DNALC Blogs » neurodegenerative diseases

Trying to unlock a new door…..

Jermel Watkins — Mon, 28 Nov 2011 21:59:10 +0000

How is drug development moving along? Well, this is a very good question for we are still plagued by some elusive diseases, cancer for example. There have been many drugs developed targeting proteins involved in disease states some of which have proven to be quite effective. However today the steam engine for identifying drug targets to proteins involved in disease is becoming ever more difficult.
Apparently over the past decade or so, the number of new drugs targeted toward disease has declined. This is primarily due to the fact that developing new medicine has become more difficult to do. It turns out that this is partly because we have sifted through all the ideal proteins that can be targeted by a drug. The remaining proteins are not ideal for developing a targeted drug. These proteins dawn small cavities or binding pockets and are relatively flat allowing for little to no interaction with a drug target. Its been said that 15% of proteins can be targeted by drugs. The percent of proteins that modify disease is 10 to 15 %. In order to alleviate this problem scientist have acquired the help of computer modeling to more thoroughly identify and test favorable small molecules that can block the activity of these undruggable protein populations related to disease. Dr. Stockwell an Associate professor at Columbia University, has attempted computer modeling and has come across compounds to target a class of E3 ligases, which are characteristically undruggable, and involved in just about every disease. Of these compounds one in particularly was a potent inhibitor. Dr. Stockwell will be publishing his findings in the next few months on the efficacy of the inhibitor. If it proves worthy this new drug will have an impact on cancer and neurodegenerative disease.

Will insulin come to the rescue of AD patients?

Jermel Watkins — Tue, 27 Sep 2011 13:20:34 +0000

Alzheimer disease (AD) is a neurodegenerative disease of the brain that is divided into early- and late-onset groups. AD is characterized by the build up of amyloid plaques, neurofibrillary tangles and the loss of connections between neurons. It is the most common type of dementia especially in the elderly. The exact causes of AD are elusive at the moment but are most likely the result of genetics and other factors. Scientist have been working hard to identify individual and or groups of genes responsible for the disease. Although the scientific community has identified may genes involved in early and late onset groups, a new discovery has shed some light on the subject. In the intimate interplay of activities within the cells of the brain scientists have identified a key player, insulin. It is thought that dysfunction of insulin plays a crucial part in the exacerbation of symptoms.

The regions of the brain such as the hippocampus and the frontal cortex are densely populated with insulin receptors. As well they are found in synapses in which insulin signaling participates in synaptic remodeling and synaptogenesis (1,2). In parallel insulin regulatesthe utilization of glucose in the hippocampus and other regions of the brain to promote optimal memory in normal metabolism (3). In AD, it has been shown that reduced levels of insulin and insulin activity exist (4,5). Interestingly insulin has a tight relationship to amyloid beta, a toxic peptide responsible for the onset of the disease. Insulin can regulate the levels of amyloid beta to deliver protection from the degenerative nature of the peptide on neurons (6-8).

A pilot clinical trial published in the archives of neurology titled, Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment, has shown insulin’ ability to be a protective new therapy in the fight against AD. The trial hosted 104 participants, of which 30 participated in the use of a placebo, while insulin at 20IU and 40IU were delivered to 36 and 38 participants respectively. The insulin was administered through a nasal drug delivery device for a total of 4 months. Surprisingly the 20IU and 40IU group experienced improved memory recall and preserved general cognition.

It was very important to identify a method of administration of insulin properly and direct to the brain without disrupting blood sugar levels. When taken as a nasal spray it reaches the brain in just a few minutes with no apparent adverse affects on the body. Although a very promising study, it is still a preliminary study, more research will have to be carried out to ensure the safety and effectiveness of insulin as a therapy for longterm use against AD.

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Zhao WQ, Townsend M. Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer’s disease. Biochim Biophys Acta. 2009;1792(5):482-496. PUBMED
McNay EC, Ong CT, McCrimmon RJ, Cresswell J, Bogan JS, Sherwin RS. Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance. Neurobiol Learn Mem. 2010;93(4):546-553. PUBMED
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Steen E, Terry BM, Rivera EJ; et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease—is this type 3 diabetes? J Alzheimers Dis. 2005;7(1):63-80. PUBMED
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Gasparini L, Gouras GK, Wang R; et al. Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci. 2001;21(8):2561-2570. FREE FULL TEXT
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RBD and Neurodegeneration

Jennifer Aiello — Thu, 02 Sep 2010 12:59:20 +0000

In an earlier post I blogged about the nature of dreams including phases of sleep and why we dream. In the blog I had mentioned a sleep disorder known as REM sleep behavior disorder (or RBD). It’s a mysterious sleep disturbance where the normal atonia (muscle paralysis) during sleep malfunctions, and the dreamer is left to act out their dreams. Those with this disorder (predominantly male) tend to have dreams that are increasingly violent and involve fighting off an attacker. In their sleep, these people act out every punch, kick, twist and scream with their sleeping bodies, often times injuring the person sharing the bed with them.

This disorder was thought to be an isolated condition, but doctors conducting follow-up studies on diagnosed patients are starting to rethink that. Anywhere from 80 to 100 percent of these RBD patients later develop neurodegenerative diseases such as Parkinson’s disease.

Doctors studying their patients conclude that there is a minimum of a 15 year difference between the onset of RBD and the onset of a neurological disorder. In some patients, the time between onsets was as much as 50 years. However long it is, this sleep disorder seems to prelude the disease by a significant amount of time. Doctors are hoping that this will allow the patient to be treated for a disease before the disease actually manifests. Perhaps one day if there is a neuroprotective treatment available, it can be used to treat these patients before the severe deterioration of their brain.