As scientists search to understand the causes of Alzheimer’s disease, no one can really claim whether tau or amyloid beta commands the bigger role because the proteins are so linked.
One of the key hallmarks in Alzheimer’s disease is the accumulation of toxic amyloid protein in the brain, which can be seen as amyloid plaques both in human patients and in many AD animal models. But no single protein can tell the whole story of such a complex disease.
Another crucial player is dysfunctional tau, a naturally occurring protein that can become corrupted like a damaged computer file and form neurofibrillary tangles and threads within neurons.
Scientists differ on which is the more impactful protein. For many years, the pendulum had been swinging toward amyloid, but more recent studies suggest tau may, in fact, be the one driving the disease.
But no one can really claim which is the more important because the proteins are so linked. To truly understand the natural history of the disease, one would need to get into the human brain, become the proverbial fly on the wall, and watch events unfold over time. This is impossible, of course. We don’t even know when AD begins, and while we know that protein misfolding and mitochondrial dysfunction exist in many neurodegenerative diseases, we don’t really know the roles they play.
The next best thing is to try and develop animal models that mimic many of the traits seen in Alzheimer’s patients. This is, as we know, a difficult challenge, and there are literally over 125 different models that reflect some aspect of the disease.
Many of the most widely used transgenic, or genetically engineered, models have been altered to over-express human genes associated with Alzheimer’s pathology—mainly the amyloid precursor protein that at high enough levels causes amyloid-β plaques to accumulate in the brain. Other models introduce mutations associated with AD into the endogenous amyloid precursor protein gene. There are also naturally aged animals that can serve as models for cognitive decline and aged rat models that are bred to develop specific cognitive impairments during aging.
But these models, particularly ones that overexpress amyloid precursor protein or introduce mutations into the endogenous gene, do not show the neurofibrillary tangles that occur in Alzheimer’s.
Researchers are swinging more to tau models that express different variations of the protein. A widely used model called P301S, recently licensed by Charles River, develops neurofibrillary tangle-like inclusions in the neocortex, amygdala, hippocampus, brain stem, and spinal cord. The neurofibrillary tangles are accompanied by microgliosis and astrocytosis, cells in the central nervous system that, together, are thought to amplify the effects of inflammation, but not amyloid plaques.
We are using the model for both in vivo efficacy studies and for studies that analyze the biological or chemical events responsible for tau build-up. The model shows progressive tau pathology and cognitive decline from approximately two months of age, and exhibits cognitive deficits by six months. By eight months, the mice also show brain atrophy, primarily in the hippocampus, as well as the neocortex and entorhinal cortex.
The growing interest in models that offer tau pathology reflect a shift of that pendulum I mentioned earlier. Drug compounds targeting the accumulation of amyloid-β plaques in the brain have not succeeded in large efficacy trials, and so, understandably, more companies are actively pursuing compounds that target tau aggregation or disrupt tau phosphorylation.
But at the end of the day, the solution to this horrible, brain-wasting disease probably won’t rest on a single protein. My own hypothesis is that it’s not really the protein’s fault at all, but rather, a combination of factors—such as aging and our environment—that throw off the homeostatic balance of these normally occurring proteins that accumulate in the brain, with no mechanisms to eliminate them.
With over 46 million people worldwide suffering from Alzheimer’s—a number that is predicted to rise to 131 million by 2050—there is now an urgent need to find therapies that work. Looking ahead, the solution to modeling this disease may come down to developing compounds that can be tested in multiple models. A more complicated approach, no doubt, but this is a truly complicated disease.
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