Nonsteroidal selective androgen receptor modulators and selective estrogen receptor β agonists moderate cognitive deficits and amyloid-β levels in a mouse model of Alzheimer's disease

ACS Chemical Neuroscience

Volumn 4, Issue 12, 2013, Pages 1537-1548

  George, Sonia ^a   Petit, Géraldine H ^a   Gouras, Gunnar K ^a   Brundin, Patrik ^a,b   Olsson, Roger ^a,c  

^a LUND UNIVERSITY   (Sweden)

^b VAN ANDEL RESEARCH INSTITUTE   (United States)

^c ACADIA PHARMACEUTICALS INC   (United States)

Author keywords

amyloid; Alzheimer's disease; cognition; ER agonist; insulin degrading enzyme; mouse model; neprilysin; SARM

Indexed keywords

AC 186; ACP 105; AMYLOID BETA PROTEIN; ANDROGEN RECEPTOR; ANDROSTANOLONE; ESTROGEN RECEPTOR BETA; HORMONE RECEPTOR STIMULATING AGENT; INSULINASE; SELECTIVE ANDROGEN RECEPTOR MODULATOR; SELECTIVE ESTROGEN RECEPTOR BETA AGONIST; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANXIETY; ARTICLE; COGNITIVE DEFECT; CONTROLLED STUDY; GONADECTOMY; IMMUNOHISTOCHEMISTRY; LOCOMOTION; LONG TERM CARE; MALE; MORRIS WATER MAZE TEST; MOUSE; NONHUMAN; OPEN FIELD TEST; PRIORITY JOURNAL; ROTAROD TEST; SPATIAL MEMORY;

ALZHEIMER DISEASE; ANDROGENS; ANIMALS; BLOTTING, WESTERN; BRAIN; CYCLOHEXANES; DISEASE MODELS, ANIMAL; ENZYME-LINKED IMMUNOSORBENT ASSAY; ESTROGEN RECEPTOR BETA; HUMANS; IMMUNOHISTOCHEMISTRY; MAZE LEARNING; MICE; MICE, TRANSGENIC; MOTOR ACTIVITY; PHENOLS;

EID: 84890649872     PISSN: None     EISSN: 19487193     Source Type: Journal    
DOI: 10.1021/cn400133s     Document Type: Article

References (55)

1. Oddo, S., Caccamo, A., Shepherd, J. D., Murphy, M. P., Golde, T. E., Kayed, R., Metherate, R., Mattson, M. P., Akbari, Y., and Laferla, F. M. (2003) Triple-Transgenic Model of Alzheimer's Disease with Plaques and Tangles Neuron 39, 409-421
2. Gouras, G. K., Xu, H., Gross, R. S., Greenfield, J. P., Hai, B., Wang, R., and Greengard, P. (2000) Testosterone reduces neuronal secretion of Alzheimer's beta-amyloid peptides Proc. Natl. Acad. Sci. U.S.A. 97, 1202-1205
3. Hogervorst, E., Williams, J., Budge, M., and Barnetson, L. (2001) Serum total testosterone is lower in men with Alzheimer's disease Neuroendocrinol. Lett. 22, 163-168
4. Moffat, S. D., Zonderman, A. B., Metter, E. J., Kawas, C., Blackman, M. R., Harman, S. M., and Resnick, S. M. (2004) Free testosterone and risk for Alzheimer disease in older men Neurology 62, 188-193
5. Billings, L. M., Oddo, S., Green, K. N., McGaugh, J. L., and Laferla, F. M. (2005) Intraneuronal Aβ Causes the Onset of Early Alzheimer's Disease-Related Cognitive Deficits in Transgenic Mice Neuron 45, 675-688
6. Moffat, S. D. (2006) Does testosterone mediate cognitive decline in elderly men? J. Gerontol., Ser. A 61, 521
7. Clinton, L. K., Billings, L. M., Green, K. N., Caccamo, A., Ngo, J., Oddo, S., McGaugh, J. L., and Laferla, F. M. (2007) Age-dependent sexual dimorphism in cognition and stress response in the 3xTg-AD mice Neurobiol. Dis. 28, 76-82
8. Rosario, E. R., Carroll, J. C., Oddo, S., Laferla, F. M., and Pike, C. J. (2006) Androgens regulate the development of neuropathology in a triple transgenic mouse model of Alzheimer's disease J. Neurosci. 26, 13384-13389
9. Ramsden, M., Nyborg, A. C., Murphy, M. P., Chang, L., Stanczyk, F. Z., Golde, T. E., and Pike, C. J. (2004) Androgens modulate β-amyloid levels in male rat brain J. Neurochem. 87, 1052-1055
10. Gao, W. and Dalton, J. T. (2007) Expanding the therapeutic use of androgens via selective androgen receptor modulators (SARMs) Drug Discovery Today 12, 241-248
11. Mohler, M. L., Bohl, C. E., Jones, A., Coss, C. C., Narayanan, R., He, Y., Hwang, D. J., Dalton, J. T., and Miller, D. D. (2009) Nonsteroidal selective androgen receptor modulators (SARMs): Dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit J. Med. Chem. 52, 3597-3617
12. Schlienger, N., Lund, B. W., Pawlas, J., Badalassi, F., Bertozzi, F., Lewinsky, R., Fejzic, A., Thygesen, M. B., Tabatabaei, A., Bradley, S. R., Gardell, L. R., Piu, F., and Olsson, R. (2009) Synthesis, Structure-Activity Relationships, and Characterization of Novel Nonsteroidal and Selective Androgen Receptor Modulators J. Med. Chem. 52, 7186-7191
13. Acevedo, S., Gardell, L., Bradley, S., Piu, F., and Raber, J. (2008) Selective Androgen Receptor Modulators Antagonize Apolipoprotein E4-Induced Cognitive Impairments Lett. Drug Des. Discovery 5, 271-276
14. Osborne, D. M., Edinger, K., and Frye, C. A. (2009) Chronic administration of androgens with actions at estrogen receptor beta have anti-anxiety and cognitive-enhancing effects in male rats Age 31, 119-126
15. Piu, F., Gardell, L. R., Son, T., Schlienger, N., Lund, B. W., Schiffer, H. H., Vanover, K. E., Davis, R. E., Olsson, R., and Bradley, S. R. (2008) Pharmacological characterization of AC-262536, a novel selective androgen receptor modulator J. Steroid Biochem. Mol. Biol. 109, 129-137
16. Frye, C. A., Edinger, K., and Sumida, K. (2007) Androgen Administration to Aged Male Mice Increases Anti-Anxiety Behavior and Enhances Cognitive Performance Neuropsychopharmacology 33, 1049-1061
17. Lund, T. D., Hinds, L. R., and Handa, R. J. (2006) The androgen 5alpha-dihydrotestosterone and its metabolite 5alpha-androstan-3beta, 17beta-diol inhibit the hypothalamo-pituitary-adrenal response to stress by acting through estrogen receptor beta-expressing neurons in the hypothalamus J. Neurosci. 26, 1448-1456
18. Nelson, C. J., Lee, J. S., Gamboa, M. C., and Roth, A. J. (2008) Cognitive effects of hormone therapy in men with prostate cancer Cancer 113, 1097-1106
19. Zhao, L. and Brinton, R. D. (2007) WHI and WHIMS follow-up and human studies of soy isoflavones on cognition Expert Rev. Neurother. 7, 1549-1564
20. Benice, T. S. and Raber, J. (2009) Dihydrotestosterone modulates spatial working-memory performance in male mice J. Neurochem. 110, 902-911
21. Carroll, J. C., Rosario, E. R., Chang, L., Stanczyk, F. Z., Oddo, S., Laferla, F. M., and Pike, C. J. (2007) Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice J. Neurosci. 27, 13357-13365
22. Spritzer, M. D., Gill, M., Weinberg, A., and Galea, L. A. M. (2008) Castration differentially affects spatial working and reference memory in male rats Arch. Sex. Behav. 37, 19-29
23. Petanceska, S. S., Nagy, V., Frail, D., and Gandy, S. (2000) Ovariectomy and 17beta-estradiol modulate the levels of Alzheimer's amyloid beta peptides in brain Exp. Gerontol. 35, 1317-1325
24. Zheng, H., Xu, H., Uljon, S. N., Gross, R., Hardy, K., Gaynor, J., LaFrancois, J., Simpkins, J., Refolo, L. M., Petanceska, S., Wang, R., and Duff, K. (2002) Modulation of A(beta) peptides by estrogen in mouse models J. Neurochem. 80, 191-196
25. Pfankuch, T., Rizk, A., Olsen, R., Poage, C., and Raber, J. (2005) Role of circulating androgen levels in effects of apoE4 on cognitive function Brain Res. 1053, 88-96
26. Heikkinen, T., Kalesnykas, G., Rissanen, A., Tapiola, T., Iivonen, S., Wang, J., Chaudhuri, J., Tanila, H., Miettinen, R., and Puoliväli, J. (2004) Estrogen treatment improves spatial learning in APP + PS1 mice but does not affect beta amyloid accumulation and plaque formation Exp. Neurol. 187, 105-117
27. Heldring, N., Pike, A., Andersson, S., Matthews, J., Cheng, G., Hartman, J., Tujague, M., Ström, A., Treuter, E., Warner, M., and Gustafsson, J.-Å. (2007) Estrogen Receptors: How Do They Signal and What Are Their Targets Physiol. Rev. 87, 905-931
28. Liu, F., Day, M., Muñiz, L. C., Bitran, D., Arias, R., Revilla-Sanchez, R., Grauer, S., Zhang, G., Kelley, C., Pulito, V., Sung, A., Mervis, R. F., Navarra, R., Hirst, W. D., Reinhart, P. H., Marquis, K. L., Moss, S. J., Pangalos, M. N., and Brandon, N. J. (2008) Activation of estrogen receptor-β regulates hippocampal synaptic plasticity and improves memory Nat. Neurosci. 11, 334-343
29. Jacome, L. F., Gautreaux, C., Inagaki, T., Mohan, G., Alves, S., Lubbers, L. S., and Luine, V. (2010) Estradiol and ERβ agonists enhance recognition memory, and DPN, an ERβ agonist, alters brain monoamines Neurobiol. Learn. Mem. 94, 488-498
30. Nilsson, S., Koehler, K. F., and Gustafsson, J. Å. (2011) Development of subtype-selective oestrogen receptor-based therapeutics Nat. Rev. Drug Discovery 10, 778-792
31. Udrisar, D. P., Wanderley, M. I., Porto, R. C., Cardoso, C. L., Barbosa, M. C., Camberos, M. C., and Cresto, J. C. (2005) Androgen-and estrogen-dependent regulation of insulin-degrading enzyme in subcellular fractions of rat prostate and uterus Exp. Biol. 230, 479-486
32. Iwata, N., Tsubuki, S., Takaki, Y., Shirotani, K., and Lu, B. (2001) Metabolic regulation of brain Aβ by neprilysin Science 292, 1550-1552
33. Farris, W., Schütz, S. G., Cirrito, J. R., Shankar, G. M., Sun, X., George, A., Leissring, M. A., Walsh, D. M., Qiu, W. Q., Holtzman, D. M., and Selkoe, D. J. (2007) Loss of Neprilysin Function Promotes Amyloid Plaque Formation and Causes Cerebral Amyloid Angiopathy Am. J. Pathol. 171, 241-251
34. Leissring, M. A., Farris, W., Chang, A. Y., Walsh, D. M., Wu, X., Sun, X., Frosch, M. P., and Selkoe, D. J. (2003) Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death Neuron 40, 1087-1093
35. Bittner, T., Fuhrmann, M., Burgold, S., Ochs, S. M., Hoffmann, N., Mitteregger, G., Kretzschmar, H., Laferla, F. M., and Herms, J. (2010) Multiple Events Lead to Dendritic Spine Loss in Triple Transgenic Alzheimer's Disease Mice PLoS One 5 e15477
36. Mega, M. S., Cummings, J. L., Fiorello, T., and Gornbein, J. (1996) The spectrum of behavioral changes in Alzheimer's disease Neurology 46, 130-135
37. Teri, L., Ferretti, L. E., Gibbons, L. E., Logsdon, R. G., McCurry, S. M., Kukull, W. A., McCormick, W. C., Bowen, J. D., and Larson, E. B. (1999) Anxiety in Alzheimer's disease: Prevalence and comorbidity J. Gerontol., Ser. A 54, M348-M352
38. Rosario, E. R. and Pike, C. J. (2008) Androgen regulation of beta-amyloid protein and the risk of Alzheimer's disease Brain Res. Rev. 57, 444-453
39. Cheng, D., Logge, W., Low, J. K., Garner, B., and Karl, T. (2013) Novel behavioural characteristics of the APPSwe/PS1ΔE9 transgenic mouse model of Alzheimer's disease Behav. Brain Res. 245, 120-127
40. Walf, A. A. and Frye, C. A. (2007) The use of the elevated plus maze as an assay of anxiety-related behavior in rodents Nat. Protoc. 2, 322-328
41. Yao, M., Nguyen, T.-V. V., Rosario, E. R., Ramsden, M., and Pike, C. J. (2008) Androgens regulate neprilysin expression: role in reducing β-amyloid levels J. Neurochem. 105, 2477-2488
42. Guan, H., Liu, Y., Daily, A., Police, S., Kim, M.-H., Oddo, S., Laferla, F. M., Pauly, J. R., Murphy, M. P., and Hersh, L. B. (2009) Peripherally expressed neprilysin reduces brain amyloid burden: a novel approach for treating Alzheimer's disease J. Neurosci. Res. 87, 1462-1473
43. Wilcock, D. M., Gharkholonarehe, N., Van Nostrand, W. E., Davis, J., Vitek, M. P., and Colton, C. A. (2009) Amyloid reduction by amyloid-beta vaccination also reduces mouse tau pathology and protects from neuron loss in two mouse models of Alzheimer's disease J. Neurosci. 29, 7957-7965
44. Rosario, E. R., Carroll, J., and Pike, C. J. (2010) Testosterone regulation of Alzheimer-like neuropathology in male 3xTg-AD mice involves both estrogen and androgen pathways Brain Res. 1359, 281-290
45. Simpson, E. R. (2003) Sources of estrogen and their importance J. Steroid Biochem. Mol. Biol. 86, 225-230
46. Carroll, J. C. and Pike, C. J. (2008) Selective Estrogen Receptor Modulators Differentially Regulate Alzheimer-Like Changes in Female 3xTg-AD Mice Endocrinology 149, 2607-2611
47. Zhao, L., Yao, J., Mao, Z., Chen, S., Wang, Y., and Brinton, R. D. (2010) 17β-Estradiol regulates insulin-degrading enzyme expression via an ERβ /PI3-K pathway in hippocampus: Relevance to Alzheimer's prevention Neurobiol. Aging 1-15
48. Pike, C. J., Nguyen, T., Ramsden, M., and Yao, M. (2008) Androgen cell signaling pathways involved in neuroprotective actions Horm. Behav. 53, 693-705
49. McFarland, K., Price, D. L., Davis, C. N., Ma, J.-N., Bonhaus, D. W., Burstein, E. S., and Olsson, R. (2013) AC-186, a Selective Nonsteroidal Estrogen Receptor β Agonist, Shows Gender Specific Neuroprotection in a Parkinson's Disease Rat Model ACS Chem Neurosci. 4, 1249-1255
50. Marr, R. A., Guan, H., Rockenstein, E., Kindy, M., Gage, F. H., Verma, I., Masliah, E., and Hersh, L. B. (2004) Neprilysin Regulates Amyloid β Peptide Levels J. Mol. Neurosci. 22, 5-12
51. Saido, T. C. and Nakahara, H. (2003) Proteolytic degradation of Aβ by neprilysin and other peptidases, in Aβ Metabolism and Alzheimer's Disease (Saido, T. C., Ed.) pp 61-74, Landes Bioscience: Austin, TX.
52. Horikoshi, Y., Mori, T., Maeda, M., Kinoshita, N., Sato, K., and Yamaguchi, H. (2004) Abeta N-terminal-end specific antibody reduced beta-amyloid in Alzheimer-model mice Biochem. Biophys. Res. Commun. 325, 384-387
53. Lauritzen, I., Pardossi-Piquard, R., Bauer, C., Brigham, E., Abraham, J. D., Ranaldi, S., Fraser, P., St George-Hyslop, P., Le Thuc, O., Espin, V., Chami, L., Dunys, J., and Checler, F. (2012) The β-Secretase-Derived C-Terminal Fragment of βAPP, C99, But Not Aβ, Is a Key Contributor to Early Intraneuronal Lesions in Triple-Transgenic Mouse Hippocampus J. Neurosci. 32, 16243-16255
54. Kumar, S., Wirths, O., Theil, S., Gerth, J., Bayer, T. A., and Walter, J. (2013) Early intraneuronal accumulation and increased aggregation of phosphorylated Abeta in a mouse model of Alzheimer's disease Acta Neuropathol. 125, 699-709
55. Wirths, O., Dins, A., and Bayer, T. A. (2012) AβPP accumulation and/or intraneuronal amyloid-β accumulation? The 3xTg-AD mouse model revisited J. Alzheimer's Dis. 28, 897-904