.

[27]   Liu, P., Wang, X., Gao, N., Zhu, H., Dai, X., Xu, Y., Ma, C., Huang, L., Liu, Y. and Qin, C. (2010) G protein-coupled receptor kinase 5, overexpressed in the alpha-synuclein up-regulation model of Parkinson’s disease, regulates bcl-2 expression. Brain Research, 1307, 134-141.

[28]   Ahn, M.J., Lee, K.H., Ahn, J.I., Yu, D.H., Lee, H.S., Choi, J.H., Jang, J.S., Bae, J.M. and Lee, Y.S. (2004) The differential gene expression profiles between sensitive and resistant breast cancer cells to adriamycin by cDNA microarray. Cancer Research and Treatment: Official Journal of Korean Cancer Association, 36, 43-49.

[29]   Penela, P., Barradas, M., Alvarez-Dolado, M., Munoz, A. and Mayor Jr., F., (2001) Effect of hypothyroidism on G protein-coupled receptor kinase 2 expression levels in rat liver, lung, and heart. Endocrinology, 142, 987-991.

[30]   Ishizaka, N., Alexander, R.W., Laursen, J.B., Kai, H., Fukui, T., Oppermann, M., Lefkowitz, R.J., Lyons, P.R. and Griendling, K.K. (1997) G protein-coupled receptor kinase 5 in cultured vascular smooth muscle cells and rat aorta. Regulation by angiotensin II and hypertension. The Journal of Biological Chemistry, 272, 32482-32488.

[31]   Fan, J. and Malik, A.B. (2003) Toll-like receptor-4 (TLR4) signaling augments chemokine-induced neutrophil migration by modulating cell surface expression of chemokine receptors. Nature Medicine, 9, 315-321.

[32]   Keys, J.R., Zhou, R.H., Harris, D.M., Druckman, C.A. and Eckhart, A.D. (2005) Vascular smooth muscle overexpression of G protein-coupled receptor kinase 5 elevates blood pressure, whichsegregates with sex and is dependent on Gi-mediated signalling. Circulation, 112, 1145-1153.

[33]   Rockman, H.A., Choi, D.J., Rahman, N.U., Akhter, S.A., Lefkowitz, R.J. and Koch, W.J. (1996) Receptor-specific in vivo desensitization by the G protein-coupled receptor kinase-5 in transgenic mice. Proceedings of the National Academy of Sciences of the United States of America, 93, 9954-9959.

[34]   Cao, T.T., Deacon, H.W., Reczek, D., Bretscher, A. and von Zastrow, M. (1999) A kinase-regulated PDZ-domain interaction controls endocytic sorting of the beta2-adrenergic receptor. Nature, 401, 286-290.

[35]   Iwata, M., Yoshikawa, T., Baba, A., Anzai, T., Nakamura, I., Wainai, Y., Takahashi, T. and Ogawa, S. (2001) Autoimmunity against the second extracellular loop of beta(1)-adrenergic receptors induces beta-adrenergic receptor desensitization and myocardial hyper-trophy in vivo. Circulation Research, 88, 578-586.

[36]   Hu, L.A., Chen, W., Premont, R.T., Cong, M. and Lefkowitz, R.J. (2002) G protein-coupled receptor kinase 5 regulates β1-adrenergic receptor association with PSD-95, The Journal of Biological Chemistry, 277, 1607-1613.

[37]   Pei, G., Kieffer, B.L., Lefkowitz, R.J. and Freedman, N.J. (1995) Agonist-dependent phosphorylation of the mouse delta-opioid receptor: Involvement of G protein-coupled receptor kinases but not protein kinase C. Molecular Pharmacology, 48, 173-177.

[38]   Gainetdinov, R.R., Bohn, L.M., Walker, J.K., Laporte, S.A., Macrae, A.D., Caron, M.G., Lefkowitz, R.J. and Premont, R.T. (1999) Muscarinic supersensitivity and impaired receptor desensitization in G protein-coupled receptor kinase 5-deficient mice. Neuron, 24, 1029-1036.

[39]   Walker, J.K.L., Gainetdinov, R.R., Feldman, D.S., McFawn, P.K., Caron, M.G., Lefkowitz, R.J., Premont, R.T. and Fisher, J.T. (2004) G protein-coupled receptor kinase 5 regulates airway responses induced by muscarinic recaptor activation. American Journal of Physiology-Lung Cellular and Molecular Physiology, 286, L312-L319.

[40]   Suo, Z., Wu, M., Citron, B.A., Wong, G.T. and Festoff, B.W. (2004) Abnormality of G-protein-coupled receptor kinases at prodromal and early stages of Alzheimer’s disease: An association with early beta-amyloid accumulation. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 24, 3444-3452.

[41]   Suo, Z., Cox, A.A., Bartelli, N., Rasul, I., Festoff, B.W., Premont, R.T. and Arendash, G.W. (2007) GRK5 deficiency leads to early Alzheimer-like pathology and working memory impairment. Neurobiology of Aging, 28, 1873-1888.

[42]   Liu, J., Rasul, I., Sun, Y., Wu, G., Li, L., Premont, R.T. and Suo, W.Z. (2009) GRK5 deficiency leads to reduced hippocampal acetylcholine level via impaired presynaptic M2/M4 autoreceptor desensitization. The Journal of Biological Chemistry, 284, 19564-19571.

[43]   Cheng, S., Li, L., He, S., Liu, J., Sun, Y., He, M., Grasing, K., Premont, R.T. and Suo, W.Z. (2010) GRK5 deficiency accelerates {beta}-amyloid accumulation in Tg2576 mice via impaired cholinergic activity. The Journal of Biological Chemistry, 285, 41541-41548.

[44]   Arawaka, S., Wada, M., Goto, S., Karube, H., Sakamoto, M., Ren, C.H., Koyama, S., Nagasawa, H., Kimura, H., Kawanami, T., Kurita, K., Tajima, K., Daimon, M., Baba, M., Kido, T., Saino, S., Goto, K., Asao, H., Kitanaka, C., Takashita, E., Hongo, S., Nakamura, T., Kayama, T., Suzuki, Y., Kobayashi, K., Katagiri, T., Kuro-kawa, K., Kurimura, M., Toyoshima, I., Niizato, K., Tsuchiya, K., Iwatsubo, T., Muramatsu, M., Matsumine, H. and Kato, T. (2006) The role of G-protein-coupled receptor kinase 5 in pathogenesis of sporadic Parkinson’s disease. The Journal of Neuroscience: The Official Journal of the Society for Neuro-science, 26, 9227-9238.

[45]   Pronin, A.N., Morris, A.J., Surguchov, A. and Benovic, J.L. (2000) Synucleins are a novel class of substrates for G protein-coupled receptor kinases. The Journal of Biological Chemistry, 275, 26515-26522.

[46]   Carman, C.V., Som, T., Kim, C.M. and Benovic, J.L. (1998) Binding and phosphorylation of tubulin by G protein-coupled receptor kinases. The Journal of biological chemistry, 273, 20308-20316.

[47]   Chen, X., Zhu, H., Yuan, M., Fu, J., Zhou, Y. and Ma, L. (2010) G-protein-coupled receptor kinase 5 phosphorylates p53 and inhibits DNA damage-induced apoptosis. The Journal of Biological Chemistry, 285, 12823-12830.

[48]   Sorriento, D., Ciccarelli, M., Santulli, G., Campanile, A., Altobelli, G.G., Cimini, V., Galasso, G., Astone, D., Piscione, F., Pastore, L., Tri-marco, B. and Iaccarino, G. (2008) The G-protein-coupled receptor kinase 5 inhibits NFkappaB transcriptional activity by inducing nuclear accumulation of IκBα. Proceedings of the National Academy of Sciences of the United States of America, 105, 17818-17823.

[49]   Sorriento, D., Campanile, A., Santulli, G., Leggiero, E., Pastore, L., Trimarco, B. and Iaccarino, G. (2009) A new synthetic protein, TAT-RH, inhibits tumor growth through the regulation of NFκB activity. Molecular Cancer, 8, 97.

[50]   Zhou, R.H., Pesant, S., Cohn, H.I., Soltys, S., Koch, W.J. and Eckhart, A.D. (2009) Negative regulation of VEGF signaling in human coronary artery endothelial cells by G protein-coupled-receptor kinase 5. Clinical and Translational Science, 2, 57-61.

[51]   Johnson, L.R., Scott, M.G. and Pitcher, J.A. (2004) G protein-coupled receptor kinase 5 contains a DNA-binding nuclear localization sequence. Molecular and Cellular Biology, 24, 10169-10179.

[52]   Kara, E., Crepieux, P., Gauthier, C., Martinat, N., Piketty, V., Guillou, F. and Reiter, E. (2006) A phosphorylation cluster of five serine and threonine residues in the C-terminus of the follicle-stimulating hormone receptor is important for desensitization but not for β-arrestin-mediated ERK activation. Molecular Endocrinology, 20, 3014- 3026.

[53]   Warabi, K., Richardson, M.D., Barry, W.T., Yamaguchi, K., Roush, E.D., Nishimura, K. and Kwatra, M.M. (2002) Human substance P receptor undergoes agonist-dependent phosphorylation by G protein-coupled receptor kinase 5 in Vitro. FEBS Letters, 521, 140-144.

[54]   Tiruppathi, C., Yan, W., Sandoval, R., Naqvi, T., Pronin, A.N., Benovic, J.L. and Malik, A.B. (2000) G protein-coupled receptor kinase-5 regulates thrombin-activated signaling in endothelial cells. Proceedings of the National Academy of Sciences of the United States of America, 97, 7440-7445.

[55]   Nagayama, Y., Tanaka, K., Namba, H., Yamashita, S. and Niwa, M. (1996) Expression and regulation of G protein-coupled receptor kinase 5 and β-arrestin-1 in rat thyroid FRTL5 cells. Thyroid, 6, 627-631.

[56]   Nagayama, Y., Tanaka, K., Hara, T., Namba, H., Yamashita, S., Taniyama, K. and Niwa, M. (1996) Involvement of G protein-coupled receptor kinase 5 in homologous desensitization of the thyrotropin receptor. The Journal of Biological Chemistry, 271, 10143-10148.

[57]   Martini, J.S., Raake, P., Vinge, L.E., DeGeorge Jr., B.R., Chuprun, J.K., Harris, D.M., Gao, E., Eckhart, A.D., Pitcher, J.A. and Koch, W.J. (2008) Uncovering G protein-coupled receptor kinase-5 as a histone deacetylase kinase in the nucleus of cardiomyocytes. Proceedings of the National Academy of Sciences of the United States of America, 105, 12457-12462.

[58]   Barker, B.L. and Benovic, J.L. (2011) G protein-coupled receptor kinase 5 phosphorylation of hip regulates internalization of the chemokine receptor CXCR4. Biochemistry, 50, 6933-6941.

[59]   Parameswaran, N., Pao, C.S., Leonhard, K.S., Kang, D.S., Kratz, M., Ley, S.C. and Benovic, J.L. (2006) Arrestin-2 and G protein-coupled receptor kinase 5 interact with NFκB1 p105 and negatively regulate lipopolysaccharide-stimulated ERK1/2 activation in macrophages. The Journal of Biological Chemistry, 281, 34159-34170.

[60]   Patial, S., Shahi, S., Saini, Y., Lee, T., Packiriswamy, N., Appledorn, D.M., Lapres, J.J., Amalfitano, A. and Parameswaran, N. (2011) G-protein coupled receptor kinase 5 mediates lipopoly-saccharide-induced NFκB activation in primary macrophages and modulates inflammation in Vivo in mice. Journal of Cellular Physiology, 226, 1323-1333.

[61]   Cai, X., Wu, J.H., Exum, S.T., Oppermann, M., Premont, R.T., Shenoy, S.K. and Freedman, N.J. (2009) Reciprocal regulation of the plate-let-derived growth factor receptor-β and G protein-coupled receptor kinase 5 by cross-phosphorylation: Effects on catalysis. Molecular Pharmacol- ogy, 75, 626-636.

[62]   Wu, J.H., Gos-wami, R., Cai, X., Exum, S.T., Huang, X., Zhang, L., Brian, L., Premont, R.T., Peppel, K. and Freed-man, N.J. (2006) Regulation of the platelet-derived growth factor receptor-β by G protein-coupled receptor kinase-5 in vascular smooth muscle cells involves the phosphatase Shp2. The Journal of Biological Chemistry, 281, 37758- 37772.

[63]   Luo, X., Ding, L., Xu, J., Williams, R.S. and Chegini, N. (2005) Leiomyoma and myometrial gene expression profiles and their responses to gonadotropin-releasing hormone analog therapy. Endocrinology, 146, 1074-1096.

[64]   Fan, X., Zhang, J., Zhang, X., Yue, W. and Ma, L. (2002) Acute and chronic morphine treatments and morphine withdrawal differentially regulate GRK2 and GRK5 gene expression in rat brain. Neuro-pharmacology, 43, 809-816.

[65]   Suo, W.Z. and Li, L. (2010) Dysfunction of G protein-coupled receptor kinases in Alzheimer’s disease. The Scientific World Journal, 10, 1667-1678.

[66]   Pitcher, J.A., Fredericks, Z.L., Stone, W.C., Premont, R.T., Stoffel, R.H., Koch, W.J. and Lefkowitz, R.J. (1996) Phosphatidylinositol 4,5-bisphosphate (PIP2)-enhanced G protein-coupled receptor kinase (GRK) activity: Location, structure, and regulation of the PIP2 binding site distinguishes the GRK subfamilies. The Journal of Biological Chemistry, 271, 24907-24913.

[67]   Pronin, A.N., Satpaev, D.K., Slepak, V.Z. and Benovic, J.L. (1997) Regulation of G protein-coupled receptor kinases by calmodulin and localization of the calmodulin binding domain. The Journal of Biological Chemistry, 272, 18273-18280.

[68]   Jaber, M., Koch, W.J., Rockman, H., Smith, B., Bond, R.A., Sulik, K.K., Ross, J., Jr., Lefkowitz, R.J., Caron, M.G. and Giros, B. (1996) Essential role of β-adrenergic receptor kinase 1 in cardiac development and function. Proceedings of the National Academy of Sciences of the United States of America, 93, 12974-12979.

[69]   Peppel, K., Boekhoff, I., McDonald, P., Breer, H., Caron, M.G. and Lefko-witz, R.J. (1997) G protein-coupled receptor kinase 3 (GRK3) gene disruption leads to loss of odorant receptor desensitization. The Journal of Biological Chemistry, 272, 25425-25428.

[70]   Gainetdinov, R.R., Bohn, L.M., Sotnikova, T.D., Cyr, M., Laakso, A., Macrae, A.D., Torres, G.E., Kim, K.M., Lefkowitz, R.J., Caron, M.G. and Premont, R.T. (2003) Dopaminergic supersensitivity in g protein-coupled receptor kinase 6-deficient mice. Neuron, 38, 291-303.

[71]   Matsui, M., Yamada, S., Oki, T., Manabe, T., Taketo, M.M. and Ehlert, F.J. (2004) Functional analysis of muscarinic acetylcholine receptors using knockout mice. Life Sciences, 75, 2971-2981.

[72]   Wess, J. (2004) Muscarinic acetylcholine receptor knock-out mice: Novel phenotypes and clinical implications. Annual Review of Pharmacology and Toxicology, 44, 423- 450.

[73]   Hsiao, K., Chapman, P., Nilsen, S., Eckman, C., Harigaya, Y., Younkin, S., Yang, F. and Cole, G. (1996) Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science, 274, 99-103.

[74]   Li, L., Liu, J. and Suo, W.Z. (2008) GRK5 deficiency exaggerates inflammatory changes in TgAPPsw mice. Journal of Neuroinflammation, 5, 24.

[75]   Le, Y., Gong, W., Tiffany, H.L., Tumanov, A., Nedospasov, S., Shen, W., Dunlop, N.M., Gao, J.L., Murphy, P.M., Oppenheim, J.J. and Wang, J.M. (2001) Amyloid (beta)42 activates a G-protein-coupled chemoattractant receptor, FPR-like-1. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 21, RC123.

[76]   Yazawa, H., Yu, Z.X., Takeda, Le, Y., Gong, W., Ferrans, V.J., Oppenheim, J.J., Li, C.C. and Wang, J.M. (2001) β amyloid peptide (Aβ42) is internalized via the G-protein-coupled receptor FPRL1 and forms fibrillar aggregates in macrophages. The FASEB Journal, 15, 2454-2462.

[77]   Langkabel, P., Zwirner, J. and Oppermann, M. (1999) Ligand-induced phosphorylation of anaphylatoxin recaptors C3aR and C5aR is mediated by G protein-coupled receptor kinases. European Journal of Immunology, 29, 3035-3046.<3035::AID-IMMU3035>3.0.CO;2-Z

[78]   Streit, W.J., Conde, J.R. and Harrison, J.K. (2001) Chemokines and Alzheimer’s disease. Neurobiology of Aging, 22, 909-913.

[79]   Levey, 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, 13541-13546.

[80]   Zhang, W., Basile, A.S., Gomeza, J., Volpicelli, L.A., Levey, A.I. and Wess, J. (2002) Characterization of central inhibitory muscarinic autoreceptors by the use of muscarinic acetylcholine receptor knock-out mice. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 22, 1709-1717.

[81]   Rossner, S., Ueberham, U., Schliebs, R., Perez-Polo, J.R. and Bigl, V. (1998) The regulation of amyloid precursor protein metabolism by cholinergic mechanisms and neuro-trophin receptor signalling. Progress in Neurobiology, 56, 541-569.

[82]   DeLapp, N., Wu, S., Belagaje, R., Johnstone, E., Little, S., Shannon, H., Bymaster, F., Calligaro, D., Mitch, C., Whitesitt, C., Ward, J., Sheardown, M., Fink-Jensen, A., Jeppesen, L., Thomsen, C. and Sauerberg, P. (1998) Effects of the M1 agonist xanomeline on processing of human β-amyloid precursor protein (FAD, Swedish mutant) transfected into Chinese hamter ovary-m1 cells. Biochemical and Biophysical Research Communications, 244, 156-160.

[83]   Lin, L., Georgievska, B., Mattsson, A. and Isacson, O. (1999) Cognitive changes and modified processing of amyloid precursor protein in the cortical and hippocampal system after cholinergic synapse loss and muscarinic receptor activation. Proceedings of the National Academy of Sciences of the United States of America, 96, 12108- 12113.

[84]   Fisher, A., Pittel, Z., Haring, R., Bar-Ner, N., Kliger-Spatz, M., Natan, N., Egozi, I., Sonego, H., Marcovitch, I. and Brandeis, R. (2003) M1 muscarinic agonists can modulate some of the hallmarks in Alzheimer’s disease: Implications in future therapy. Journal of Molecular Neuroscience, 20, 349-356.

[85]   Liskowsky, W. and Schliebs, R. (2006) Muscarinic acetylcholine receptor inhibition in transgenic Alzheimer-like Tg2576 mice by scopolamine favours the amyloidogenic route of processing of amyloid precursor protein. International Journal of Developmental Neuroscience, 24, 149-156.

[86]   Budd, D.C., McDonald, J., Emsley, N., Cain, K. and Tobin, A.B. (2003) The C-terminal tail of the M3-muscarinic receptor possesses anti-apoptotic properties. The Journal of Biological Chemistry, 278, 19565-19573.

[87]   Postina, R. (2008) A closer look at alpha-secretase. Current Alzheimer research, 5, 179-186.

[88]   Sadot, E., Gurwitz, D., Barg, J., Behar, L., Ginzburg, I. and Fisher, A. (1996) Activation of m1 muscarinic acetylcholine receptor regulates tau phosphorylation in transfected PC12 cells. Journal of Neurochemistry, 66, 877- 880.

[89]   Pemberton, K.E., Hill-Eubanks, L.J. and Jones, S.V. (2000) Modulation of low-threshold T-type calcium channels by the five muscarinic receptor subtypes in NIH 3T3 cells. Pflügers Archiv, 440, 452-461.

[90]   Crespo, P., Xu, N., Simonds, W.F. and Gutkind, J.S. (1994) Ras-dependent activation of MAP kinase pathway mediated by G-protein beta gamma subunits. Nature, 369, 418-420.

[91]   Kim, S.S., Choi, J.M., Kim, J.W., Ham, D.S., Ghil, S.H., Kim, M.K., Kim-Kwon, Y., Hong, S.Y., Ahn, S.C., Kim, S.U., Lee, Y.D., Suh-Kim, H. (2005) cAMP induces neuronal differentiation of mesenchymal stem cells via activetion of extracellular signal-regulated kinase/MAPK. Neuroreport, 16, 1357-1361.

[92]   Kiermayer, S., Biondi, R.M., Imig, J., Plotz, G., Haupenthal, J., Zeuzem, S. and Piiper, A. (2005) Epac activation converts cAMP from a proliferative into a differentiation signal in PC12 cells. Molecular Biology of the Cell, 16, 5639-5648.

[93]   Malbon, C.C., Tao, J. and Wang, H.Y. (2004) AKAPs (A-kinase anchoring proteins) and molecules that compose their G-protein-coupled receptor signalling complexes. Biochemical Journal, 379, 1-9.

[94]   Tasken, K. and Aandahl, E.M. (2004) Localized effects of cAMP mediated by distinct routes of protein kinase A. Physiological Reviews, 84, 137-167.

[95]   Dumaz, N. and Marais, R. (2005) Integrating signals between cAMP and the RAS/RAF/MEK/ERK signalling pathways. Based on the anniversary prize of the Gesell-schaft fur Biochemie und Molekularbiologie Lecture delivered on 5 July 2003 at the Special FEBS Meeting in Brussels. FEBS Journal, 272, 3491-3504.

[96]   Chin, P.C., Majdzadeh, N. and D’Mello, S.R. (2005) Inhibition of GSK3β is a common event in neuroprotection by different survival factors, Brain research. Molecular Brain Research, 137, 193-201.

[97]   Fang, X., Yu, S.X., Lu, Y., Bast, R.C., Jr., Woodgett, J.R. and Mills, G.B. (2000) Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A. Proceedings of the National Academy of Sciences of the United States of America, 97, 11960-11965.

[98]   Buller, C.L., Loberg, R.D., Fan, M.H., Zhu, Q., Park, J.L., Vesely, E., Inoki, K., Guan, K.L. and Brosius III, F.C. (2008) A GSK-3/TSC2/mTOR pathway regulates glucose uptake and GLUT1 glucose transporter expression. American Journal of Physiology-Cell Physiology, 295, C836- C843.

[99]   Zhao, Y., Altman, B.J., Coloff, J.L., Herman, C.E., Jacobs, S.R., Wieman, H.L., Wofford, J.A., Dimascio, L.N., Ilkayeva, O., Kelekar, A., Reya, T. and Rathmell, J.C. (2007) Glycogen synthase kinase 3α and 3β mediate a glucose-sensitive antiapoptotic signaling pathway to stabilize Mcl-1. Molecular and Cellular Biology, 27, 4328-4339.

[100]   Hur, E.M. and Zhou, F.Q. (2010) GSK3 signalling in neural development. Nature Reviews. Neuroscience, 11, 539-551.

[101]   Imahori, K. and Uchida, T. (1997) Physiology and pathology of tau protein kinases in relation to Alzheimer’s disease. Journal of Biochemistry, 121, 179-188.

[102]   Roy, S., Zhang, B., Lee, V.M. and Trojanowski, J.Q. (2005) Axonal transport defects: A common theme in neurode-generative diseases. Acta Neuropathologica, 109, 5-13.

[103]   Trojanowski, J.Q. and Lee, V.M. (1995) Phosphorylation of paired helical filament tau in Alzheimer’s disease neurofibrillary lesions: Focusing on phosphatises. FASEB Journal, 9, 1570-1576.

[104]   Morfini, G., Szebenyi, G., Elluru, R., Ratner, N. and Brady, S.T. (2002) Glycogen synthase kinase 3 phosphorylates kinesin light chains and negatively regulates kinesin-based motility. The Embo Journal, 21, 281-293.

[105]   Stokin, G.B., Lillo, C., Falzone, T.L., Brusch, R.G., Rock-enstein, E., Mount, S.L., Raman, R., Davies, P., Masliah, E., Williams, D.S. and Goldstein, L.S. (2005) Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science, 307, 1282-1288.

[106]   Thathiah, A. and De Strooper, B. (2009) G protein-coupled receptors, cholinergic dysfunction, and Abeta toxicity in Alzheimer’s disease. Science Signaling, 2, re8.

[107]   Bartus, R.T., Dean, R.L., Pontecorvo, M.J. and Flicker, C. (1985) The cholinergic hypothesis: A historical overview, current perspective, and future directions. Annals of the New York Academy of Sciences, 444, 332-358.

[108]   Woolf, N.J. (1996) The critical role of cholinergic basal forebrain neurons in morphological change and memory encoding: A hypothesis. Neurobiology of Learning and Memory, 66, 258-266.

[109]   Ladner, C.J. and Lee, J.M. (1998) Pharmacological drug treatment of Alzheimer disease: The cholinergic hypothesis revisited. Journal of Neuropathology and Experimental neurology, 57, 719-731.

[110]   Fisher, A. (2008) Cholinergic treatments with emphasis on M1 muscarinic agonists as potential disease-modifying agents for Alzheimer’s disease. Neurotherapeutics, 5, 433-442.

[111]   Small, D.H. and Cappai, R. (2006) Alois Alzheimer and Alzheimer’s disease: A centennial perspective. Journal of Neurochemistry, 99, 708-710.

[112]   De Strooper, B., Vassar, R. and Golde, T. (2010) The secretases: Enzymes with therapeutic potential in Alzheimer disease. Nature Reviews. Neurology, 6, 99-107.

[113]   Davis, K.L., Mohs, R.C., Marin, D., Purohit, D.P., Perl, D.P., Lantz, M., Austin, G. and Haroutunian, V. (1999) Cholinergic markers in elderly patients with early signs of Alzheimer disease. JAMA, 281, 1401-1406.

[114]   Bartus, R.T. and Emerich, D.F. (1999) Cholinergic markers in Alzheimer disease. JAMA, 282, 2208-2209.