Sam Gandy led this live discussion on 5 December 2001. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

View Transcript of Live Discussion — Posted 30 December 2001

Background Text
By Sam Gandy

Many independent lines of evidence implicate β 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 β-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-β) 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-β 42 have been associated with an increased risk for AD (Mayeux, 1999; Ertekin-Taner, 2000). Regulated A-β 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-β 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-β 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-β 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-β 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-β 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-β 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 on Live Discussion
	Comment by:  Richard Bowen
	Submitted 29 November 2001  |  Permalink	Posted 29 November 2001
	Participants in the forum may be aware that there has been an ongoing dialogue between myself and Dr. Gandy on the role of gonadal hormones in the etiology of Alzheimer's disease and this discussion has been recently published as letters in JAMA. While epidemiological evidence implicates a role for estrogen/testosterone in AD, and estrogen and testosterone modulate APP processing in cell lines and mice, a number of observations indicate that the decrease or absence of circulating estrogen/testosterone cannot entirely explain AD. 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...  Read more Participants in the forum may be aware that there has been an ongoing dialogue between myself and Dr. Gandy on the role of gonadal hormones in the etiology of Alzheimer's disease and this discussion has been recently published as letters in JAMA. While epidemiological evidence implicates a role for estrogen/testosterone in AD, and estrogen and testosterone modulate APP processing in cell lines and mice, a number of observations indicate that the decrease or absence of circulating estrogen/testosterone cannot entirely explain AD. 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. View all comments by Richard Bowen
	Comment by:  Ming Chen
	Submitted 2 December 2001  |  Permalink	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 β- and γ 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? View all comments by Ming Chen
	Comment by:  Samuel Gandy
	Submitted 2 December 2001  |  Permalink	Posted 2 December 2001
	Reply by Sam Gandy The mechanism(s) by which estradiol/testosterone control(s) Aβ 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 Aβ 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. View all comments by Samuel Gandy
	Comment by:  Samuel Gandy
	Submitted 2 December 2001  |  Permalink	Posted 2 December 2001
	Reply by Sam Gandy 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. View all comments by Samuel Gandy
	Comment by:  Ming Chen
	Submitted 4 December 2001  |  Permalink	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 Aβ is overly produced in the same period and whole world is developing inhibitors in order to reduce the activities of β- and γ-secretases. So the question here is why and how REDUCED ERK activity could OVERLY ACTIVATE β- and γ-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. View all comments by Ming Chen

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