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AD is characterized by the presence of numerous senile plaques and neurofibrillary tangles accompanied by neuronal loss. The extracellular senile plaques are composed of amyloid beta-peptides. The intracellular neurofibrillary tangles are composed of highly phosphorylated tau proteins. The amyloid cascade hypothesis (Yamada et al., 1999) proposes that amyloid beta-peptides trigger a neurotoxic cascade, thereby causing neurodegeneration and AD.AD is also associated with apolipoprotein E genes (APOE) on chromosome 19. There are three major alleles of APOE: APOE2, APOE3, and APOE4. APOE4 is a susceptible gene of AD or risk factor in familial forms of AD. APOE4 binds to amyloid beta-peptides and promotes amyloid fibril formation.
Many areas in the brain have been found to play a role in AD. Neurons in the hippocampal formation, neocortex, medial septum, diagonal band of Broca, and nucleus basalis magnocellularis are severely affected by AD and are thought to contribute to the cognitive decline associated with AD-related dementia. These areas are important in learning and memory and attentional processes.
Positive Effects of Estrogen Replacement Therapy on AD
Postmenopausal women who receive ERT are 40-60% less likely to be diagnosed with Alzheimer's. Estrogen Replacement Therapy (ERT) has been found to both reduce the risk of developing AD and slow its progression in many studies. Women who receive ERT perform better on cognitive tasks than untreated women, which suggests that estrogen lessens the severity of AD. A study by Asthana et al., (1999) looked at the effects of 17 beta-estradiol, the most potent form of estrogen, on several cognitive domains typically impaired in patients with AD. Subjects, all women with mild-moderate AD were randomly placed in one of two groups. The first group received 0.05 mg/day of 17-b-estradiol and the second group received a placebo, both via a skin patch for 8 weeks. Before treatment, and then every two to three weeks following treatment, a battery of tests were administered which targeted several cognitive domains, including memory, attention, and language that are characteristically impaired by AD. It was found that treatment with estradiol improved aspects of attention and verbal memory, but did not improve language. The authors speculate that the beneficial effects of estrogen may be restricted to certain cognitive domains. Moreover, estrogen-induced enhancements in both memory and attention diminished when treatment was terminated. The results indicate that short-term administration of estrogen has the potential to enhance cognition for postmenopausal women. Numerous other studies have found similar results.
The Mechanisms of ERT in AD
ERT elicits its positive effects in the treatment of Alzheimer's in many ways. Numerous studies have documented the different effects of estrogen by looking at one effect at a time. But it seems to be agreed upon that the effects of estrogen do not act independently of one another. The most well known and documented is estrogen's effect on cholinergic neurons. Estrogen also promotes neuronal growth and cerebral blood flow, reduces the generation of amyloid beta-peptides, and increases the expression of APOE mRNA.
Enhancement of Cholinergic Projections to the Hippocampus and Cortex
Studies have shown an association between AD and the reduction in the number of basal forebrain cholinergic neurons. There are also corresponding reductions in choline acetyltransferase (ChAT) activity, high-affinity choline uptake (HACU), and acetlycholine (ACh) production in the hippocampus and cortex. Continuous estrogen replacement results in increases in ChAT activity within specific regions of the rat basal forebrain, hippocampus, and frontal cortex. Gibbs and Aggarwal (1998) suggest that ERT may enable the neurons to maintain elevated levels of acetylcholine release during periods of increased demand, while at the same time, having relatively little impact on basal cholinergic tone. These effects may have very little impact on a young, healthy brain, but they are significant in AD because of the reduction in cholinergic cells and greater demand on remaining cells.
It is unclear exactly how estrogen influences basal forebrain cholinergic neurons. It has been found that cholinergic neurons contain high-affinity estrogen binding sites indicative of estrogen receptors. It has more recently been suggested that estrogen may directly influence the cholinergic neurons by binding to intracellular receptors followed by direct steroid-mediated effects on gene transcription (Gibbs Aggarwal, 1998). The possibility that estrogen may affect cholinergic neurons indirectly must also be considered.
Cholinergic neurons in the medial septum and nucleus basalis magnocellularis are also affected by nerve growth factor (NGF), which is produced in the hippocampus and cortex. NGF has been shown to promote both the survival and function of basal forebrain cholinergic neurons during development and adulthood. There is evidence that estrogen can significantly affect the expression of ChAT and NGF receptors in specific basal forebrain cholinergic neurons, and therefore exert and effect on both cholinergic and NGF-related systems. The effects of estrogen on basal forebrain cholinergic neurons could result from effects of estrogen on NGF and NGF receptor cells.
Increases in cholinergic function are dose-dependent in determining effects of estrogen on cognitive processes. For example, one study found that increases in cholinergic function was not maintained in response to uninterrupted treatment with high levels of estradiol, and another found beneficial effects following low-dose but not high-dose, or short-term but not long-term, estrogen treatment (Gibbs Aggarwal, 1998). Short-term treatment seems to be the consensus, but an optimal dose has not been agreed upon.
Estrogen also regulates brain derived growth factor (BDNF).
Promotion of Neuronal Growth
Brinton et al. (1997) found that 17-b-estradiol induced an increase in the fine structure of rat hippocampal neurons within 5 minutes of exposure.
This suggests that the effect of 17-b -estradiol was mediated by a process that could be independent of estrogen nuclear receptor activation. Increased cell growth was specific to 17-b-estradiol, as increased outgrowth did not occur in response to other steroids. Nine other estrogenic steroids were tested. Five of the estrogenic steroids had no effect on neuronal growth in the cortex. The five that increased neuronal growth in the occipital lobe were 17-b-estradiol, equilin, estriol, mestranol, and estrone. This suggests that neuronal growth in the occipital lobe is steroid specific with certain estrogens inducing effects while other estrogens are without effects. Equilin produced highly significant increases in occipital nerve cell growth. It also produced effects in nerve cells from frontal and temporal lobes. Nerve cells in the parietal lobe showed some growth, but the results were not significant.
It was also found that the growth-promoting effects of equilin are dependent upon activation of the NMDA glutamate receptor. Phosphorylation by the protein kinase A increases the amplitude of glutamate-induced current. This increase in NMDA-mediated current could account for the neurotrophic effects of both 17-b-estradiol and equilin.
Reduction in amyloid beta-peptides
It has been found that estrogen diminished amyloid beta-peptide release in cultures from rodent and human fetal cerebral cortex. ERT reduces amyloid beta-peptides, which contributes to the ability of ERT to protect against AD. The amyloid beta-peptide25-35 fragment has been shown to be the toxic portion of the amyloid beta-peptide1-40. This peptide causes cell death in primary neuronal cultures. Simpkins et al., 1997 exposed brain cells to amyloid beta-peptide25-35 for four days. Amyloid beta-peptide25-35 fragment caused a dose-dependent reduction in these cells ranging from 36% to 83%. The addition of beta-estradiol, the major form of circulating estrogen in the body, reduced the fragment toxicity by 83% and 51% in two different studies. The exact mechanisms are unknown.
Increased Production of APOE Protein
Apolipoprotein (APOE) has been implicated in the transport of cholesterol and phospholipids for the repair, growth, and maintenance of membranes that occur during development or after injury. It is also involved in maintenance of dendritic complexes. APOE is present in the senile plaques of AD brains. Of the various APOE isoforms, E2, E3, and E4 differ by one unit of net charge. APOE4 has been associated with increased risk for AD. While some studies have found that APOE4 inhibits neuronal growth, a recent study shows that APOE3 and APOE4 have a protective effect against the toxicity of amyloid aggregates.
Part of the effect of estrogen could be related to the regeneration of injured brain induced by the neurotrophic action of APOE itself, which is independent of the isoform expressed. It is also possible that ERT could override the possible reduction in naturally occurring estrogen, and in this way induce the synthesis of APOE in astrocytes and glial cells. This would result in a positive response in the regeneration of neurons, especially at the cholinergic level in the basal forebrain and hippocampus. It is also possible that estrogen can modulate the expression of APOE receptors either directly or indirectly, enhancing the NGF-mediated pathway that induces APOE.
Stone et al. (1998) suggest that estradiol increases compensatory synaptic sprouting by upregulating local transporters of cholesterol and other hydrophobic membrane components. Thus, estradiol could increase synaptic sprouting by increased production of APOE protein or increased uptake of APOE-containing lipoproteins. Increased APOE production or uptake in response to estrogen could improve the effects of AD through two pathways: increased compensatory synaptic sprouting and increased ChAT activity.
More Web Resources on ERT and Alzheimer's
The Foundation for Better Health Care
The Foundation for Better Health Care provides resources on various topics of women's health
Alzheimer Research Forum on Estrogen
Asthana, S., Craft, S., Baker, L. D., Raskind, M. A., Birnbaum, R. S., Lofgreen, C. P., Veith, R. C., Plymate, S. R. (1999). Cognitive and neuroendocrine response to transdermal estrogen in postmenopausal women with Alzheimer's disease: Results of a placebo-controlled, double-blind, pilot study. Psychoneuroendocrinology, 24, 657-677.
Brinton, R. D., Yamazaki, R. S. (1998). Advances and challenges in the prevention and treatment of Alzheimer's disease. Pharmaceutical Research, 15, 386-398.
Brinton, R. D., Proffitt, P., Tran, J., Luu, R. (1997). Equilin, a principle component of the estrogen replacement therapy Premarin, increases the growth of cortical neurons via an NMDA receptor-dependent mechanism. Experimental Neurology, 147, 211-220.
Gibbs, R. B., Aggarwal, P. (1998). Estrogen and basal forebrain cholinergic neurons: Implications for brain aging and Alzheimer's disease-related cognitive decline. Hormones and Behavior, 34, 98-111.
Green, P. S., Gridley, K. E., Simpkins, J. W. (1998). Nuclear estrogen receptor-independent neuroprotection by estratrienes: A novel interaction with glutathione. Neuroscience, 84, 7-10.
Inestrosa, N. C., Marzolo, M. P., Bonnefont, A. B. (1998). Cellular and molecular basis of estrogen's'neuroprotection: Potential relevance for Alzheimer's disease. Molecular Neurobiology, 17, 73-86.
Schneider, L. S., Farlow, M. R., Pogoda, J. M. (1997). Potential role for estrogen replacement in the treatment of Alzheimer's dementia. The American Journal of Medicine, 103, 46S-50S.
Simpkins, J. W., Green, P. S., Gridley, K. E., Singh, M., de Fiebre, N. C., Rajakumar, G. (1997). Role of estrogen replacement therapy in memory enhancement and the prevention of neuronal loss associated with Alzheimer's disease. The American Journal of Medicine, 103, 19S-25S.
Stone, D. J., Rozovsky, I., Morgan, T. E., Anderson, C. P., Finch, C. E. (1998). Increased synaptic sprouting in response to estrogen via an apolipoprotein E-dependent mechanism: Implications for Alzheimer's disease. The Journal of Neuroscience, 18, 3180-3185.
Xu, H., Gouras, G. K., Greenfield, J. P., Vincent, B., Naslund, J., Mazzarelli, L., Fried, G., Jovanovic, J. N., Seeger, M., Relkin, N. R., Liao, F., Checler, F., Buxbaum, J. D., Chait ,B. T., Thinakaran, G., Sisodia, S. S., Wang, R., Greengard, P., Gandy, S. (1998). Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides. Nature Medicine, 4, 447-451.
Yamada, K., Ren, X., Nabeshima, T. (1999). Perspectives of pharmacotherapy in Alzheimer's disease. The Japanese Journal of Pharmacology, 80, 9-14.