. Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice. J Neurosci. 2007 Nov 28;27(48):13357-65. PubMed.

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  1. Estrogen combined with progesterone (CEE+MPT, or Prempro) constitutes the most common HRT for postmenopausal women who still have their uterus. Research on the combined HRT in AD is rather limited and controversial. However, there is now experimental evidence that the aging nervous system remains sensitive to progesterone in both males and females, while decreases in neuronal sensitivity to estrogen were observed in the female aged brain (Vina et al., 2007; Frye et al., 2006).

    The current study by Pike et al. is interesting and important. It provides new insight into the mechanism of progesterone alone on AD pathology, by altering both tau biology and cognitive behavior. Little information is known concerning changes in the brain levels of progesterone with aging and in AD. Brain hormone levels, including that of estrogen, might be more critical than peripheral hormone levels to AD development (Yue et al., 2005). Therefore, it would be interesting to identify the role of brain progesterone (and keep in mind that progesterone could be processed further into estradiol) in AD animal models in future studies. This will help both basic and clinical research in developing new HRT for the prevention of AD. In addition, because both aged males and females in animal studies retain neuronal responses to progesterone (Ibanez et al., 2004; Stein and Hoffman, 2003), the study of progesterone in aging and AD might provide a new therapeutic approach for AD for both genders.

    References:

    . Effect of gender on mitochondrial toxicity of Alzheimer's Abeta peptide. Antioxid Redox Signal. 2007 Oct;9(10):1677-90. PubMed.

    . Progesterone's effects to reduce anxiety behavior of aged mice do not require actions via intracellular progestin receptors. Psychopharmacology (Berl). 2006 Jun;186(3):312-22. PubMed.

    . Brain estrogen deficiency accelerates Abeta plaque formation in an Alzheimer's disease animal model. Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):19198-203. PubMed.

    . Systemic progesterone administration results in a partial reversal of the age-associated decline in CNS remyelination following toxin-induced demyelination in male rats. Neuropathol Appl Neurobiol. 2004 Feb;30(1):80-9. PubMed.

    . Estrogen and progesterone as neuroprotective agents in the treatment of acute brain injuries. Pediatr Rehabil. 2003 Jan-Mar;6(1):13-22. PubMed.

  2. The Many Faces of Progesterone: The Other Ovarian Hormone
    While the issue of hormone therapy and Alzheimer disease (AD) is still controversial, the increased risk and prevalence of AD in women remain a therapeutic and health care challenge. In this regard, the present findings from the Pike laboratory provide an important advance in our understanding of hormonal regulation of Alzheimer’s pathology and the potential impact for the chronic continuous combined regimen for hormone therapy (1).

    As part of our NIA program project on Progesterone in Brain Aging and Alzheimer’s disease, Christian Pike and his team sought to determine the direct impact of progesterone (P4) on β amyloid (Aβ) load and hyperphosphorylated tau, followed by an analysis of P4 effects on estradiol (E2) regulation of AD pathology. Using the LaFerla lab’s triple transgenic mouse model (3xTgAD), Jenna Carroll and her colleagues ovariectomized 3-month-old female 3xTgAD mice and immediately treated animals with vehicle or ovarian hormones, either alone or in a continuous combined regimen for 3 months. At 3 months of age, Aβ is barely detectable and AT8 immunoreactive phospho-tau is not apparent, whereas both Aβ and AT8 positive neurons are detectable by 6 months.

    Results of their analyses indicate that in 3xTgAD female mice, E2 alone significantly reduced Aβ load, whereas P4 alone had no significant effect on Aβ load. Despite having no effect by itself, P4 in a chronic continuous combined regimen with E2 did result in a loss of the Aβ-lowering effect of E2 alone.

    In contrast to the lack of a direct effect of P4 on Aβ, chronic P4 alone induced a dramatic reduction in hyperphosphorylated tau. E2 alone prevented the ovariectomy-induced rise in the number of neurons positive for hyperphosphorylated tau, whereas either P4 alone or in combination with E2 reduced the number of hyperphosphorylated tau-positive neurons to below that seen in sham control female 3xTgAD mice.

    How did these changes in AD pathology map onto a behavioral memory task? At the end of the 3-month hormone intervention, Carroll and colleagues tested all mice on a simple test of working memory, the Y maze. Ovariectomy induced a significant reduction in working memory performance, which was completely prevented by E2 replacement, while P4 alone did not reverse the working memory deficit, nor did it block prevention of the deficit by E2.

    The lack of an effect of P4 on the memory task in this study stands in contrast to the finding of van Wingen and coworkers in young women, in which a single dose of P4 was found to impair memory function within 1-3 hours of P4 exposure (2). At least four reasons might account for this disparity:

    1. It is well documented that P4 metabolite neurosteroids, such as allopregnanolone, potentiate GABAA receptor function. This can lead to enhanced inhibition, sedation, and thus compromise cognitive function shortly after administration (3).

    2. Chronic exposure to P4 may lead to adaptation of the brain to P4’s modifying effects on memory circuits.

    3. Memory function in mice may not be a good predictor of human memory function.

    4. Acute versus chronic dosing is a substantial difference in the studies, and requires further investigation of impact on cognitive function.

    5. The memory tasks used in the studies are quite different in both content and complexity, and thus may be differentially affected by P4.

    In a larger context, these data once again (see below) demonstrate the profound impact that a loss of ovarian hormones can have on development of AD pathology in the brain. Further, these data from an animal trial of continuous combined ovarian hormone intervention raise concerns regarding the long-term impact of continuous combined hormone therapy regimens in humans. Pike and colleagues are currently testing the impact of cyclical hormone replacement on AD pathology development in female 3xTgAD animals. As part of our NIA program project, five research projects are investigating the “critical window of opportunity” hypothesis with the goal of providing insights into the optimal time and type of hormone intervention.

    The present study by Carroll and coworkers builds on earlier in-vitro and in-vivo basic science studies that investigated the impact of ovariectomy and E2 replacement on development of AD pathology. In the first in-vivo report of E2 regulation of Aβ, Suzana Petanceska, Sam Gandy, and colleagues found that removal of the ovaries increased Aβ level in guinea pig brain with a greater increase in Aβ42 relative to Aβ40 (4). These early findings were later replicated in three transgenic mouse strains with increased Aβ accumulation in brain (5,6). In both Karen Hsiao’s Tg2576 APP and Karen Duff’s PS1/APP transgenic mice, ovariectomy significantly increased Aβ level in brain, and in both models E2 replacement partially reversed the ovariectomy-induced rise (5). Further, in the PS1/APP mice, E2 preferentially reduced Aβ42 with a less dramatic effect on Aβ1-40, which suggested either an effect on APP processing or Aβ clearance, or both (5,7). Several laboratories, including our own, have noted that female AD transgenic mice show a greater amyloid accumulation in brain relative to age and transgene-matched males (8).

    Results of the Pike study in the 3xTgAD mouse model replicated both the ovariectomy-induced rise in Aβ and reversal of the increase by E2 replacement. It should be noted that not all transgenic AD mouse models show an ovariectomy-induced rise in Aβ, and these models similarly do not show an E2 response (9). However, across the four animal models in which ovariectomy resulted in an increase in Aβ (1,4-6), several common features emerge:

    1. Ovariectomy results in a significant and substantial increase in Aβ.

    2. The ovariectomy-induced rise in Aβ occurs within a matter of weeks.

    3. The route of E2 administration can vary from inclusion in rat chow as a powder (4) to administration through the drinking water (5) to implantation of a subcutaneous pellet (1,5) without a loss in efficacy.

    4. It appears that delay in administering E2 results in diminished efficacy.

    A final note on a mechanistic perspective. As P4 alone neither increased nor decreased Aβ levels, this would suggest that P4 is blocking E2 action through regulating E2 receptors. Alternatively, the P4-induced signaling pathway could interact with the E2 signaling cascade to derail E2’s prevention of the Aβ rise following ovariectomy. Regardless of the mechanism, it appears that chronic continuous exposure to P4 alone has a substantial benefit on reducing hyperphosphorylation of tau in neurons, but that it is without effect to either prevent ovariectomy-induced rise in Aβ load or deficit in working memory. Collectively, these data from the Pike study indicate that chronic continuous combined E2 and P4 generates a mixed profile of efficacy with a particularly disturbing loss in E2 regulation of Aβ production.

    References:

    . Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice. J Neurosci. 2007 Nov 28;27(48):13357-65. PubMed.

    . How progesterone impairs memory for biologically salient stimuli in healthy young women. J Neurosci. 2007 Oct 17;27(42) PubMed.

    . Neurosteroids: endogenous regulators of the GABA(A) receptor. Nat Rev Neurosci. 2005 Jul;6(7):565-75. PubMed.

    . Ovariectomy and 17beta-estradiol modulate the levels of Alzheimer's amyloid beta peptides in brain. Neurology. 2000 Jun 27;54(12):2212-7. PubMed.

    . Modulation of A(beta) peptides by estrogen in mouse models. J Neurochem. 2002 Jan;80(1):191-6. PubMed.

    . Brain estrogen deficiency accelerates Abeta plaque formation in an Alzheimer's disease animal model. Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):19198-203. PubMed.

    . Estrogen lowers Alzheimer beta-amyloid generation by stimulating trans-Golgi network vesicle biogenesis. J Biol Chem. 2002 Apr 5;277(14):12128-36. PubMed.

    . Augmented senile plaque load in aged female beta-amyloid precursor protein-transgenic mice. Am J Pathol. 2001 Mar;158(3):1173-7. PubMed.

    . Estrogen therapy fails to alter amyloid deposition in the PDAPP model of Alzheimer's disease. Endocrinology. 2005 Jun;146(6):2774-81. PubMed.