Drug Corrects Brain Abnormalities in Mice With Down Syndrome


Down syndrome (DS) results when human babies have three copies of chromosome 21 rather than the normal two copies. However, three copies of pieces of chromosome 21 can also cause DS, and the region of chromosome 21 called the “Down Syndrome Critical Region” can also cause the symptoms of DS. The Down Syndrome Critical Region is located 21q21–21q22.3. Within this region are several genes, that, when present in three copies, seem to be responsible for the symptoms of DS. These genes are APP or amyloid beta4 precursor protein, SOD1 or Superoxide dismutase, DYRK or Tyrosine Phosphorylation-Regulated Kinase 1A, IFNAR or Interferon, Alpha, Beta, and Omega, Receptor, DSCR1 or the Down Syndrome Critical Region Gene 1 (some sort of signaling protein), COL6A1 or Collagen, type I, alpha 1, ETS2 or Avian Erythroblastosis Virus E26 Oncogene Homolog 2, and CRYAz or alpha crystalline (a protein that makes the lens of the eye).

All of these genes have been studied in laboratory animals, and the overproduction of each one of them can produce some of the symptoms of DS. For example, APP overproduction in mice leads to the death of neurons in the brain and inadequate transport of growth factors in the brain (see A.Salehi et al., Neuron, July 6, 2006; and S.G. Dorsey et al., Neuron, July 6, 2006). Also, the overexpression of CRYA1 seems to cause the increased propensity of DS patients to suffer from cataracts. Likewise, overexpression of ETS2 leads to the head and facial abnormalities in mice that are normally seen in human DS patients (Sumarsono SH, et al. (1996). Nature 379 (6565): 534–537).

People can also have only portions of the DS Critical Region triplicated and this leads to graded types of DS that only have some but not all of the symptoms of DS.

Why all this introduction to DS? It is among the most frequent genetic causes of intellectual disability. Therefore, finding a way to improve the cognitive abilities of DS patients is a major goal. T

There is a mouse strain called Ts65Dn mice that recapitulates some major brain structural and behavioral symptoms of DS and these include reduced size and cellularity of the cerebellum and learning deficits associated with the hippocampus.

Roger Reeves at Johns Hopkins University has used a drug that activates the hedgehog signaling pathway to reverse the brain deficits of Ts65Dn mice. Yes you read that right.

A single treatment given the newborn mice of the Sonic hedgehog pathway agonist SAG 1.1 (SAG) results in normal cerebellar morphology in adults.

cerebellum

But wait, there’s more. SAG treatment at birth also improved the hippocampal structure and function. The hippocampus is involved in learning and memory.

hippocampus

SAG treatment resulted in behavioral improvements and normalized performance in a test called the “Morris water maze task for learning and memory. The Morris water maze test essentially takes a mouse from a platform in shallow water and then moves the mouse through the maze and then leave it there. The mouse has to remember how they got there and retrace their steps to get back to the platform before they get too tired from all that swimming. Normally Ts65Dn mice do very poorly at this test. However, after treating newborn Ts65Dn mice with SAG, they improved their ability to find their way back.

SAG treatment also produced other effects in the brain. For example, the ratios of different types of receptors in the brain associated with memory are skewed in Ts65Dn mice, but after treatment with SAG, these ratios became far more normal. Also, the physiology of learning and memory was also more normal in the brains of SAG-treated Ts65Dn mice.

These results are extremely exciting. They confirm an important role for the hedgehog pathway in cerebellar development. Also, they suggest that the development of the cerebellum (a small lobe at the back of the brain involved in coordination and fine motor skills, direct influences the development of the hippocampus. These results also suggest that it might be possible to provide a viable therapeutic intervention to improve cognitive function for DS patients.

This excitement must be tempered. This is an animal model and not a perfect animal model. Also, it is unclear if such a compound will work in humans. Much more work must be done, but this is a fascinating start.

Why Do Some People Get Alzheimer’s Disease but Others Do Not?


Everyone has a brain that has the tools to develop Alzheimer’s disease. Why therefore do some people develop Alzheimer’s disease (AD) while others do not? An estimated five million Americans have AD – a number projected to triple by 2050– the vast majority of people do not and will not develop the devastating neurological condition. What is the difference between those whole develop AD and those who do not?

Subhojit Roy, associate professor in the Departments of Pathology and Neurosciences at the University of California, San Diego School of Medicine, asked this exact question. In a paper published in the journal Neuron, Roy and colleagues offer an explanation for this question. As it turns out, in most people there is a critical separation between a protein and an enzyme that, when combined, trigger the progressive cell degeneration and death characteristic of AD.

“It’s like physically separating gunpowder and match so that the inevitable explosion is avoided,” says principal investigator Roy, a cell biologist and neuropathologist in the Shiley-Marcos Alzheimer’s Disease Research Center at UC San Diego. “Knowing how the gunpowder and match are separated may give us new insights into possibly stopping the disease.”

Neurologists measure the severity of AD by the loss of functioning neurons. In terms of pathology, there are two tell-tale signs of AD: a) clumps of a protein called beta-amyloid “plaques” that accumulate outside neurons and, b) threads or “tangles” of ‘tau” protein found inside neurons. Most neuroscientists believe AD is caused by the accumulation of aggregates of beta-amyloid protein, which triggers a sequence of events that leads to impaired cell function and death. This so-called “amyloid cascade hypothesis” puts beta-amyloid protein at the center of AD pathology.

Creating beta-amyloid requires the convergence of a protein called amyloid precursor protein (APP) and an enzyme that cleaves APP into smaller toxic fragments called beta-secretase or BACE.

“Both of these proteins are highly expressed in the brain,” says Roy, “and if they were allowed to combine continuously, we would all have AD.”

It sounds inexorable, but it doesn’t always happen. Using cultured hippocampal neurons and tissue from human and mouse brains, Roy and Utpal Das, a postdoctoral fellow in Roy’s lab who was the first author of this paper, and other colleagues, discovered that healthy brain cells largely segregate APP and BACE-1 into distinct compartments as soon as they are manufactured, which ensures that these two proteins do not have much contact with each other.

“Nature seems to have come up with an interesting trick to separate co-conspirators,” says Roy.

What then brings APP and BACE together? Roy and his team found that those conditions that promote greater production of beta-amyloid protein also increase the convergence of APP and BACE. Specifically, an increase in neuronal electrical activity, which is known to increase the production of beta-amyloid, also increased the convergence of APP and BACE. Post-mortem examinations of AD patients have shown that the cellular locations of APP and BACE overlap, which lends credence to the pathophysiological significance of this phenomenon in human disease.

Neurons were cotransfected with APP:GFP and BACE-1:mCherry, neurons were stimulated with glycine or picrotoxin (PTX), and the colocalization of APP and BACE-1 fluorescence was analyzed (see Experimental Procedures for more details). (B) Note that stimulation with glycine greatly increased APP/BACE-1 colocalization in dendrites (overlaid images on right). (C and D) Quantification of APP/BACE-1 colocalization. Note that increases in glycine-induced APP/BACE-1 convergence can
Neurons were cotransfected with APP:GFP and BACE-1:mCherry, neurons were stimulated with glycine or
picrotoxin (PTX), and the colocalization of APP and BACE-1 fluorescence was analyzed (see Experimental Procedures for more details).
(B) Note that stimulation with glycine greatly increased APP/BACE-1 colocalization in dendrites (overlaid images on right).
(C and D) Quantification of APP/BACE-1 colocalization. Note that increases in glycine-induced APP/BACE-1 convergence can

Das says that their findings are fundamentally important because they elucidate some of the earliest molecular events triggering AD and show how a healthy brain naturally avoids them. In clinical terms, they point to a possible new avenue for ultimately treating or even preventing the disease.

“An exciting aspect is that we can perhaps screen for molecules that can physically keep APP and BACE-1 apart,” says Das. “It’s a somewhat unconventional approach.”