Activating just the β isoform of the estrogen receptor (ERβ) is enough to improve learning and memory in mice, according to a paper published in the February 24 Nature Neuroscience. Researchers led by Feng Liu, Mark Day, and Nicholas Brandon at Wyeth Pharmaceuticals, Monmouth Junction, New Jersey, and Collegeville, Pennsylvania, report that selectively activating ERβ increases synaptic strength in the hippocampus, an area of the brain that plays a key role in learning and memory. ERβ agonists also improve hippocampus-dependent cognition, according to the paper. The finding supports the idea that selective estrogen receptor modulators, or SERMs, are worth pursuing as therapeutics for AD and other cognitive disorders, and that they might yield better results than natural estrogens, which have so far proved disappointing in clinical trials.
Potential side effects notwithstanding, estrogen replacement therapy was once touted as a treatment for dementia, and with good reason. Epidemiological evidence suggested that hormone replacement therapy (HRT) in postmenopausal women lowered the risk of getting AD (see, e.g., Zandi et al., 2002). Molecular evidence offered up a plausible explanation for this protection: in the mammalian brain, estrogen promotes dendritic spines and synaptic activity, increases long-term potentiation, elevates expression of glutamatergic NMDA receptors, and even protects against Aβ deposition in a triple transgenic mouse model of AD (see Carroll et al., 2007). But results from the Women’s Health Initiative Memory Study (WHIMS) of HRT proved disappointing. Not only did combination estrogen/progesterone offer no protection against cognitive decline, but it actually increased the risk of getting AD (see Shumaker et al., 2003). Estrogen alone was no better (see Shumaker et al., 2004).
This setback curtailed clinical research into estrogen and cognition, and sent researchers back to the drawing board. Some posited that timing is the key. Administering HRT 15 years after menopause (as in many of the WHIMS participants) may do more harm than good, the theory goes, while taking it around the time of menopause may help (see ARF related news story). This is the premise of KEEPS (Kronos Early Estrogen Prevention Study), which plans to examine if HRT, given within 3 years of menopause, prevents cardiovascular disease. Cognition is a secondary endpoint of that trial.
An alternative approach to reaping a neurologic benefit from estrogen signaling is to selectively target estrogen receptors, something estradiol itself doesn't do. ERβ, for example, seems to have a better neuroprotective profile than ERα (see Tiwari-Woodruff et al., 2007), and the new data from the Wyeth group support this idea.
Joint first authors Feng Liu, Mark Day, and colleagues report that estradiol improves learning and memory when given to ovariectomized mice, but not when given to Esr2 knockout animals (the Esr2 gene encodes ERβ protein). They also report that ERβ-selective compounds developed at Wyeth (WAY-200070 and WAY-202779) mimic the effect of estrogen on the hippocampus in ways that the ERα agonist PPT (4,4',4''-[4-propyl-(1H)-pyrazole-1,3,5-triyl]trisphenol) does not. For example, when given to ovariectomized animals, the Wyeth compounds cause nuclear estrogen receptor levels in the hippocampus to rise—this indicates receptor activation. They also cause hippocampal phospho-CREB to rise—this is an early event during learning and memory encoding. WAY-200070, the more brain-soluble of the two, also increased levels of the glutamate receptor GluR1 and postsynaptic density 95, two proteins important in synaptic activity. These proteins stayed unchanged when the compound was given to Esr2-/- mice or when PPT was used instead.
These findings suggest that the ERβ compounds may accentuate synaptic transmission. In fact, the researchers found that dousing hippocampal slices with WAY-200070 enhanced long-term potentiation. Furthermore, they report that synaptic architecture changed when ovariectomized rats were given WAY-20070. Dendritic interactions among CA1 pyramidal cells increased, and in the dentate gyrus the number of dendritic branches and mushroom-shaped spines grew (these are stable spines believed to be necessary for memory storage). Finally, the researchers report that their compound improved spatial memory: in a radial arm maze, ovariectomized rats on WAY-200070 made fewer errors than untreated animals and performed on par with estradiol-treated rats. The ERα agonist had no effect.
The results suggest that ERβ activation may be one way of treating cognitive disorders, according to the authors. “Activation of this pathway may confer some of the CNS-mediated benefits of estrogen without the feminizing side effects and may offer a new therapeutic approach for diseases with cognitive deficits such as Alzheimer's disease and schizophrenia,” they write. However, there may be some work to do yet to fully understand the ramifications of selectively activating estrogen receptors. For example, Christian Pike at the University of Southern California, Los Angeles, just reported that other ERα and ERβ agonists have differential effects on amyloid deposits in the triple transgenic mice. In those experiments, the ERα agonist PPT reduced Aβ in the hippocampus, subiculum, and amygdala but less so in the frontal cortex. The ERβ agonist DPN, on the other hand, reduced Aβ in the amygdala, but not in the hippocampus and subiculum. Unlike the ERα agonists, DPN had no effect on memory, whereas PPT significantly improved hippocampal-dependent working memory in these animals, as judged by a spontaneous alternation task (see Carroll and Pike, 2008). Whether that memory improvement is related to the reduction in Aβ is not clear. Nevertheless, the differential effects of ERα and ERβ agonists on neurons and Aβ pathology suggest that, as with HRT, timing SERM treatment might be important for successful prevention or treatment of AD.—Tom Fagan
- Zandi PP, Carlson MC, Plassman BL, Welsh-Bohmer KA, Mayer LS, Steffens DC, Breitner JC. Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. JAMA. 2002 Nov 6;288(17):2123-9. PubMed.
- Carroll JC, Rosario ER, Chang L, Stanczyk FZ, Oddo S, Laferla FM, Pike CJ. Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice. J Neurosci. 2007 Nov 28;27(48):13357-65. PubMed.
- Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, Hendrix SL, Jones BN, Assaf AR, Jackson RD, Kotchen JM, Wassertheil-Smoller S, Wactawski-Wende J, . Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003 May 28;289(20):2651-62. PubMed.
- Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, Fillit H, Stefanick ML, Hendrix SL, Lewis CE, Masaki K, Coker LH, Women's Health Initiative Memory Study. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA. 2004 Jun 23;291(24):2947-58. PubMed.
- Tiwari-Woodruff S, Morales LB, Lee R, Voskuhl RR. Differential neuroprotective and antiinflammatory effects of estrogen receptor (ER)alpha and ERbeta ligand treatment. Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14813-8. PubMed.
- Carroll JC, Pike CJ. Selective estrogen receptor modulators differentially regulate Alzheimer-like changes in female 3xTg-AD mice. Endocrinology. 2008 May;149(5):2607-11. PubMed.
- Liu F, Day M, Muñiz LC, Bitran D, Arias R, Revilla-Sanchez R, Grauer S, Zhang G, Kelley C, Pulito V, Sung A, Mervis RF, Navarra R, Hirst WD, Reinhart PH, Marquis KL, Moss SJ, Pangalos MN, Brandon NJ. Activation of estrogen receptor-beta regulates hippocampal synaptic plasticity and improves memory. Nat Neurosci. 2008 Mar;11(3):334-43. PubMed.