Continuous and cyclic progesterone differentially interact with estradiol in the regulation of Alzheimer-like pathology in female 3xTransgenic-Alzheimer's disease mice.
Depletion of estrogens and progesterone at menopause has been linked to an increased risk for the development of Alzheimer's disease (AD) in women. A currently controversial literature indicates that although treatment of postmenopausal women with hormone therapy (HT) may reduce the risk of AD, several parameters of HT may limit its potential efficacy and perhaps, even exacerbate AD risk. One such parameter is continuous vs. cyclic delivery of the progestogen component of HT. Recent experimental evidence suggests that continuous progesterone can attenuate neural actions of estradiol (E(2)). In the present study, we compared the effects of continuous and cyclic progesterone treatment in the presence and absence of E(2) in ovariectomized 3xTg-AD mice, a transgenic mouse model of AD. We found that ovariectomy-induced hormone depletion increases AD-like pathology in female 3xTg-AD mice, including accumulation of beta-amyloid, tau hyperphosphorylation, and impaired hippocampal-dependent behavior. E(2) treatment alone prevents the increases in pathology. Continuous progesterone did not affect beta-amyloid levels when delivered alone but blocked the Abeta-lowering action of E(2). In contrast, cyclic progesterone significantly reduced beta-amyloid levels by itself and enhanced rather than inhibited the E(2) effects. These results provide new insight into the neural interactions between E(2) and progesterone that may prove valuable in optimizing HT regimens in postmenopausal women.
Carroll
Jenna C
JC
University of Southern California, 3715 McClintock Avenue, Los Angeles, California 90089-0191. cjpike@usc.edu
Rosario
Emily R
ER
Villamagna
Angela
A
Pike
Christian J
CJ
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004334:Drug Administration Schedule; D004958:Estradiol / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D007150:Immunohistochemistry; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010052:Ovariectomy; D010766:Phosphorylation; D011374:Progesterone / Q000008:administration & dosage* / Q000627:therapeutic use*; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016875:tau Proteins; D011374:Progesterone; D004958:Estradiol
Neurosci Lett. 2002 May 3;323(3):191-4
11959417
Neuroscience. 1999;91(3):1143-53
10391490
Arch Neurol. 1994 Sep;51(9):896-900
8080389
Endocrinology. 2008 May;149(5):2607-11
18276750
J Cereb Blood Flow Metab. 2009 Aug;29(8):1359-72
19458604
Horm Behav. 2003 Nov;44(4):319-26
14613726
Brain Res. 2006 Jul 12;1099(1):206-10
16793026
Curr Pharm Des. 2006;12(6):677-84
16472157
Behav Brain Res. 2009 Jan 23;196(2):254-60
18926853
Neuroreport. 2004 Dec 3;15(17):2659-63
15570173
Scand J Clin Lab Invest. 2008;68(8):814-22
18821130
Exp Neurol. 1994 Sep;129(1):64-9
7925843
Neurobiol Aging. 2001 Jul-Aug;22(4):575-80
11445258
Trends Endocrinol Metab. 2002 Aug;13(6):229-30
12128278
JAMA. 2002 Nov 6;288(17):2123-9
12413371
Neuropsychopharmacology. 2006 Nov;31(11):2405-14
16482087
J Neurosci. 1996 Feb 1;16(3):1049-55
8558233
Int Semin Surg Oncol. 2005 Feb 08;2(1):3
15701175
Int J Dev Neurosci. 2000 Jul-Aug;18(4-5):347-58
10817919
Nat Med. 2006 Apr;12(4):379-80
16598276
Eur J Obstet Gynecol Reprod Biol. 1999 Apr;83(2):207-11
10391534
Exp Neurol. 2005 Jun;193(2):522-30
15869954
Brain Res. 2009 Aug 4;1283:177-85
19497309
Science. 2002 Jul 19;297(5580):353-6
12130773
Neuroscience. 2000;101(4):931-8
11113342
Semin Reprod Med. 2009 May;27(3):283-93
19401959
JAMA. 2002 Nov 6;288(17):2170-2
12413378
Lancet. 1996 Aug 17;348(9025):429-32
8709781
Eur J Neurosci. 2009 Feb;29(3):447-54
19175406
Neurology. 1997 Jun;48(6):1517-21
9191758
Neurology. 1999 Mar 23;52(5):965-70
10102413
JAMA. 2004 Jun 23;291(24):2947-58
15213206
Obstet Gynecol. 1995 Feb;85(2):304-13
7824251
Lancet Neurol. 2005 Mar;4(3):190-4
15721829
Pediatr Rehabil. 2003 Jan-Mar;6(1):13-22
12745891
JAMA. 2003 May 28;289(20):2651-62
12771112
Brain Res. 1997 Feb 21;749(1):143-6
9070640
J Neurosci Res. 2003 Dec 1;74(5):637-43
14635215
J Neurobiol. 2006 Aug;66(9):916-28
16758493
Curr Opin Pharmacol. 2008 Dec;8(6):740-6
18929681
Neurobiol Learn Mem. 2008 Jan;89(1):17-26
17988898
Neurology. 1999 Dec 10;53(9):1992-7
10599770
Neuroscience. 2002;113(4):907-14
12182896
Front Neuroendocrinol. 2008 May;29(2):313-39
18374402
Arch Med Res. 2002 Jan-Feb;33(1):6-14
11825624
CNS Drugs. 2004;18(7):405-22
15139797
Epilepsia. 2004 Dec;45(12):1531-8
15571511
J Neurosci. 2006 Dec 20;26(51):13384-9
17182789
Science. 2003 Nov 14;302(5648):1136-8
14615508
Scand J Clin Lab Invest. 2005;65(8):699-705
16319044
J Comp Neurol. 1993 Oct 8;336(2):293-306
8245220
Age (Dordr). 2009 Jun;31(2):143-53
19322681
JAMA. 1995 Jan 18;273(3):199-208
7807658
Clin Obstet Gynecol. 2008 Sep;51(3):618-26
18677155
Front Neuroendocrinol. 2009 Jul;30(2):239-58
19427328
Obstet Gynecol. 1990 Apr;75(4 Suppl):59S-76S; discussion 81S-83S
2179792
Semin Reprod Med. 2005 May;23(2):172-9
15852203
Neurology. 1992 Jan;42(1):115-9
1734291
JAMA. 2004 Jun 23;291(24):2959-68
15213207
J Neurochem. 2003 Nov;87(4):902-13
14622121
Br J Pharmacol. 1999 Sep;128(2):419-27
10510453
Horm Behav. 2008 Aug;54(3):386-95
18579142
Acta Psychiatr Scand. 1987 Nov;76(5):465-79
3324647
Arch Intern Med. 1996 Oct 28;156(19):2213-7
8885820
Eur J Neurosci. 2006 Jul;24(1):229-42
16882019
Behav Genet. 2007 Jan;37(1):214-22
17177116
J Neuroendocrinol. 2009 Jan;21(1):77-81
19094096
Psychopharmacology (Berl). 2006 Jun;186(3):312-22
16538472
Neuroscience. 2002;115(2):547-58
12421621
J Cardiovasc Transl Res. 2009 Sep;2(3):228-39
19668346
J Neurosci. 2007 Nov 28;27(48):13357-65
18045930
Neuron. 2003 Jul 31;39(3):409-21
12895417
Annu Rev Pharmacol Toxicol. 2001;41:569-91
11264469