A New Approach Towards the Treatment of Alzheimer's Disease
9 May, 2007 01:09 pm
Alzheimer's disease (AD) is a progressive neurological disorder that slowly attacks and purloins the minds of its victims. It is the most common of all neurodegenerative disorders, with approximately 25 million people worldwide suffering from this devastating disease. One of the main risk factors of AD is increased age. As life expectancies continue to rise, AD is becoming tragically common. It is estimated that the number of people afflicted with AD will triple by the year 2050 and cause a huge economical and emotional burden to our societies. Despite intensive studies, effective therapies still await discovery. Particularly therapeutic strategies that would regenerate the neuronal network and recover the ability for learning and memory are of utmost importance because brain atrophy is a very early event in AD pathogenesis and the majority of patients are only diagnosed when substantial brain damage has already occurred.
In our recent work we used a mouse model in that we could induce Alzheimer’s like brain damage in aged mice. Those mice display the main hallmarks of Alzheimer’ s disease including severe learning impairment. It is however important to note that although the term “learning & memory is often used as a single phrase, AD patients show impairments that draw a distinction between learning and memory. With other words, the impairment of learning is only one aspect in demented patients. Equally important is the fact that these patients also suffer from the inability to remember important life events and sometimes cannot even recognize close relatives or other attributes of long-term memory. The latter aspect has barely been explored in preclinical research. Taken advantage of our inducible “Alzheimer mice” we were able to investigate the loss of long-term memories. In brief, mice were trained to learn certain tasks such as to associate a certain room with an aversive experience or to find a hidden platform in a water pool and allowed to form a long-term memory. Only afterwards neurodegeneration was induced. We found that when 25-30% of the forebrain neurons were lost mice could not remember the task they had previously learned when they were young. Hence, we had established a model to investigate learning impairment but also “real” memory loss.
We then showed that improving the function of the remaining neuron in the degenerated brain restored the learning ability but most remarkably also re-established the access to formerly “lost” memories. We therefore conclude that even in demented patients memories are not necessarily lost but rather become inaccessible. This is in line with observations that even patients suffering from severe dementia eventually experience short episodes of apparent clarity, a phenomenon termed “fluctuating memories”.
We achieved the functional improvement of the remaining neuronal network by housing the mice in an “enriched environment”. To this end the mice were exposed to a number of toys that were changed on a daily basis and had to perform certain tasks along with the chance to exercise. That a combination of mental and physical exercise improves cognitive function in healthy rodents but also in humans is known for a long time and was first described by the neuro-scientific pioneer Donald Hebb in 1947, when he realized that the rats he brought home to play with his kids were always much smarter in various learning tasks that rats that lived in his laboratory. It is nowadays also well established that “enrichment” induces the formation of new connection among neurons. Our data however shows that “enrichment strategies” could be very beneficial to treat learning impairment and also memory loss.
One drawback is that virtually nothing is known about the molecular mechanisms underlying enrichment, making it difficult to develop pharmacological approaches based on the “enrichment effect”.
To this end we found that the enrichment affects the DNA structure in the nucleus. The DNA is wrapped around a protein complex. Whether or not the DNA is “active”, with other words allows the expression of genes, is tightly regulated by modifications of this DNA-protein complex. Enrichment specifically modified the structure of this complex. Importantly we were able to recapitulate the “enrichment effect” by using histone-deacetylase (HDAC) inhibitors. HDACs are proteins that affect the DNA structure and regulate gene expression. Remarkably treatment of our “Alzheimer mice” with HDAC inhibitors reinstated learning and also lead to the recovery of long-term memories.
This is particularly exciting because some HDAC inhibitors are already approved or used in clinical trials to treat various forms of cancer or depression. Although we do not know whether the commonly available HDAC inhibitors are suitable to treat Alzheimer patients we hope that our findings will translate into therapeutic strategies rather soon.
In summary our data raised hope for patients that suffer from cognitive impairment even after substantial neuronal loss has already occurred.
1: European Neuroscience Institute (ENI), Medical School University Goettingen, Max Planck Society, Germany
2: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Howard Hughes Medical Institute ,Cambridge, MA, USA
Fischer A., et al, Recovery of learning and memory is associated with chromatin remodeling, Nature advance online publication, 29 April 2007