Today I'll point out a few recent examples of research into Alzheimer's disease; they are representative of present shifts in emphasis taking place in the field. There is a great deal of reexamination of existing mechanisms, alongside a search for new mechanisms. This is prompted by the continued failure to obtain meaningful progress towards patient improvement via clearance of amyloid, which some are interpreting as a need to look elsewhere for a viable basis for therapy. I believe it probably has more to do with the condition arising from multiple processes that have similarly sized contributions to cognitive decline: amyloid, tau, immune dysfunction, and vascular aging. Partially address one, and it may be hard to prove that a useful difference was made in patients because the other mechanisms are still present, still causing harm.
The Alzheimer's-related portion of the broader field of aging research represents a sizable fraction of the output of the medical life science community these days. That is because much of the budget of the NIA has for some time been directed towards the study of Alzheimer's disease, and that in turn influences the strategy taken by larger private funding sources and research programs. The grant-seeking portion of the scientific world, which is to say most of it, sedately follows the availability of funds in much the same way as flowers follow the sun. Over time, the funding landscape shapes the endeavor of science just as much as the state of the science shapes availability of funding.
It has often appeared to me somewhat arbitrary as to which aspects of aging are considered an emergency, a priority. The modern public consensus on the need for a massive cancer research institution and a timeline for bringing cancer under medical control is in fact quite modern - it didn't exist much prior to the 1930s. Presentation of the various forms of dementia as a major public concern is a much more recent development. Yet these issues have long existed. We might view it as progress that at least a few pieces of degenerative aging have been pushed over time from the "way things are, cannot be changed" bucket into the "addressable, must fix" bucket. But most people have yet to take the necessary next step, which is to consider aging as a whole a medical condition with clear root causes, a state of ill health that the research community can work towards treating. The dominant conceptual approach of breaking down aging into named diseases has obscured the most important possibility, that aging as a whole can be repaired and reversed.
Although scientists have studied for years what happens when tau forms aggregates inside neurons, it still is not clear why brain cells ultimately die. One thing that scientists have noticed is that neurons affected by tau accumulation also appear to have genomic instability. Previous studies of brain tissues from patients with other neurologic diseases and of animal models have suggested that the neurons not only present with genomic instability, but also with activation of transposable elements.
"Transposable elements are short pieces of DNA that do not seem to contribute to the production of proteins that make cells function. They behave in a way similar to viruses; they can make copies of themselves that are inserted within the genome and this can create mutations that lead to disease. Although most transposable elements are dormant or dysfunctional, some may become active in human brains late in life or in disease. That's what led us to look specifically at Alzheimer's disease and the possible association between tau accumulation and activated transposable elements."
The researchers began their investigations by studying more than 600 human brains. One of the evaluations is the amount of tau accumulation across many brain regions. In addition, researchers comprehensively profiled gene expression in the same brains. The researchers found a strong link between the amount of tau accumulation in neurons and detectable activity of transposable elements. Other research has shown that tau may disrupt the tightly packed architecture of the genome. It is believed that tightly packed DNA limits gene activation, while opening up the DNA may promote it. Keeping the DNA tightly packed may be an important mechanism to suppress the activity of transposable elements that lead to disease.
While the link between amyloid-beta and Alzheimer's disease is well-established, what has baffled researchers to date is how amyloid-beta starts to aggregate in the brain, as it is typically present at very low levels. "The levels of amyloid-beta normally found in the brain are about a thousand times lower than we require to observe it aggregating in the laboratory - so what happens in the brain to make it aggregate?" The researchers found in in vitro studies that the presence of cholesterol in cell membranes can act as a trigger for the aggregation of amyloid-beta.
Since amyloid-beta is normally present in such small quantities in the brain, the molecules don't normally find each other and stick together. Amyloid-beta does attach itself to lipid molecules, however, which are sticky and insoluble. In the case of Alzheimer's disease, the amyloid-beta molecules stick to the lipid cell membranes that contain cholesterol. Once stuck close together on these cell membranes, the amyloid-beta molecules have a greater chance to come into contact with each other and start to aggregate - in fact, the researchers found that cholesterol speeds up the aggregation of amyloid-beta by a factor of 20. "The question for us now is not how to eliminate cholesterol from the brain, but about how to control cholesterol's role in Alzheimer's disease through the regulation of its interaction with amyloid-beta. We're not saying that cholesterol is the only trigger for the aggregation process, but it's certainly one of them."
Since it is insoluble, while travelling towards its destination in lipid membranes, cholesterol is never left around by itself, either in the blood or the brain: it has to be carried around by certain dedicated proteins, such as ApoE, a mutation of which has already been identified as a major risk factor for Alzheimer's disease. As we age, these protein carriers, as well as other proteins that control the balance, or homeostasis, of cholesterol in the brain become less effective. In turn, the homeostasis of amyloid-beta and hundreds of other proteins in the brain is broken. By targeting the newly-identified link between amyloid-beta and cholesterol, it could be possible to design therapeutics which maintain cholesterol homeostasis, and consequently amyloid-beta homeostasis, in the brain.
For more than 20 years, much of the leading research on Alzheimer's disease has been guided by the "amyloid hypothesis." But with a series of failed clinical trials raising questions about this premise, some researchers are looking for deeper explanations into the causes of Alzheimer's and how this debilitating condition can be treated. Among these investigators are researchers focused on axonal transport - the complicated, internal highway system that conveys precious, life-giving materials from one part of a nerve cell to another. Breakdowns in this transport system can lead to "traffic jams," and some scientists hypothesize that such blockages precede the formation of plaques in neurological diseases like Alzheimer's.
Using the neurons of fruit fly larvae, researchers have been investigating the role of presenilin - another Alzheimer's-linked protein - in axonal transport for several years. "We are looking at processes that occur before cell death, before you start to see plaques in the brain. A lot of the treatments being developed for Alzheimer's are targeting beta-amyloid, but maybe we should be targeting processes that happen earlier on, before plaques are formed."
The researchers' latest study provides details on how presenilin interacts with GSK-3β, and reports that a specific molecular structure within presenilin - a loop region - is necessary for proper traffic control. Presenilin has an important role in Alzheimer's: The protein aids in the production of beta-amyloid, which, when overproduced, causes plaques to form in patients' brains. But the latest work shows that presenilin may also have another role - this one positive - in regulating the flow of traffic within brain cells and preventing blockages that over time can lead to death of the cell and disease. "What does this protein normally do? As we learn more about presenilin, it's possible that our research will result in new, more targeted opportunities for treating or preventing Alzheimer's disease."