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Friday, May 30, 2014

New AD Mice Models


Dear Readers,

In a recent study published in Nature Neuroscience, researchers at the Riken Brain Science Institute in Japan have reported after a 12 year effort, the creation of two new mouse models of Alzheimer’s disease that may better mirror the disease in humans.

As readers will recall, many compounds that work in mice have not translated to new drugs in human studies. Some of the difficulty is the inadequacy of current mouse models to replicate the same conditions of Alzheimer's disease that would allow for an understanding of the underlying mechanisms that lead to dementia. Specifically, the current mouse models overproduce the protein amyloid precursor protein, or APP, which gives rise to the amyloid-beta (Abeta) peptides that accumulate in the brain, eventually leading to the neurodegeneration that characterizes Alzheimer's disease. However, in mice the overproduction of APP gives rise to additional effects which are not seen in human Alzheimer's disease.

The mouse model developed (NL-F/NL-F) was ‘knocked in’ with two mutations found in human familial Alzheimer's disease. These mice show early accumulation of beta-amyloid peptides, and importantly, were found to undergo cognitive dysfunction similar to the progression of AD seen in human patients. Inflammation accumulated around the amyloid plaques in the mouse brains as also seen in the brains of people with AD. And looking at the hippocampus, the knock-in mice also lose synapses in the same areas. Beginning at 18 months, NL-F mice also had trouble learning, which is seen in humans after plaques and tangles have developed. A second model, with the addition of a further mutation that had been discovered in a family in Sweden, showed even faster initiation of memory loss which occurs at six months.

These two mouse models represent a heroic effort to more closely model human AD and will undoubtedly help advance our search for early diagnostics and effective treatments.


Thanks for reading,


Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California San Diego
 
Author: Michael Rafii MD, PhD at 8:46 AM 0 Comments

Friday, May 09, 2014

Young Blood and Old Brains


Dear Readers,
In a study published last week in the journal Nature Medicine, researchers at Stanford University School of Medicine looked at changes in the brains of old mice given the blood of young mice. They also compared how the old mice performed on standard tests of memory after they had received infusions of plasma – the cell-free part of blood – from young mice, versus no plasma at all. By transferring young plasma into an old mouse once every three days for three weeks, they found that old mice injected with plasma from young mice outperformed untreated old mice in two separate memory tests. Specifically, after a day of training, the mice treated with plasma from young mice averaged about 25 percent better than those of mice injected with aged plasma. Moreover, the treated mice also showed more neurogenesis (new brain cell production), synaptic density (brain cell communication) and less inflammation.

In a separate study published the same day in the prestigious journal Science, work from the Harvard Stem Cell Institute demonstrated that young blood reinvigorated blood vessels in the brains of old mice. In the treated old mice, the volume of blood vessels in the brain almost doubled. They formed new branches and allowed more blood to flow through them towards various brain regions. This, in turn, led to an increase in the number stem cells in the brain.

From the studies, it appears that young blood contains ‘pro-youthful’ factors that can reverse age related brain impairments while old blood may contain ‘pro-aging’ factors that lead to age-related brain impairment.

Surely, these findings are very exciting and could represent potential targets for intervention with regards to age-related brain disease. Still, much work is needed to understand the factors within plasma that are exerting such changes after transfusion and for how long. It is also important to keep in mind that the studies were conducted in mice, not humans, and that neither study looked at the type of cognitive impairment that is seen in Alzheimer’s disease or in animal models of Alzheimer’s disease. Only through well designed, placebo-controlled clinical trials in humans would the benefits of such treatments be fully understood.




Thanks for reading,


Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California San Diego
 
Author: Michael Rafii MD, PhD at 8:58 AM 0 Comments

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The Alzheimer's Disease Cooperative Study (ADCS) was formed in 1991 as a cooperative agreement between the National Institute on Aging (NIA) and the University of California, San Diego. The ADCS is a major initiative for Alzheimer's disease (AD) clinical studies in the Federal government, addressing treatments for both cognitive and behavioral symptoms. This is part of the NIA Division of Neuroscience's effort to facilitate the discovery, development and testing of new drugs for the treatment of AD and also is part of the Alzheimer's Disease Prevention Initiative.

The ADCS was developed in response to a perceived need to advance research in the development of drugs that might be useful for treating patients with Alzheimer's disease (AD), particularly drugs that might not be developed by industry.