discussion about hypothesised link between the menopause and Alzheimer disease

Posted comment on ´Changing your mind`  by J. Hamzelou and published in New Scientist 3141 2nd September 2017 p.36.

SUMMARY

Hamzelou began her article by describing some of the symptoms experienced by some women going through menopause. She stated that the cognitive changes observed in menopause, eg. migraines, mood swings, anxiety, short-temper, forgetfulness and insomnia, resemble the presenting symptoms observed with sufferers of Alzheimer disease and may in fact signal the start of that disease. In order to support her view Hamzelou quoted work by Brinton, a Californian scientist who studies the hypothesised link between the menopause and Alzheimer disease. Brinton hopes to develop therapies that artificially boost hormone levels that would lead to protecting the brain from the detrimental changes that could lead to dementia later in life.

Hamzelou continued her article by describing the biological basis of menopause and listed the common non-cognitive symptoms observed, eg. fatigue and weight gain. She said that in comparison to those obvious symptoms, cognitive symptoms are often overlooked since they occur at a time when other reasons can be given to their appearance eg. ageing and also because society demands a level of expectation and endurance when considering mental health problems. However, research given by Hamzelou as being carried out in the last decade, has shown that a decrease in oestrogen level has effects on memory, mood and even what has been termed the  ´brain health` of men and women. Research by Brinton and others has shown that reduced levels of oestrogen are correlated to alterations in the type of energy the brain cell uses and to a reduction in the production of energy. Under normal conditions, oestradiol increases the activity of the mitochondria in brain cells involved in normal cellular energy production and therefore, it helps cells recover from damage associated with normal ageing. Grimm of the University of Queensland, Australia supports Brinton`s view and was quoted in the article as saying that the drop in oestrogen makes the brain more sensitive to damage that could lead to death of neurons. Brinton believes that the fall in oestrogen that occurs in the menopause causes the brain to produce less energy and to change the type of energy it uses. Glucose is the normal energy source of brain and this is reduced by 25% in tissues of menopausal sufferers. To overcome the shortage of glucose the cells, according to Hamzelou and Brinton, begin a ´starvation` response and use fats as their energy source instead. They are also believed to use myelin as well which can be found in the protective shield around the neurons themselves. Although their studies were carried out on mice, Brinton suggested that the results could also apply to humans and some research supports this. A decrease in glucose metabolism, a change in white matter volume and grey matter volume and an increase in beta amyloid production relative to men have been observed. The switch in energy source was also suggested by Brinton to provide an explanation for some of the other symptoms of menopause. For example, the metabolism of fat because it is a less efficient energy source than glucose creates more heat and this excess heat in the brain was suggested in some animal studies as possibly triggering the menopausal non-cognitive symptom of  hot flushes.

Hamzelou continued her article by describing why some researchers link the supposed protective effect of oestrogen on cognitive function and hence why the menopause and its cognitive symptoms can be linked with symptoms observed in Alzheimer sufferers. Brinton investigates why women are more susceptible to Alzheimer`s illness and thinks that the hormonal transition occurring  in the perimenopause stage and full menopause may be the cause and start of Alzheimer illness in some women. Studies have shown that two thirds of people with Alzheimer`s illness are women and even though the disease is diagnosed when they are in their seventies, the disease actually starts around 15-20 years earlier when the natural menopause occurs.  The link to energy production during the hormonal transitions occurring in menopause was supported by work from others. For example brain scans measuring how much glucose is being metabolised across different brain regions were carried out in 2005 by Mosconi and colleagues of the New York University and they observed reduced glucose metabolism with Alzheimer sufferers and women who were in perimenopausal or postmenopausal stages. These observations compared favourably to Brinton`s observations in mice and suggested a link between a decline in glucose metabolism in the menopause, ageing and Alzheimer illness.

Hamzelou then went on to describe the natural progression of such results – if oestrogen has a brain effect when it falls, then what happens when it is replaced? Some studies suggested that hormone replacement therapy (HRT) could prevent dementia, but a trial of 7500 women in 2005 by the Women`s Health Initiative Memory Study found that HRT actually quickened cognitive decline and increased the risk of not only dementia, but also breast cancer and cardiovascular disease.  Hamzelou quotes researchers who believe that the study was flawed and describes the study by Pinkerton at the University of Virginia who looked at women given conjugated equine oestrogens. They stated that the negative link between HRT and cognition was incorrect since the administered oestrogen was obtained from pregnant horses and therefore, not an appropriate hormone source for premenopausal women and that the women taking part in the study were already over 65 and were therefore, too old to be described as suitable menopause subjects. They said that their brains had already adapted to low oestrogen levels and that the number of relevant receptors had already decreased. Pinkerton went on to say that there appeared to be an optimum time for HRT treatment (termed ´window of opportunity`) and that this time period was limited to between the appearance of the menopausal symptoms and the time when the brain was still responsive to treatment. They said that oestrogen can work better on healthy cells and therefore, HRT works better when women take it around the time of the menopause. In response to the increase of detrimental side effects observed with HRT administration, Pinkerton said that in the case of breast cancer, administration of HRT was linked to only an increase in breast cancer of under one case in a thousand. Pinkerton concluded by saying that HRT should be used only if women experience unpleasant symptoms, but the view of ´lowest dose for shortest amount of time` should be replaced by the caveat of ´making sure that the treatment is appropriate`. The determination of what is appropriate has not yet been made. Hamzelou continued by suggesting that the better solution may be to use oestrogens that only work on specific organs eg. one that works on brain, but by-passes breast tissue. She quoted in her article work by Raber of Oregon Health and Science University in Portland who reports that drugs of this nature are already in development. Hamzelou also quotes Brinton who suggests a nutritional approach to protect the brain from the effects of hormone loss. This view is linked to food obtained from the diet and brain function. For example, ketogenic diets appear to benefit epilepsy sufferers. In the case of the menopause, a high fat diet is not advised for people at risk of weight gain and against the view of a healthy diet rich in fruit, vegetables and grains being good for brain health. She also recommended exercise and keeping active, which has been shown to boost mood and cognition and can increase bone mass.

The article concluded with Brinton describing the future with individually tailored hormone therapies given at the right time to treat menopause symptoms and prevent Alzheimer`s illness.

COMMENT

The menopause can be regarded as a ´sensitive` topic at the best of times particularly with women, but when it is linked in scientific research to the appearance of Alzheimer disease then the feelings it evokes are intensified. Therefore, any research into the association between these two topics should be rigorously examined because unlike other factors causing changes in memory and cognitive capability (eg. the administration of certain drugs or a stroke) the natural decline of a hormone due to increasing age is something that transcends effects under the control of the person herself. Experimentation into the menopause in humans is beset with problems. For example, because the onset is variable and the occurrence of relevant symptoms is individual. We know that natural occurring menopause is clearly defined as existing one year after the last menstrual period, but definition of the ´last menstrual period` is difficult to define itself since women experience differing forms of menstrual periods in the perimenopausal phase. The definition of the beginning of menopause is therefore easier to establish when it occurs through surgical intervention eg. hysterectomy or also through disease such as polycystic ovarian syndrome. Even if the beginning of menopause can be determined accurately time-wise the variation in symptoms whether physiological, cognitive or emotional makes interpretation of results difficult in humans. Physiological symptoms such as hot flushes or loss of sleep are probably easier to see and measure, but the cognitive symptoms (eg. irritability, loss of spatial memory) on which this Blog is focussed are more difficult since they are in part ascertained through self-reporting which can be unreliable and are subjective with daily variations and differences depending on personal situations. However, we can say that the menopause is a physiological condition or state brought about by decreased levels of circulating oestrogen/oestradiol and therefore, we can assume that whatever symptoms are observed then they occur as a result of this decrease in circulating hormone.

Oestrogen is produced from progesterone by the ovaries and instigates a wide variety of effects in the whole body. However, it is also produced in the brain, blood vessels and bone synthesised from cholesterol to various intermediate compounds eventually to pregnenolone which then is converted to 17alpha-hydroxyprogesterone then to androstendione (to estrone),  to testosterone and eventually to oestradiol. Since this Blog focusses on the brain and neurochemical processes we shall concentrate here in this post on effects of oestrogen in the brain and on neurons. It can be said that the presence of oestrogen in this organ and on these types of cells has a general effect on neuronal firing and is said to elicit intracellular effects associated with changes in the DNA, membranes and from the article reviewed here on cellular energy production. This general positive synaptic effect translates into an influence on firing and is said to provide a protective effect on neurons and their functions. Exposure to oestrogen or oestradiol can mean that cells are more likely to survive hypoxia, oxidative stress and exposure to neurotoxins for example and hence, also elicit a protective effect against the development of certain mental illnesses such as multiple sclerosis, Parkinson´s disease and dementia.

When considering the effect of oestrogen on brain cell firing we should assume that the effect is not major since for example there are other systems in play which have far more wide-ranging effects (eg. NMDA concentration, glial cell functioning) and that there is a natural variation in oestrogen level anyway with the menstrual cycle with no major signal transmission shut down when oestrogen is at a low level. Therefore, we should probably consider oestrogen more as an instrument of ´fine tuning` of the neurobiological system in the same vein as the emotional system (eg. a positive influence from dopamine on the emotional system and neuromodulation of prefrontal cortex firing) or like the effect of tiredness and sleep deprivation. In order that such an influence can occur the cells in question must have oestrogen ´acceptor` capability and this will be described in more detail later on. The possession or absence of such a capability could explain why some brain areas are affected by oestrogen and why some are not and hence, why some cognitive functions are affected and others independent from oestrogen influence.

For now in the context of a positive effect on synaptic firing, oestrogen has been shown to increase neuronal firing due to the growth of neurites (increases cell viability) and an increased number of dendritic spines. For example in the case of the hippocampus, the number of spines varies with the level of oestradiol in vivo with both peaking together. The presence of oestradiol also shows that the area grows more excitatory synapses and the new spines have more NMDA receptors on them. Hence, the long-term plasticity of the hippocampus is increased in the presence of oestrogen. Also oestrogen can initiate its effect directly in the hippocampus by depressing the synaptic inhibition mechanism. Oestrogen receptors have been found on the inhibitory interneurons in the area which do not grow more spines on exposure.  The oestradiol causes the inhibitory cells to produce less GABA so there is less inhibition of firing and hence greater general neural activity which somehow triggers an increase in spine growth in the area and increases the number of excitatory synapses on the pyramidal cells. In the presence of low oestrogen then decreased spine density and a decreased number of NMDA receptors is observed as expected, but also increased acetylcholinesterase activity is seen. This implies that an effect on the cholinergic firing mechanism in the area is also influenced. These effects on the hippocampus give an explanation in part as to why certain memory systems are said to be affected in menopause since the hippocampus is believed to be responsible for the relay of information in the brain and with the neighbouring entorhinal cortex area responsible for the binding of information together. Hence, effects on object recognition and verbal memory in menopause where there is a reduced level of circulating oestrogen are seen.

Another brain area said to be affected by oestrogen is the prefrontal cortex. It has been found that dopamine activity in this area is enhanced by oestradiol and in its presence then bigger synapses are observed. The effect is associated with the presence of oestrogen receptors of the alpha type. Therefore, in this case oestrogen could influence the neuromodulatory control associated with this area and dopamine, thus explaining in part the observed cognitive symptoms in menopause linked to the emotional pathway eg. irritability, and lower decision-making capability eg. assessment of values of events.

The synaptic and firing effects observed in the presence of oestrogen are brought about by intracellular processes involving the hormone. These are believed to be associated with DNA binding and/or cellular membrane effects and also as suggested by the authors in the article reviewed in this blog, by changes in the energy producing mechanisms taking place in the cell`s mitochondria. The DNA effect is well documented and begins with the transfer of the hormone through the cell`s membrane – a process that is simple due to its non-polar molecular structure. Once inside the cell it binds to a highly specific soluble receptor protein in the cell`s cytosol. These oestrogen receptors are of the alpha or beta type and are known as nuclear oestrogen receptors (ERalpha, ERbeta). It is thought that it is the alpha type in the hippocampal CA1 area that is linked to the increased synaptic plasticity described above. The hormone/receptor complex then interacts directly with specific binding sites on the DNA called oestrogen response elements (EREs) and ultimately, this binding modulates gene transcription. The DNA binding domain is highly conserved with 9 cysteine residues, 8 of which bind zinc ions which stabilise the structure of the domain (called zinc finger domains). The ligand binding site exists at the carboxyl end and is comprised of alpha helices. Ligand binding in a hydrophobic pocket in the centre leads to conformational changes that allow the recruitment of a coactivator protein such as SRC-1, GRIP -1 or NcoA-1. These have a common modular structure and bind to the ligand binding domain of the receptor dimer. Binding to the DNA ultimately changes gene transcription so that certain proteins are either down- or up-regulated so that the oestrogen influence on the cell is realised.

The other known cellular effect of oestrogen is its binding to membrane-bound receptors (mERs) eg. GPER (GPR30), ER-X and Gg-mER. These receptors can be rapidly activated on exposure to oestrogen and their effects are believed to be associated through the attachment of caveolin-1. Complexes are formed mostly with G protein coupled receptors, striatin, receptor tyrosine kinases (eg. EGFR, IGF-1) or non-receptor kinases (eg. Src) and each causes different effects. Although binding through G protein coupled receptors eg. GPR30 has an unknown role, binding to other structures cause cellular effects eg. through striatin – some of the membrane bound oestrogen receptor complex may lead to increased levels of calcium ions and nitric oxide; through receptor kinases – signals sent to the nucleus via the mitogen activated protein kinase MAPK/ERK pathway and the phosphoinositide 3 kinase (PI3K/AKT) pathway; and finally through glycogen synthase kinase 3 (GSK- 3beta) which inhibits transcription by the nuclear oestrogen receptor by inhibiting phosphorylation of serine 118 of the nuclear oestrogen alpha receptor. Phosphorylation of the GSK-3beta removes its inhibitory effect and this is achieved by PI3K/AKT pathway and MAPK/ERK pathway via rsk.

Another possible mechanism involving the membrane is the oestrogen receptor complex`s effect on the lipid domain as a whole and the subsequent increased or decreased action of other neurotransmitter complexes existing in that same lipid domain. It is known that oestrogen elicits an effect on NMDA receptors in the hippocampus, but it also affects acetylcholine binding to the M2 acetylcholine receptor. In general, however it is likely that the overall effect of oestrogen by binding to membrane-bound receptors is increased firing activity as described above.

The third action of oestrogen at the intracellular level is that suggested by Hamzelou and researchers such as Brinton who hypothesise that the presence of oestrogen supports the use of glucose as fuel source in the cell in its energy production mechanisms, but its absence causes a change in fuel source to fats and even myelin and a decrease in mitochondrial function. What does this actually mean? In the brain, the sole source of fuel for cells is glucose under normal circumstances and we have to assume that there are normal circumstances even in the low levels of oestrogen in parts of the menstrual cycle because of diet and that the glucose transport into the cells is below maximum capacity and hence, an increase in brain cell activity will still keep glucose transport into the cell within its limits. As already described in another Blog post, cell energy production mechanisms can change according to certain conditions eg. conditions of low oxygen/high altitude. In this case, the lack of oxygen means cellular adaptation of the biochemical processes supplying energy to the cell occurs.  In low oxygen conditions, the normal mechanism of energy production means that glucose is still being metabolised by a chain of enzymatic reactions (called glycolysis) to produce pyruvate just as that occurring in aerobic respiration (ie. in the presence of oxygen),  but the second stage of the process is altered. This stage is where the pyruvate is converted by another chain of reactions into the energy molecules, ATP.  If oxygen is not present at the level required for this aerobic mechanism, then a process called lactic acid fermentation is initiated (anaerobic respiration). Lactic acid fermentation means that pyruvate is then converted to lactate by the enzyme lactate dehydrogenase (LDH). However, this anaerobic process does not produce the same number of ATP molecules as normal aerobic mechanisms, but it does provide some. The other potential problem of this scenario is the build-up of lactate which is observed in muscle cells. However, it is likely that in the brain which is dependent on a constant supply of glucose and energy that a safeguarding mechanism is in place called the Cori cycle which transports the lactate out of the cell, back to the liver where it is converted into glucose by a process known as gluconeogenesis. Again the LDH enzyme is involved and this conversion could explain the lack of appetite experienced by some when undergoing rising altitude.

In the case of the menopause, Hamzelou and researchers such as Brinton suggest that the source of fuel in the brain cell changes from glucose to fats when oestrogen levels are low. Normally, fatty acids are bound to albumin in the blood and cannot cross the blood brain barrier, but under conditions such as starvation for example,  ketone bodies are generated by the liver and transported in the blood across the blood brain barrier to partly replace the glucose as fuel in the brain cells. Therefore, Hamzelou and Brinton suggest that ketone bodies are used as fuel source. The acetyl coA formed in fatty acid oxidation enters the citric acid cycle only if levels of fat and carbohydrate degradation are balanced. This is because of the availability of the substrate oxalocitrate which forms citrate, the next substrate in the cycle. Oxalocitrate concentration is lower if carbohydrates are not available.  In fasting or diabetes, oxalocitrate is used to form glucose by the gluconeogenic pathway and therefore the substrate is not available for acetyl coA production. Therefore, acetyl coA is converted to acetoacetate (by a 3 step mechanism) and D-3-hydroxybutyrate (formed by reduction of acetoacetate in mitochondrial matrix) which with acetone (formed from slow spontaneous decarboxylation of acetoacetate) forms compounds known as ketone bodies. The major site of production of ketone bodies is in liver mitochondria and these are transported via the blood to other tissues. They are used as fuel sources in the muscle, renal cortex and brain in cases of starvation (75% of fuel in prolonged starvation) and insulin-dependent diabetes mellitus. In the latter, the absence of insulin means that the liver cannot absorb glucose and as a result cannot provide oxaloacetate for the fatty acid derived acetyl coA process and cannot prevent fatty acid mobilisation by the adipose tissue. Therefore, the liver produces large amounts of ketone bodies which are strong acids and the presence of such high levels causes severe acidosis. This results in a decrease in intracellular pH which impairs tissue function – a condition already described in a previous Blog post when considering cell function in high altitude conditions. The brain begins to use acetoacetate after 3 days of starvation (a third of energy needs met), but after several weeks it is a major source. The advantage is that ketone bodies are built from released fat and this preferable to breaking down muscle instead.

Although the hypothesis by Hamzelou, Brinton and supporters about the switch from glucose to fat and even myelin may be true and that glucose metabolism is reduced in the brain in low oestrogen, then if this hypothesis is correct, then we must assume that in menopause, the brain cells are not getting their normal fuel source because of the lack of oestrogen. Therefore, under normal conditions oestrogen would then aid the transport of glucose into the cell by affecting the insulin signal on the glucose transporters, or by directly effecting the glucose transporters themselves. Is there any proof of this? There are no reports of significant effects on insulin sensitivity or levels or glucose levels in the menopause. However, there is a report of the change in insulin metabolism. Therefore, the cause of effect could be indirect through reported changes in diet in menopausal women where diet is altered to counteract the increased weight gain and fat deposits observed around the middle. A strict diet could translate into starvation conditions and hence, changes in fuel sources as indicated above could be observed. It is likely that if a normal diet is maintained then such an effect on fuel source would not be seen.

Therefore, the overall conclusion about the action of oestrogen in the brain is that it is a molecular compound that affects cell functioning of susceptible cells by either binding to the cell membrane or by internally binding to receptors which bind directly to the DNA and affect gene transcription. This can result in either a negative or positive effect on cell functioning. If the cell has oestrogen acceptor capability then oestrogen can affect that cell, that area and ultimately have an effect on cognitive function of some sort linked to that brain area eg. oestrogen influences the activity of the hippocampus by inhibiting the interneurons and hence, increasing synaptic firing and increased plasticity of area in question. An absence of the hormone will lead to observed changes in verbal memory, object recognition, spatial memory (only rats), short term memory, learning new associations, long term memory, working memory plus depression. However, the action of oestrogen should be considered more in terms of ´fine tuning` systems and mechanisms already in place rather like the effects of tiredness. This would in part explain why there appears to be a neuroprotective effect with oestrogen ie. cells are more likely to survive hypoxia, oxidative stress, exposure to neurotoxins for example or protection against diseases such as multiple sclerosis, Parkinson`s disease and dementia if exposed to oestrogen or oestradiol. The positive oestrogen effect on gene transcription and synaptic firing would counter-balance the negative effects caused by the cellular stresses.

This leads on to the hypothesis proposed by Brinton and others and explained by Hamzelou in her article about a link between the menopause and Alzheimer`s disease. It is said that there are several similarities between the two conditions eg. the start of menopause is considered to be linked to the same time as the start of Alzheimer`s disease; women are far more susceptible than men; and the presenting symptoms relating to cognition appear to be the same or similar. Therefore, we must question whether this is just circumstantial or whether there is a real link. With regards to timing, the menopause or reduction in oestrogen as described above could initiate some minor temporary changes in physiology which could lead on to changes in sleep patterns, depression and anxiety and small changes in performance of some cognitive functions. Although the physiological changes seen with Alzheimer`s disease are known for times later on in the disease progression, the physiological changes associated with the early stages are to date not clearly defined. It could be that these are actually the same changes as those observed in menopause ie. changes in sleep patterns, susceptibility to depression and anxiety, reduced levels of interest and hence, lower levels of mental stimulation etc. and therefore, the timing of the menopause and onset of Alzheimer disease would appear to be the same. Of course, it should be remembered that not all women who experience the menopause go on to develop Alzheimer disease and menopause and Alzheimer disease  are associated with more elderly people and hence, timing could be a reflection of the normal ageing process and the changes in life style, aspirations, emotional stability that could accompany this particular life period.

The second association between the menopause and Alzheimer disease according to Hamzelou, Brinton and others is the observation that Alzheimer disease is more prevalent in women and understandably, the menopause is a female condition. Since brain neurochemical mechanisms are independent of gender then we must assume that the difference is due to either physiological differences between the female and male brain, or possibly could the reflect the way in which men and women mentally approach and carry out events. The latter is probably a product of the former and therefore, the observation that oestrogen level has an effect on the performance of the hippocampus (described above) could explain why there is a gender difference in the appearance of Alzheimer disease. The hippocampus is an important brain area with multiple roles in cognitive functions such as information intake and binding, memory mechanisms, working memory and decision-making and is known to be progressively and extensively negatively affected as Alzheimer disease progresses. Women appear to have naturally larger hippocampal areas and therefore, this could provide a possible reason why women appear to suffer from Alzheimer disease more than their male counterparts.

The third similarity proposed by Hamzelou, Brinton and others linking menopause to Alzheimer disease is that the cognitive symptoms of the menopause are similar to those seen with sufferers of Alzheimer disease. Both appear to be a collection of cognitive symptoms linked to relaying information taken in, binding of information together, value assessment for example and hence, the similarity of symptoms of for example lack of memory, decision-making problems and emotional status changes are understandable. As stated above, circulating oestrogen appears to affect synaptic functioning and as with the timing association physiological changes would instigate observable performance changes. Since both produce to some extent permanent changes in physiology eg. menopause causes minor changes due to its ´fine tuning` role and Alzheimer disease massive changes because of amyloid deposits and abnormally high apoptosis of neurons then symptoms would be appear to be the same.

There is however a difference between menopause and Alzheimer disease in relation to whether cognitive performance can be restored by treatment of oestrogen replacement therapies. With Alzheimer disease in the later stages of the disease, administration of oestrogen replacement therapies appears to have no beneficial effect. In the former however, treatment can reverse some of the symptoms eg. verbal memory, short term memory are improved and there are positive effects on sleep and emotional state disturbances, eg. depression is reduced. This is understandable since falling levels of circulating oestrogen are being boosted by the administered oestrogen compounds and hence, the positive effects on DNA transcription and synaptic firing are being restored. Increased expression of the oestrogen alpha receptor in hippocampal CA1 area and increased NMDAR synaptic transmission have been observed with the administration of oestrogen compounds to mice menopausal models. However, most research appears to suggest that the positive effect of this oestrogen administration appears to be limited to only a short period when falling levels are minimal (called the ´window of opportunity`) which implies that in the long-term other changes are occurring in the synapse and brain areas that are not associated with the fine tuning mechanism brought about by the presence of the oestrogen hormone. These physiological changes could be those linked with natural ageing for example or instigated through life-style changes brought about by a variety of reasons. This may be important because other things appear to be beneficial for reduction of menopausal cognitive symptoms eg. exercise, proper diet, social contact, mental stimulation, appropriate sleep patterns. These can possibly restore the balance or counteract the loss of oestrogen experienced in the menopause. One factor that should be considered relating to this is the importance of zinc in brain cell functioning. Zinc deficiency is known to cause anorexia, lethargy, diarrhoea, impaired immune system, growth restriction, intellectual disability, depression, loss of appetite and disorders of fear conditioning. There is a range of effects because zinc ions have important functions in general in nerve conduction in the brain, roles in correct enzyme functioning such as carbonic anhydrase, aspartate transcarboamylase, aminoacyl –tRNA synthase, metalloproteases and in neurons in particular an important role in the phospholipid cell membrane signal and in relation to menopause in  steroid binding to the receptor as seen in the case of oestrogen. It is possible that menopausal women could suffer from zinc deficiency due to dieting and/or poor diet. Food stuffs containing zinc are bread, eggs, oysters, liver, meat, dairy products and pulses and weight gain associated with falling oestrogen levels may mean that the diet is restricted of these zinc containing foods. This deficiency could lead to the wide range of effects attributed to the multiple cellular roles of zinc.

Therefore, can we definitively say that oestrogen reduction in menopause is linked with Alzheimer disease? It is likely that oestrogen is not a major player in neuron function rather it provides a ´fine tuning` mechanism for synaptic physiology and function in the same way as tiredness or emotional state changes can. It appears that its effect in the brain is limited to particular areas such as hippocampus and prefrontal cortex which play important roles in cognitive functions such as memory and decision-making. Therefore, the presence of oestrogen may provide a neuroprotective effect on certain neurons which allows these cells to more likely survive extreme negative conditions such as those seen with  hypoxia, oxidative stress and exposure to neurotoxins. This of course naturally translates then into positive changes on cognitive functions so that oestrogen is said to have a protective effect against certain mental illnesses such as multiple sclerosis, Parkinson`s disease and dementia. It is then understandable that conditions where there is an absence of oestrogen or where levels are low such as the menopause lead to minor effects on cognitive performance. However, the effect could be also attributed to normal ageing processes being experienced at that time. The association between menopause and Alzheimer illness, although symptoms appear similar, is likely to be indirect with general ageing, certain conditions such as stroke and lifestyle changes being the main causes of the appearance of the disease. Therefore, it is understandable that boosting the level of oestrogen when it is naturally falling can provide some positive effect on certain cognitive functions, but only temporarily. Probably of more benefit to women experiencing the menopause is the continuation and maintenance of good life style practices.

Since we`re talking about the topic………..

…..if synaptic firing is enhanced by the presence of oestrogen because of the inhibition of hippocampal interneurons can we assume that the administration of a GABA antagonist preferably targeted to the hippocampal area simultaneously with the administration of oestrogen to ovariectomised mice will block this positive effect? Would the expected behavioural changes relating to restored spatial memory also be absent?

…..using real-time functional MRI would it be possible to chart connectivity between certain brain areas eg. hippocampus, amygdala and prefrontal cortex during the course of a problem-solving type task using menopausal subjects and to monitor the effects that the administration of either oestrogen or progesterone pre-testing would make on those connectivity patterns?

…..performance of place recognition tasks was found to be reduced in female rats who were in the proestrus (high oestrogen) phase of their oestrous cycle. An excessive consumption of sugar sweetened drinks daily beginning 14 days before testing was found to protect the rats from this negative change. This was attributed to the sugar consumption causing functional changes in the hippocampus. Object recognition appeared not to be effected. Can we assume that the same pattern of results would be unlikely to be observed with human females because of the effect of insulin, but may produce a problem in those that suffer from diabetes?

Advertisements
This entry was posted in Alzheimer disease, glucose, menopause, neuronal firing, oestrogen, Uncategorized and tagged , , , , . Bookmark the permalink.