The role of glial cells in Parkinson's Disease

The glial reaction is generally considered to be a consequence of neuronal death in neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and Parkinson's disease. In Parkinson's disease, postmortem examination reveals a loss of dopaminergic neurons in the substantia nigra associated with a massive astrogliosis and the presence of activated microglial cells. Recent evidence suggests that the disease may progress even when the initial cause of neuronal degeneration has disappeared, suggesting that toxic substances released by the glial cells may be involved in the propagation and perpetuation of neuronal degeneration. Glial cells can release deleterious compounds such as proinflammatory cytokines (TNF-α, Il-1β, IFN-γ), which may act by stimulating nitric oxide production in glial cells, or which may exert a more direct deleterious effect on dopaminergic neurons by activating receptors that contain intracytoplasmic death domains involved in apoptosis. In line with this possibility, an activation of proteases such as caspase-3 and caspase-8, which are known effectors of apoptosis, has been reported in Parkinson's disease. Yet, caspase inhibitors or invalidation of TNF-α receptors does not protect dopaminergic neurons against degeneration in experimental models of the disease, suggesting that manipulation of a single signaling pathway may not be sufficient to protect dopaminergic neurons. In contrast, the antiinflammatory drugs pioglitazone, a PPAR-γ agonist, and the tetracycline derivative minocycline have been shown to reduce glial activation and protect the substantia nigra in an animal model of the disease. Inhibition of the glial reaction and the inflammatory processes may thus represent a therapeutic target to reduce neuronal degeneration in Parkinson's disease.

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AD-Cholesterol Connection

As I had mentioned in class, there has been an establishment of cholesterol as a risk factor in the pathogenesis of Alzheimer’s disease (AD). This is a major focus of current research for AD. I came across a review article from PubMed titled, Alzheimer’s disease: the cholesterol connection, and found that in the past few years, this link has been supported through genetic, epidemiological and biochemical data. The review was from Harvard Medical School’s Neurobiology of Disease Laboratory and Genetics and Aging Research Unit.

In all forms of Alzheimer’s disease (AD) there is an abnormal accumulation of the beta-amyloid protein in specific brain regions, which is regulation by cholesterol. It was found that elevated levels of cholesterol increase the beta-amyloid protein in cellular and most animal models of AD, and that drugs that inhibit cholesterol synthesis lower the beta-amyloid levels. Recent studies have shown that the total amount and distribution of cholesterol within neurons impact the beta-amyloid biogenesis. I mentioned in class the role of the apolipoprotien E gene, the identification of a variant of this gene as a major genetic risk factor for AD is consistent with a role for cholesterol in the pathogenesis of AD.

The review describes its recent findings concerning the molecular mechanisms underlying the cholesterol-AD connection. Drugs that lower cholesterol levels are currently being considered and tested as potential therapies for the treatment of AD. Statins, which are relatively safe and have been used for a long time against high cholesterol levels, are now being directly tested in clinical trials for efficacy against AD. Some of the potentially beneficial effects of statins might also represent improved cardiovascular health, resulting in a reduction in ischemic events that are also considered risk factors for AD. An effective therapy for patients whose cognitive function does not benefit from statin treatment may ultimately consist of a combination of lipid regulating products, perhaps in combination with statins. Alternative products for cholesterol management so far include extended-release niacin, cholesterol absorption inhibitiors, ACAT inhibitors and cholesteryl ester transfer protein (CETP) inhibitors. Results from in vitro studies suggest that ACAT inhibitors are good candidates for regulating beta-amyloid biogenesis, but more research is needed to understand the exact molecular mechanisms underlying the AD-cholesterol connection. Also, it is necessary to gain an in-depth understanding of brain cholesterol metabolism. With new technology that is developing, we may be able clarify how plasma and brain cholesterol contribute to AD.

Full PDF text found at EBSCHOhost:
Title: Alzheimer's disease: the cholesterol connection.
Author: Puglielli, Luigi; Tanzi, Rudolph E.; Kovacs, Dora M.;http://web.ebscohost.com/ehost/pdfviewer/pdfviewer?vid=2&hid=106&sid=86523406-21ed-4ee6-8f03-87d50b8af3df%40sessionmgr110

Sunlight (UV) and Multiple Sclerosis?

As I mentioned in class, the 2010 CDC study found a correlation between areas of highest MS prevalence and greater UV exposure. I've chosen to explore this idea and I've found an article which I've referenced below which discusses an exploration of this trend:

For some time now, the observation that MS prevalence increases with latitude, meaning the further from the equator one gets, the higher likelihood of MS in the environment. Researchers in this article therefore look at Vitamin D and how its levels may in these different latitudes may help explain the differences in prevalence.

The article notes that 400,000 people in the U.S. have MS, of nearly 309, 055, 803 people in the U.S. (U.S. Census Bureau). UV exposure, as well as vitamin D levels can effect immune responses, but the question which arises is whether immunoregulation is done via UV exposure, or indirectly via vitamin D levels, or the two? As referenced in the article, research somewhere (not cited) has shown that increased levels of the active form of vitamin D can "block" the disease in animals.

The experiment uses mice which are genetically predisposed to an MS-like disease state, and the mice are injected with nerve antigen to initiate the disease. After initiation, one group of animals were exposed to "moderate" UV strength (equal to 2 hours of direct summer sun) for one week and the other group was irradiated every 2nd or 3rd day. They found that the exposure reduced the expression of symptoms for MS, but not the prevalence, especially in those mice irradiated every other day. The researchers also deduced that although vitamin D levels were increased with UV exposure, that factor alone could not explain the results.

The groups next area of study is to see what role skin may play with UV exposure to the production and expression of compounds involved in inflammation and the inflammatory response. The article identifies two possibilities of usefulness:

1. In the short term, if they can identify the specific active wavelength at which these same results can be obtained, this can be used as a therapy for those people suffering from MS.

2. In a more long term goal, if the group can discover the compound or compounds that the skin may be producing, the may be able to isolate or synthesize the compound and market a drug treatment.

The group does caution that this information is in the early experimental stages of development, and that results of a similar treatment may not lead to intentions.

Article

Food Allergies linked to RA???

In class we discussed the possibility (mentioned in one of our lay articles) that RA may be linked to an "allergic" type of response to certain foods.

I did a little bit of research on the subject and found an article that suggests that RA symptoms may be caused by an "allergic" immune response to foods such as milk and other dairy products. The basic premise of the study the article mentions is that your body may produce antibodies to certain foods. These antibodies form immune complexes in your intestines and from there, these complexes can travel throughout your body and become inflammatory mediators.

This article mentions a study done by an individual doctor who noticed that up to a third of his RA patients felt improvement in their symptoms when they eliminated most allergy-causing foods and reverted to a basic "Stone Age" diet of fruits, vegetables, fish, and plain meat.

Here is a link to the article :http://www.arthritistoday.org/conditions/rheumatoid-arthritis/healthy-living/ra-food-allergies-2.php

Neurodegenerative Disease

This week, we will be discussing inflammation associated with neurodegenerative disease. Neurodegenerative disease is the umbrella term that encompasses diseases that involve progressive dysfunction and loss of neurons in the central nervous system. Some examples of neurodegenerative diseases include Parkinson disease, Alzheimer disease, multiple sclerosis, Huntington's disease, amyotrophic lateral sclerosis or Lou Gherig's disease, and Friedreich's ataxia. These diseases may cause decline of motor functioning and cognitive functioning, and eventually death. The impact of these diseases can be devastating to patients and their family members, not only functionally and emotionally but also economically. Thousands of dollars are spent on medical care provided by physicians, nurses, pharmacists, physical therapists, occupational therapists, speech-language pathologists, dietitians, and social workers. Thousands of dollars are also spent on research focused on preventing or remediating these diseases.

The articles for this week's discussion indicated that, while researchers are making progress toward understanding the mechanisms behind these diseases, effective treatment approaches for these diseases have not yet been discovered. Even when treatment approaches seem to work in the early phases of research, they later prove to be ineffective and even sometimes result in lethal side effects. As economic times become even more challenging, fewer and fewer studies will be approved, and the progress toward finding effective therapeutic approaches will likely be stalled even more.

What are your suggestions for improving the system for research that we have now to facilitate progress toward finding effective treatments for neurodegenerative diseases?

Arthritis and Intereukin 1

One of the presented articles this week compared anti-TNF treatments with anti-IL-1 treatments in the CIA model. The article showed many more benefits when using the anti-IL-1 treatment, but did not have much information regarding human clinical trials. This article was from 1999, so I was very curious to see what some of the current anti-IL-1 treatments were.

I found the review article "Actual status of antiinterleukin-1 therapies in rheumatic diseases," which reviews some of the current clinical options for arthritis and rheumatic diseases. The article summarizes the pathophysiologic role of IL-1 and also goes over the three major types of anti-IL-1 treatments including Anakinra, Canakinumab, and Rilonacept. Anakinra is a treatment which prevents the binding of IL-1 by occupying the IL-1 receptors. Canakinumab is a fully human monoclonal anti-IL-1 beta antibody, which works by binding and neutralizing IL-1 beta. This was recently granted orphan drug status in Europe and the United States for the treatment of systemic juvenile idiopathic arthritis. Rilonacept is a dimeric fusion protein that consist of the ligand-binding domain of IL-1RI and its accessory protein, which is designed to bind and neutralize circulating IL-1.

Many of the studies have so far concluded short-term benefits in terms of biochemical markers, joint damage, and inflammation, but data for long-term use is still being collected. The advancement of these types of treatments in the past decade has really helped fight arthritis by increasing therapeutic options, but continued observation for long-term effects and further advancement is still necessary.

The full article and description of the reviewed studies can be found here:

http://www.ncbi.nlm.nih.gov.ezproxy2.library.arizona.edu/pubmed/20150813