3.0 Preventing Alzheimer's Disease

Alzheimer's Disease
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Alzheimer's disease (AD) is the only one of the top 10 causes of death in the United States for which concrete strategies of prevention have not been found.[1] By 2050, there are estimated to be 13 million dementia patients in the United States alone.[2] As the most common form of Dementia, it is imperative that possible methods of prevention be found in order to combat this neurodegenerative disease. Several substances have been found to reduce the risk of AD, including Angiotensin II receptor blockers, Vitamin D, and Omega 3 fatty acids. With further research and perhaps application of a combination of these factors, it may be possible to prevent or dramatically reduce the risk of AD.

1.0 Angiotensin II Receptor

Angiotensin II Receptor pathways
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The pathways activated by Angiotensin II receptors AT1 and AT2.
AT1 pathway tends to be damaging while AT2 pathway is neuroprotective. [3]

Angiotensin II is involved in the Renin-Angiotensin System (RAS) pathway, which is involved with hypertension and is now suggested to be involved with AD. Aging is known to be the single greatest risk factor with regards to AD, and in combination with hypertension (RAS pathway), aging increases the harmful effects of hypertension significantly.[4] Angiotensin II is implicated to be involved in the development of several factors that are currently considered the most likely causes of AD. These factors that are influenced by Angiotensin II include, amyloid metabolism, tau phosphorylation, and oxidative stress (especially in vasculature). [5] Alzheimer's Disease hypotheses (For reference to understand the mechanisms through which these prevention methods work.)

The combination of Angiotensin II and age were studied by Csiszar et al., and they showed that Angiotensin II did indeed lead to a significant level of cognitive impairment, especially in aged mice. By inducing hypertension through the infusion of Angiotensin II in young and aged mice, the hypertensive mice performed significantly worse in learning and memory tests such as the Y maze and reaction to novel stimuli. [4]

1.1 AT1 Receptor Blocker

The AT1 receptor is the primary receptor for Angiotensin II.[6] Activation of this receptor leads to a variety of negative effects including a decrease in cerebral blood flow, increased oxidative stress, inflammation of the central nervous system (CNS), and the aging of cells. [6] Several studies have been conducted on blocking AT1 receptor activity either through blocking the receptor directly through Angiotensin II receptor blockers (ARB) or through Angiotensin converting enzyme inhibitors (ACE). In the application of ARBs to mice, it was shown that they had antioxidant effects, which combated the release of reactive oxygen species (ROS) associated with high Angiotensin II levels, and rescued the LTP impairment phenotype induced in mice with Aβ 1-40. [5] Additionally, in mice with induced Aβ plaque deposition through injection of Angiotensin II, showed reduced Aβ oligomerization after the use of ARBs. [5] These studies show that ARBs are effective at preventing AD symptoms that arise as a result of Angiotensin II in mice, therefore with further research this may be one of the most promising methods of preventing AD. Interestingly, ARBs are more effective when used in conjunction with ACEs, however this is not ideal due to a large amount of stress on the kidneys. [5] With further development it maybe possible to use both in conjunction with eachother, with minimal burden on other organs.

1.2 AT2 Receptor Agonist

AT2 receptor agonist C21
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The escape latency (in Morris Water Maze) of mice treated with
C21 and Memantine is significantly lower than control mice and mice
treated with only C21 or Memantine. [7]

Angiotensin II type 2 receptors (AT2) are expressed in both the vasculature and the brain. AT2 have been known to have neuroprotective properties, enhancing learning and preventing cognitive decline through increased cerebral blood flow, increased neuronal differentiation and by preventing the formation of amyloid-β (Aβ) plaques. [7] In fact, mice with a deletion of AT2 receptors show lower cognitive function in comparison to wild type, showing how important this receptor is. [6] In order to increase the neuroprotective properties of AT2 receptors, the application of an AT2 receptor agonist could be used. Currently there is a direct receptor agonist known as Compound 21 (C21), which when administered to mice, led to improvements in learning and a decrease in cognitive impairment when injected with aβ. [7] Iwanami et al.'s lab tested C21 in combination with Memantine, a drug that protects neurons from glutamate damage (elevated levels of glutamate are released in AD patients) in mice. [7] The results showed that these compounds led to increased cerebral blood flow, excitatory post synaptic potential (EPSP), acetylcholine levels, and BDNF expression.[7] All of these factors contribute to preventing cognitive impairment. In addition to all of the beneficial effects, another factor making C21 a good potential candidate is the fact that it can pass through the blood brain barrier and act directly on receptors, making it significantly more convenient to use. [7]

2.0 Vitamin D

Aβ levels in Vitamin D3 deficient and enriched mice.
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Mice are either on a control diet, Vitamin D3
enriched diet (VD) or a Vitamin D3 deficient diet (VDD).
VD mice have a significantly lower number of Aβ aggregates
in comparison to the other groups.[8]

Morris Water Maze escape Latency and Vitamin D3
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The escape latency (in Morris Water Maze) of mice
on either a control diet, Vitamin D3 enriched diet (VD)
or a Vitamin D3 deficient diet (VDD). It is clear that VD
mice have a significantly lower escape latency in comparison
to the other two groups.[8]

Vitamin D is essential to the functioning of the human body, and is naturally produced through the interaction of UV light and skin, which converts 7-DHC to Vitamin D3 through a multi step process. [8] This source alone is not always enough however, and it is possible to supplement the body with dietary Vitamin D3 in the form of 25-hydroxyvitamin D3 [25 (OH)D3] which is then converted to 1,25-dihydroxyvitamin D3 [1,25(OH)2 D3] which is the most active form of vitamin D, and is also known as calcitriol.[8] Ninety percent of the elderly have Vitamin D3 hypovitaminosis, and there is growing evidence linking AD and Vitamin D3 deficiencies. [9]

In a study conducted by Yu et al. mice were fed either a normal diet, Vitamin D deficient diet (VDD) or Vitamin D enriched diet (VD). These mice were then tested with the Morris water maze test and the Vitamin D enriched diet group showed a significantly decreased escape latency in comparison with the control group, which itself showed a decreased latency in comparison to the Vitamin D deficient group who were the slowest. [8]

One of the key mechanisms that Vitamin D3 is proposed to have an effect upon is the formation of Aβ plaques. Studies were conducted by several different groups and all of them arrived at a similar results. One group found that Vitamin D3 deficient mice had significantly higher levels of Aβ plaques in comparison to control, and decreased levels of Neprilysin (NEP) which is a metallo-proteinase that degrades Aβ aggregates. [9] In a continuation of Yu et al's study, they also found that mice with the Vitamin enriched diet had significantly less amyloid plaque formation in comparison to control and vitamin deficient diets. [8] One of the proposed mechanisms for Vitamin D3's effect on Aβ plaques is its regulatory role in Ca2+ homeostasis. Aβ plaques disrupt the Ca2+ homeostasis in the brain which has toxic effects, but this may be regulated by Vitamin D3. [10]) Other suggested mechanisms of Vitamin D3 include the clearance of Aβ plaques by macrophages, inhibition of free radical production, and protection from Aβ induced apoptosis. [11]

3.0 Omega - 3 Fatty Acids

OHDHA induced membrane changes
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The addition OHDHA into the membrane
alters its structure to a liquid disordered state which
is not conducive to Aβ protein binding and oligomerization.
[12]

Aging and AD has been associated with the decline of Omega-3 fatty acid level, specifically docosahexanoic acid (DHA). [12] Studies have found that there is an inverse relationship between the intake of DHA and the incidence of AD. [12] There are several proposed mechanisms by which DHA may act to prevent AD. One way DHA acts is to prevent Aβ synthesis by preventing the cleavage of amyloid precursor protein (APP) by beta and gamma secretases by preventing their co-localization. It also promotes cleavage by alpha secretases which do not form amyloid plaques. [13] DHA has also been shown to increase cerebral blood flow, counteracting the effects of Aβ plaques. (Koivisto et al.) On the other hand, it has also been suggested that DHA changes the composition of the membrane and its fluidity, which promotes the non amyloidal processing of APP and prevents peptide misfolding. [14] The one clear consensus between these studies however, seems to be that it promotes cleavage of APP into a non amyloid form, thus preventing Aβ plaque buildup.

In a study by Torres et al., OHDHA, a modified DHA with a longer half-life, was used and it was shown that Aβ levels were reduced in cell cultures treated with OHDA.[12]This levels of APP were not reduced however, suggesting that the difference was in the processing of the APP. Insertion of OHDHA into the membrane alters the composition into liquid-disordered domains, which is not conducive to Aβ formation and prevents any existing Aβ from oligomerizing. [12]These results were corroborated by another study conducted by Vitiello et al. They used normal DHA however, instead of OHDHA, and investigated the oligomerization of Aβ proteins in 3 membranes of differing compositions. Once again, it was shown that the membranes with higher omega 3 fatty acid content showed lower affinity for Aβ binding and oligomerization. [14] In another study, wild type mice and APP/PS1 transgenic mice were fed control diets and omega 3 rich diets. These mice were then tested for their olfactory response to novel stimuli, the loss of which is a characteristic of AD. It was found that the transgenic mice with the enriched diets showed similar results in response to novel stimuli as wild type control mice, but the transgenic mice on a control diet however showed no preference for the novel stimuli over familiar stimuli. [13]

Because Omega 3 is so readily available in natural food sources such as fish, and also widely available as a nutritional supplement, this makes for an ideal method of preventing AD. There are many studies showing that Omega 3 is effective in preventing AD, and it provides a broad range of health benefits aside from its neuroprotective properties. Therefore Omega 3 poly unsaturated fatty acids are an idea, cheap, and easily attained method of preventing AD.

4.0 Other methods of prevention

4.1 P25 and Fisetin

Fisetin and P25
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Fisetin inhibits the cleavage of P35 to P25. [1]

Fisetin and AD
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Trial results of WT mice, AD transgenic + Fisetin mice,
and AD transgenic mice. [1]

Fisetin is a small, orally administered molecule that has been implicated in preventing the development of learning and memory deficit in double transgenic AD mice.[1] Fisetin was chosen because it acts on many of pathways related to AD at once. It has been shown to promote LTP in an ERK dependant manner, reduce cyclin dependant kinase 5 (Cdk5) activator p25 levels, and reduce neuroinflammation and oxidative stress.[1]

A study was conducted by Currais et al. and it was found that at 9 months, AD transgenic mice fed with Fisetin showed similar performance to wild type mice in a Morris water maze test.[1] The transgenic mice that were not treated with fisetin showed significantly less learning behaviour. Also an elevated plus maze was used to test for social disinhibition (a characteristic of AD). AD mice spent significantly more time in the open arms, indicating disinhibition, in comparison to wild type and Fisetin fed transgenic mice.[1]

The mechanisms behind the marked improvements are not completely clear, but Fisetin is known to act on a variety of factors. Fisetin fed mice showed significantly reduced Aβ 1-40 plaque levels (not Aβ 1-42 levels however).[1] Aβ plaques are one of the most researched topics with regards to causing AD. Also, Fisetin fed mice (both WT and AD transgenic) showed reduced oxidative stress, as determined by protein carbonylation. and increased ERK phosphorylation. [1]

One of the key molecules acted on by Fisetin is the molecule p25 which is the cleavage product of p35.[1] AD patients consistently show elevated p25 levels, thus prompting investigation. Fisetin promotes ERK phosphorylation which in turn promotes p35 expression by preventing its cleavage into p25. The truncated form of p35, p25 causes abnormal Cdk5 activation, leading to neuroinflammation which causes astrogliosis. Fisetin reduced p25 formation and established a better ratio of p35:p25.[1]

After studying all the benefits of taking Fisetin as a method of preventing AD, the safety of the molecule had to be determined. The molecule did not show any toxicity and there were no significant physical differences in the long term health of animals fed with Fisetin,[1] thus with more research it Fisetin could prove to be an effective and safe method of preventing Alzheimer's disease.

4.2 Ca2+ levels

The Ca2+ pathway
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Shows the declining activity levels with age,
and the increasing Ca2+ concentration. Cell death
occurs past a threshold level. [15]

Fluorescent staining of Ca2+
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Bradykinin (Ca2+ agonist) is used to
create a surge in Ca2+ concentration. The older
cells retain Ca2+ for longer as shown by the fluorescnece [15]

CA2+ is needed for cells to respond to stimuli. It regulates neurotransmission and brain function, and proper CA2+ homeostasis is therefore crucial to proper functioning in the brain.[15]

CA2+ concentration are found to be consistently higher in older cells in comparison to younger cells.[15] This led to the theory of "calcium overload". The theory suggests that high concentrations causes hyperactivation of CA2+ dependent enzymes. ie. Calpain. This eventually leads to cell death in AD.[15]

However, in Nguyen et al.'s investigation, Calpain activity was found to be lower in older cells, despite higher [CA2+]. Despite that, dying cells still showed a sharp spike in Calpain activity to 2 - 4 fold normal levels.[15]

Higher CA2+ concentrations in older cells were determined to be unrelated to changes in channel or receptor density, but instead results from inefficient CA2+ processing. An example of inefficient processing is the compromising of extrusion pumps by oxidative stress and energy depletion, which occurs as cells age.[15] Interestingly, this state can be rescued by high energy substances (ie. PEP or PCr) in older cells. This suggests that mitochondrial dysfunction and the subsequent oxidative stress maybe involved.[15]

Overall, it was determined that energy, CA2+ signalling activity and calpain activity all decline with age.[15] These declining factors are likely to play a role in cell death and the triggering of sporadic AD. In order to use this pathway as a target for prevention, one can target the declining energy levels and signalling activity involved in the CA2+ pathway.[15] Not much is known about the precise mechanisms, meaning much more research is needed if this pathway is to be used in the prevention of AD.

Bibliography
1. Currais, A. et al. (2013). Modulation of p25 and inflammatory pathways by fisetin maintains cognitive function in Alzheimer's disease transgenic mice. Aging Cell. pp 1- 12.
2. Qiu, W.Q., et al. (2013). Angiotensin converting enzyme inhibitors and the reduced risk of Alzheimer's disease in the absence of Apoliprotein E4 allele. Journal of Alzheimer's disease, 37, 421-428.
3. Mogi, M., Iwanami, J., Horiuchi, M. (2012). Roles of Brain Angiotensin II in Cognitive Function and Dementia. International Journal of Hypertension. 2012: doi:10.1155/2012/169649
4. Csiszar, A. et al. (2013). Synergistic effects of hypertension and aging on cognitive function and hippocampal expression of genes involved in β-amyloid generation and Alzheimer's disease. AJP Heart, 305, doi:10.1152/ajpheart.00288.2013.
5. Kurinami, H., Shimamura, M., Sato, N., Nakagami, H., Morishita, R. (2013) Do angiotensin receptor blockers protect against Alzheimer's disease? Drugs Aging, 30, 367-372
6. Mogi, M., Iwanami, J., Horiuchi, M. (2012) Roles of brain angiotensin II in cognitive function and dementia. International Journal of Hypertension, 2012, doi:10.1155/2012/169649
7. Iwanami, J., et al. (2013) Possible synergistic effect of direct angiotensin II type 2 receptor stimulation by compound 21 with memantine on prevention of cognitive decline in type 2 diabetic mice. European Journal of Pharmacology, 724, 9-15.
8. Yu, J., Gattoni-Celli, M., Zhu, H., Bhat, N., Sambamurti, K., Gattoni-Celli, S., Kindy, M.S. (2011) Vitamin D3 enriched diet correlates with a decrease of Amyloid plaques in the brain of AβPP transgenic mice. Journal of Alzheimer's Disease, 25, 295-307.
9. Grim, M.O.W., et al. (2013) Impact of Vitamin D on amyloid precursor protein processing and amyloid-β peptide degredation in Alzheimer's disease. Neurodegenerative Diseases, 13, 75-81
10. Dursun, E., Gezen-Ak, D., Yilmazer, S. (2011) A novel perspective for Alzheimer's disease: Vitamin D receptor suppression by amyloid- β and preventing the amyloid- β induced alterations by Vitamin D in cortical neurons. Journal of Alzheimer's Disease, 23, 207-219.
11. Afzal, S., Bojesen, S.E., Nordestgaard, B.G. (2013) Reduced 25-hydroxyvitamin D and risk of Alzheimer's disease and vascular dementia. Alzheimer's and Dementia, 1-7.
12. Torres, M., et al. (2013) Membrane lipid modifications and therapeutic effects mediated by hydroxydocohexaenoic acid on Alzheimer's Disease. Biochimica et Biophysica Acta, http://dx.doi.org/10.1016/j.bbamem.2013.12.016
13. Koivisto, H., et al. (2013) Special lipid-based diets alleviate cognitive deficits in the APPswe/PS1dE9 transgenic mouse model of Alzheimer's disease independent of brain amyloid deposition. Journal of Nutritional Biochemistry, 25, 157-169.
14. Vitiello, G., Marino, S.D., D'Ursi, A.M., D'Errico, G. (2013) Omega-3 fatty acids regulate the interaction of the Alzheimer's Aβ (25-35) peptide with lipid membranes. Langmuir, 29, 14239-14245.
15. Nguyen, H.T., Sawmiller, D.R., Markov, O., Chen, M. (2013) Elevated [Ca2+]i levels occur with decreased calpain activity in aged fibroblasts and their reversal by energy rich compounds: new paradigm for Alzheimer's Disease prevention. Journal of Alzheimer's Disease, 37, 835-848.

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