Abstract/Summary
Resveratrol, mostly known to be found in red grape wines, has been linked to prevent or slow aging whilst having an interaction with sirtuins. It has also been found to have a similar effect as a caloric restrictor ultimately extending lifespan. Research using resveratrol has been tested on mice models, and humans. Similarly, etazolate has been found to have a positive effect on patients with Alzheimer’s. Although, previous findings have explored the effect of resveratrol on AD patients, many of these research studies do not include Down Syndrome patients with AD. Currently, there is limiting information on Down Syndrome patients suffering from AD and the effects of many other FDA approved drugs. As known, DS patients have a greater risk and predisposition to AD respectively due to the extra chromosome 21, which means DS patients carry an extra gene that could enhance their predisposition to AD. The following proposal will explore the effects of resveratrol and etazolate on DS/AD mice. The possible outcomes could show either an improvement on spatial and non-spatial memory conducted by a Water T-maze and a passive avoidance test, respectively. The medication would be tested on DS mice with an early onset and late onset of AD. Future experimentations should provide insight on Alzheimer’s treatments for the Down Syndrome community, also resulting in better treatment and care for these individuals. Also other polyphenols should be explored found in plants and foods. And improve the dietary supplement to minimize or delay the effects of Alzheimer’s not only in non-down syndrome patients.
Objectives or Specific Aims
As known, Down syndrome patients have a higher risk of developing AD due to the extra chromosome 21.The aim of this study is to observe the effects of a polyphenol (resveratrol), and a current phase IIA trial medication (Yiannopoulou & Papageorgiou, 2013) (Etazolate) on DS/AD mice.
The following research proposal will provide insight to a scarcely explored side of AD. The purpose is to evaluate the effects of resveratrol and etazolate on DS/AD mice This treatment will be observed in DS mice diagnosed with Alzheimer’s disease. This will serve to uncover other AD aspects, and provide better information about the DS community to essentially find better treatments and strategies. Additionally, it will serve to inspire other researchers to explore other polyphenols, and FDA approved drugs and their effects on DS patients diagnosed with Alzheimer’s Disease. Researchers would then be able to brainstorm a possible dietary supplement or diet that could minimize various AD aspects seen in an advanced progression of AD.
Introduction and background
Alzheimer’s Disease:
Alzheimer’s Disease has been categorized as an incurable disease that scientists have had difficulty finding treatments that do not only delay but minimize many of its hallmarks. The most prominent hallmarks are the tau phosphorylation and amyloid beta accumulation in the brain. Other less mentioned ones are the accumulation of activated microglia (Naert & Rivest, 2011), and astrocytes around the Ab plaques. Many drugs have been tested on clinical trials but none can eliminate in its entirety the plaques found in the brain. However, we have a fair amount that can minimize or delay some of these hallmarks.
Alzheimer’s Disease on Down Syndrome patients:
An association dedicated to fight dementia, Alzheimer’s Society reveals that little research has been done on drug and non-drug treatments on people who also have Down’s syndrome. Many of the non-drug treatments that include music therapy and environmental therapies did not include patients with this condition (Watchman, 2017). It is important to note that studies of Alzheimer’s Disease on Down Syndrome patients can help in better treatments and strategies to treat the disease for a better health status that could expand the lives of those already experiencing Alzheimer’s disease. In recent times, researchers have delved into this branch of AD but the information is still very limiting. A clinical longitudinal study that ended in 1989 is the one of the few observational study that has been done (Lai & Williams, 1989). Since then thus not providing enough information about the present population of Down’s syndrome patients with AD, especially since new technology and treatments have been discovered for regular AD patients but not tested on DS patients with AD. Studying AD in DS might help uncover new links and strategies for AD people without DS.
Resveratrol:
Various studies on resveratrol, found in plants, have shown neuroprotective action as well as a significant improvement in efficiency and proliferation of neural progenitor cells in Down Syndrome (DS) patients (Valenti, 2016). Even though the effects were studied on the overall realm of Down syndrome, it does not specifically address the effects of resveratrol on Down syndrome patients with diagnosed Alzheimer’s Disease.
Etazolate:
Etazolate has shown that it can inhibit Aβ-induced neuronal death on patients with mild to moderate AD. It was also shown that patients show a high tolerability and the efficacy is positive over time (Yiannopoulou & Papageorgiou, 2013).
Hypothesis:
→ DS/AD mice treated with resveratrol will show little improvement for both early and late onset groups.
→ DS/AD mice treated with etazolate will show a more significant improvement for both early and late onset groups.
C. Experimental design and Methods
Transgenic Mice (Ts65Dn + APPSwe/PS1)
Ts65Dn mice are for the most part used as a model for Down Syndrome. These mice contain an extra chromosome 17 with a small distal end segment from chromosome 16. This segment is homologue to the chromosome 21 in humans (Jackson Laboratory, 2018).
In order to obtain Ts65Dn mice, females that carried the 1716 chromosome mated with mice of the C3H background [(C57BL/6JEi x C3H/HeJ)F1(JAX#JR1875)] (Kleschevnikov, et al 2004). APPSwe mice (C3H/HeJ × C57BL/6J) males mated PS1 (C3H/HeJ × C57BL/6 F3) female mice to create APPSwe /PS1 mice (Salehi, 2006).The males are then used to mate with (B6EiC3H-a/A-Ts65Dn) females to create a DS mice (with APPSwe/PS1).
There will be a total of 6 groups observed. The control groups would be regular mice with an early onset AD and a late onset AD. The experimental groups would be Down syndrome mice with APPSwe /PS1 (human beta precursor protein and presenilin 1) and the other will not have these factors but will be DS mice with mice AD.
Administration of Drugs
Table 2: Drugs, dose, and type of drug
The administration quantities for both drugs were determined based on other research studies (Siopi, 2013), (Valenti, 2016), (Yiannopoulou, 2013) that have tested the effects on other mice models for AD and DS separately. It is important to note none of these studies explored its effect on DS mice with human beta precursor protein and presenilin 1 together. Resveratrol will be mixed in their meals, while Etazolate will be administered peritoneally (Siopi, 2013).
Improvement Observation through Water T-Maze and Passive Avoidance Test
These two tests will be used to observe the mice’s spatial and non-spatial memory improvement or deterioration under the treatment period. The same methods provided by Naert & Riest (2011) on both tests will be followed.
Expected results and possible interpretations
Mouse Models
Subgroups
Expected Results (Resveratrol)
Expected Results (Etazolate)
The expected results will show a greater effect of both drugs on DS mice with APPSwe/PS1 during an early onset compared to the late onset group. This will probably because the amount provided daily was probably too low for an advanced progression of AD. Thus for future examination a larger dose might be needed. Etazolate overall has a significantly greater effect almost in all groups but for the late onset, the dose should be modified for future examination.
Water T-maze
DS mice (with APPSwe /PS1) will show improvement in their spatial memory significantly higher in the early onset group under both resveratrol and etazolate compared to the late onset as the duration of the treatment increases.
DS mice (without APPSwe /PS1) will also show improvement in their spatial memory significantly higher in the early onset group under both resveratrol and etazolate.
The non-DS mice with AD will have the greatest peak increase in improvement compared to the rest of mice models.
Passive Avoidance Test
DS mice (with APPSwe /PS1) will show improvement in their non- spatial memory significantly higher in the early onset group under both resveratrol and etazolate compared to the late onset as the duration of the treatment increases.
DS mice (without APPSwe /PS1) will also show improvement in their non-spatial memory significantly higher in the early onset group under both resveratrol and etazolate. However, the late onset group will need a higher dose.
The non-DS mice with AD will have the greatest peak increase in improvement compared to the rest of mice models.
Discussion
During the water t-maze test, DS+AD will show improvement significantly higher in the early onset group under both resveratrol and etazolate compared to the late onset. During the non-spatial memory test, DS mice (with APPSwe /PS1) will show improvement significantly higher in the early onset group under both resveratrol and etazolate compared to the late onset over time. However, the results will not be similar to the AD-only control group. These findings could potentially show that more studies should be done with DS+AD patients.
Resveratrol is used mostly in supplementary diets which could explain the low improvement change between the DS+AD and the DS mice, because it is not used as treatment on its own (Aschemann-Witzel & Grunert, 2015). The improvement seen however could serve as a supplementary dosage safe for everyday use to hopefully in the long-term diminish the AD development in DS patients. On the other hand, etazolate, will have a higher improvement compared to resveratrol since etazolate is an FDA drug known as a inhibitor of neuronal death (Yiannopoulou & Papageorgiou, 2013). However, when the etazolate DS+AD, and DS mice are compared to regular AD mice, etazolate will have a even greater positive effect on AD-only mice. This also shows that there is lack of information on FDA approved drugs for DS individuals. Overall, these findings could improve the current therapeutic approach for DS patients with AD symptoms, and serve to inspire more researchers to investigate other current FDA approved medications known to ameliorate patients with AD (only) and expand into the DS+AD community.