Gonadal Hormone Withdrawal, Apoptosis, and Generation of Beta Amyloid Peptide: A Vicious Cycle of Amyloidogenesis and Neurotoxicity in Alzheimer's Disease

Updated 24 January 2002

Discussion text prepared by Sam Gandy MD PhD
Director, Farber Institute for Neurosciences at Thomas Jefferson University
Professor of Neurology, Biochemistry and Molecular Biology
1025 Walnut Street Philadelphia PA 19107
samgandy@earthlink.net
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Note: A live chat was held 5 December 2001, noon-1PM EST.

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Many independent lines of evidence implicate b amyloidosis in brain as the key event in the development of Alzheimer's disease (AD). Strongest among this evidence is the linkage of cerebral amyloidosis and the clinical phenotype of autosomal dominant, completely penetrant familial AD to pro-amyloidogenic missense mutations in the amyloid precursor protein (APP) or in one of the presenilins, key regulators of the b-amyloid-generating gamma secretases (Gandy, 1999). Less well defined is how cerebral amyloidosis is initiated or propagated when identifiable mutations are absent, as is the case for the disease that we now know as typical, late-onset, sporadic AD.

One metabolic risk factor that controls the age-at-onset of AD may be gonadal senescence: i.e., menopause in women and andropause in men. Gonadal hormones appear to control neuronal amyloid beta peptide (A-b) metabolism in cultured cells (Xu, 1998; Gouras, 2000), in the brains of experimental animals (Petanceska, 2000), and in the circulation (Gandy, 2001) and cerebrospinal fluid of human subjects (Schonknecht, 2001). Elevated levels of circulating A-b 42 have been associated with an increased risk for AD (Mayeux, 1999; Ertekin-Taner, 2000). Regulated A-b metabolism may underlie these phenomena, perhaps via the protein kinase C-regulated pathway (PKC; Buxbaum, 1993) or extracellular-signal-regulated protein kinase-regulated pathway (ERK; Mills, 1997; Singh, 2000). Direct interaction between one member of the steroid receptor family and the protein kinase src has recently been described (Boonyaratanakornkit, 2001), providing novel evidence for a direct link between hormone receptor signaling and signal transduction via protein phosphorylation.

Relationships might also exist involving hormone withdrawal, A-b metabolism and programmed cell death, or apoptosis. A classical experimental model for apoptosis involves withdrawal of the neurotrophic factor NGF from cultured neurons (Hamburger and Yip, 1984). It is well established that estrogens play key roles in regulating the levels of NGF receptors (Sohrabji, 1994), raising the possibility that estrogen withdrawal might mimic some of the features of trophic factor withdrawal (Zhang, 2001).

Neuroprotective activities have now been discovered for testosterone, acting via the androgen receptor (Hammond, 2001) and for phytoestrogens (Wang, 2001). The hormone/neuroprotection/apoptosis data dovetail well with observations from others, indicating that activation of apoptosis increases A-b generation (LeBlanc, 1995; Gervais, 1999; Guo, 2001), as does oxidative stress (Olivieri, 2001). While it is worth noting that some of these relationships are controversial (Gervais, 1999; Soriano, 2001), the apparent association of these phenomena suggests a possible model for some of the pathways that cause the molecular neuropathology of AD. In such a scenario, propagation of A-b amyloidosis might occur in a situation of diminished protection against caspase activation and oxidative stress; caspase activation and oxidative stress might, in turn, stimulate A-b generation.

This model is summarized in the chart below. This model also provides a mechanism to explain how hormone replacement therapy (HRT) can apparently delay or prevent AD (Tang, 1996), since both A-b generation and caspase activation would be minimized by HRT.

Recent treatment trials involving the prescription of estrogen replacement therapy for existing AD have mostly failed (see reviews by Toran-Allerand, 2000, Marder and Sano, 2000), although a recent treatment trial was more promising (Asthana, 2001). As of this writing, then, the potentially useful therapeutic (or prophylactic) issue surrounding HRT and AD has to do with whether delay or prevention of AD might be an indication for HRT in asymptomatic subjects at high risk for AD. This question is under study in 5- and 10-year primary prevention trials: the results are eagerly awaited and will begin to become available in 2003 (M. Sano, personal communication).

References

Asthana S, et al. High-dose estradiol improves cognition for women with AD: Results of a randomized study Neurology 57, 605-612; 2001. Abstract.

Boonyaratanakornkit V, et al. Progesterone receptor contains a proline-rich motif that directly interacts with SH3 domains and activates c-src family tyrosine kinases. Molecular Cell 8, 269-280, 2001. Abstract

Buxbaum JD, et al. Protein phosphorylation inhibits production of Alzheimer amyloid ß/ A4 peptide. Proc Natl Acad Sci USA 90, 9195-9198 ; 1993. Abstract

Ertekin-Taner N, et al. Linkage of plasma A-b 42 to a quantitative locus on chromosome 10 in late-onset Alzheimer's disease. Science 290, 2303-2304; 2000. Abstract

Gandy S. Neurohormonal regulation of Alzheimer's beta amyloid precursor metabolism. Trends Endocrinol Metab 10, 273-279; 1999. Abstract

Gandy S, et al. Chemical andropause and amyloid-beta peptide. JAMA 285, 2195-2196; 2001. Abstract

Gervais FG, et al. Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic A beta peptide formation. Cell 97, 395-406; 1999. Abstract

Gouras G, et al. Testosterone reduces neuronal secretion of Alzheimer's beta-amyloid peptides. Proc Natl Acad Sci USA 97, 1202-1205; 2000. Abstract

Guo Q, et al. Prostate apoptosis response-4 enhances secretion of amyloid beta peptide 1-42 in human neuroblastoma IMR-32 cells by a caspase-dependent pathway. J Biol Chem 276, 16040-16044; 2001. Abstract

Hamburger V, Yip JW. Reduction of experimentally induced neuronal death in spinal ganglia of the chick embryo by nerve growth factor. J Neurosci. 4, 767-74; 1984. Abstract

Hammond J, et al. Testosterone-mediated neuroprotection through the androgen receptor in human primary neurons. J Neurochem 77, 1319-1326; 2001. Abstract

LeBlanc A, et al. Increased production of 4 kDa amyloid beta peptide in serum deprived human primary neuron cultures: Possible involvement of apoptosis. J Neurosci 15, 7837-7846; 1995. Abstract

Mayeux R, et al. Plasma amyloid beta-peptide and incipient Alzheimer's disease. Annals of Neurology 46,412-416; 1999. Abstract

Mills J, et al. Regulation of amyloid precursor protein catabolism involves the mitogen-activated protein kinase signal transduction pathway. J Neurosci. 17, 9415-22 ; 1997. Abstract

Olivieri G, et al. Mercury induces cell cytotoxicity and oxidative stress and increases beta-amyloid secretion and tau phosphorylation in SHSY5Y neuroblastoma cells. J Neurochem. 74,231-236; 2000. Abstract

Petanceska S, et al. Ovariectomy and 17-beta estradiol modulate the levels of Alzheimer's amyloid beta peptides in brain. Neurology 54, 2212-2217; 2000. Abstract

Marder, K., Sano, M. Estrogen to treat Alzheimer's disease: Too little, too late? So what's a woman to do? Neurology 54, 2035-2037; 2000. Abstract

Schonknecht P, et al. Reduced cerebrospinal fluid estradiol levels are associated with increased beta-amyloid levels in female patients with Alzheimer's disease. Neurosci Lett 307, 122-124 ; 2001. Abstract

Singh M, et al. Estrogen-induced activation of the mitogen-activated protein kinase cascade in the cerebral cortex of estrogen receptor-alpha knock-out mice. J Neurosci. 20, 1694-700 ; 2000. Abstract

Sohrabji F, et al. Estrogen differentially regulates estrogen and nerve growth factor receptor mRNAs in adult sensory neurons. J Neurosci. 14, 459-71; 1994. Abstract

Soriano S, et al. The amyloidogenic pathway of amyloid precursor protein (APP) is independent of its cleavage by caspases. J Biol Chem 2001 Aug 3;276(31):29045-50. Abstract

Tang MX, et al. Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease. Lancet 348, 429-432; 1996. Abstract

Toran-Allerand CD. Estrogen as a treatment for Alzheimer disease. JAMA. 284, 307-308; 2000. Abstract

Wang CN, et al. The neuroprotective effects of phytoestrogens on amyloid beta protein-induced toxicity are mediated by abrogating the activation of caspase cascade in rat cortical neurons. J Biol Chem 276, 5287-5295; 2001. Abstract

Xu H, et al. Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides. Nature Medicine 4, 447-451; 1998. Abstract

Zhang Y, et al. 17-{beta}-estradiol induces an inhibitor of active caspases. J. Neurosci. 21, 176; 2001. Abstract

Comments

This is best exemplified by the lack of AD-like changes observed during pre-pubescence when circulating concentrations of sex steroids during this 12 to 14 year period are extremely low. The possible role of the intermediate hormones that regulate estrogen and testosterone production have been largely ignored with regards to AD. This is despite the facts that changes in sex steroid levels cause a reciprocal change in gonadotropin (Gn) levels, Gn's cross the blood brain barrier, and that Gn receptors are in the brain with the highest density found in the hippocampus.

We recently reported a two-fold increase in circulating Gn (luteinizing hormone and follicle stimulating hormone) in individuals with AD compared with age-matched control individuals (Bowen et al., 2000). We are currently investigating potential mechanisms by which Gn's may be contributing to the pathogenesis of AD. - Richard Bowen, MD - Posted 29 November 2001

Reply from Sam Gandy -- Posted 2 December 2001

We have no data on gonadotrophins and either Abeta metabolism or Alzheimer risk, though it should be relatively straightforward to obtain. In general, I would suspect that the neurobiology of hormone withdrawal following decades of their presence (menopause and andropause) to be very different from that found in the relatively hormone-naive pre-pubertal brain.

Comment by Ming Chen -- Posted 2 December 2001

Hormone reduction (gonadal, estrogen, testosterone) is one of the most salient changes in aging (amid energy and growth factor decline, metal imbalance, free radicals, etc.). So it is expected and has been shown to contribute to (though may not be solely responsible for) the generation of amyloid. I agree with this picture but also consider the next two questions crucial:

1. Through what pathways can hormone reduction lead to amyloid plaques? Today everybody says amyloid is due to b- and g secretases. But why and how can hormone reduction eventually activate these enzymes?

2. Hormone reduction occurs in all elderly, but why do only some of them, but not others, develop AD? This may be easily explained by an "excessive hormone reduction" in the patients. But what has caused the excessive reduction in the first place? Will AD be explained without answering these questions?

Reply from Sam Gandy -- Posted 2 December 2001

The mechanism(s) by which estradiol/testosterone control(s) Ab levels are yet to be definitively elucidated. Our working model is that estradiol/testosterone activate ERK (MAPK), a signalling pathway well-known to be estrogen-sensitive (Toran-Allerand, et al.) and to modulate Ab release (Mills, et al J Neurosci).

Assuming that "sporadic" AD is really "polygenic" AD, we would propose a model whereby menopause/andropause "tip the scales" toward amyloidogenesis in individuals who also have the phenotype of marginal abeta economy. This should be testable, since these individuals might have modest elevations in plasma abeta levels.

I agree that it might be true that those individuals whose hormones fall farthest and/or fastest are probably at the most risk, but this is an opinion that I cannot support with data.

Comment by Ming Chen -- Posted 4 December 2001

Dr. Gandy proposes that estradiol/testosterone activate ERK, so that hormone withdrawal would decrease ERK, a reasonable scheme since many hormone-regulated pathways are reduced in aging.

But Ab is overly produced in the same period and whole world is developing inhibitors in order to reduce the activities of b- and g-secretases. So the question here is why and how REDUCED ERK activity could OVERLY ACTIVATE b- and g-secretases. Perhaps a more direct question is, should amyloid deposition be conceived to be due to something overly activated, or rather, due to something decreased? This may be a starting point for our reasoning. - Ming Chen

Reply from Sam Gandy -- Posted 4 December 2001

I don't have a teleological explanation for the connection between ERK and Ab, but we have recently observed that ERK inhibitors cause the most dramatic increase in Abeta generation of any compound studied to date (S. Petanceska, L. Refolo, T. Ramabhadran, S.G., unpublished observations). Of course, for me, this observation makes it even more tantalizing to sort out why the ERK signaling pathway is (apparently) importantly connected to the control of Ab metabolism!

Question from Laura Fisher, M.D. (lbfisher@xmission.com). -- Posted 6 December 2001.

I am a 54-year-old psychiatrist on estradiol and testosterone replacement. My 82-year-old father has a presumptive diagnosis of Alzheimer's dementia. His sister and father were thought to have had Alzheimer's (no autopsies). My father has profound word-finding difficulty UNLESS he takes Androgel. I have word-finding difficulty UNLESS I take estradiol. Why not set up a study of the offspring of Alzheimer's patients, many of whom will be menopause/andropause age or better, and do periodic dementia scale testing on them with and without gonadal hormone replacement?

Also I would like to know if there is an informed estimate as to the extent and quality of resistance to the connection between gonadal hormone deficiency and dementia within the research-funding community. In many areas of medical research there is considerable vested interest in maintaining the disease because various drug treatments are so lucrative. Of course, in the case of any topic concerning sex or sex hormones, we all have feelings about them and these color our individual views of the facts.

Reply from Sam Gandy -- Posted 10 December 2001

To Dr Fisher,

Thank you for your interest.

Certainly a family history of Alzheimer's will be recorded in any clinical trial, and we always encourage participation from the spouse and family members from our affected patients. We typically use the patient as an index and recruit as many relatives as possible.

Regarding acceptance of the connection between hormones and Alzheimer's, the retrospective and longitudinal epidemiological data are quite clear; what we require now is a prospective placebo controlled blind primary prevention trial. Several of these are underway, and results will be available in 2003 and 2008. These should be very compelling results, whether positive or negative. If the former, then lowering Alzheimer risk will become a factor in the decision of women to initiate ERT. If the primary prevention data are negative, the study of hormones and Alzheimer's will be set back...perhaps abandoned altogether.

Question from Richard Bowen (rbowenmd@earthlink.net)-- Posted 24 January 2002

Sam, most studies evaluating sex steroids and AD cite gender differences in prevalence as the reason for the study. If there is no gender difference in AD, what would be the rationale for researching sex steroids?

Reply from Sam Gandy -- Posted 24 January 2002

The idea is that both testosterone and estradiol regulate amyloid levels, and that following gonadal senescence (menopause & andropause), hormone levels fall and amyloid levels rise, tipping the balance toward amyloidosis in individuals with marginal amyloid economy. By extrapolation, ERT should delay AD and/or protect women and TRT should delay AD and/or protect men. Indeed, even transgender HRT might well delay/protect as well. Among these possibilities, only ERT in women has been widely applied and studied, so the focus on women & estradiol has to do with the availability of reliable, replicated clinical epi data. The major contributor to the increased prevalence of AD in women is a "survival effect"; i.e., the effect of CAD to diminish male longevity.