Preventing the Death of Neurons in Alzheimer's Disease without Clearing Amyloid and Tau Aggregates
This is an excellent example of what I consider to the wrong high-level strategy for medical research, particularly so given that the results appear promising. Rather than attacking the root causes of an age-related condition, scientists search for ways to block one or more of the consequences of those root causes, a much narrower set of potential benefits. Here, in the context of Alzheimer's disease, the root causes include aggregation of misfolded or otherwise problematic proteins - amyloid-β and tau. The biochemistry surrounding these aggregates causes cell dysfunction and death. Researchers have now found a way to block much of the resulting cell death without actually removing the aggregates, and this also prevents much of the cognitive decline, at least in an animal model of the condition.
These results represent an unusually effective outcome for this approach to therapy. We should consider that since it fails to clear aggregates, any and all of the other effects that might occur as a result of their presence are still in fact taking place. For example, amyloid is thought to negatively impact vascular function. In general this is the problem with blocking consequences rather than removing causes: because cellular biochemistry is so very complex, it is very hard to block more than a narrow slice of the consequences of any given set of the causes of aging. It is hard to even effectively map and catalog all of those consequences. And yet sometimes very promising results are produced, amidst the myriad failures and marginal outcomes, and that encourages people to continue trying this development strategy rather than to work on addressing the root causes of the problem. Nonetheless, it remains the case that if the root cause can be addressed, then all of its consequences are also addressed, whether or not they are known and mapped. It is a much more efficient way forward, on balance.
A soon-to-be-published study indicates that protecting nerve cells with a specific compound helps prevent memory and learning problems in lab animals. Although the treatment protects the animals from Alzheimer's-type symptoms, it does not alter the buildup of amyloid plaques and neurofibrillary tangles in the rat brains. "We have known for a long time that the brains of people with Alzheimer's disease have amyloid plaques and neurofibrillary tangles of abnormal tau protein, but it isn't completely understood what is cause or effect in the disease process. Our study shows that keeping neurons alive in the brain helps animals maintain normal neurologic function, regardless of earlier pathological events in the disease."
Researchers used an experimental compound called P7C3-S243 to prevent brain cells from dying in a rat model of Alzheimer's disease. P7C3-based compounds have been shown to protect newborn neurons and mature neurons from cell death in animal models of many neurodegenerative diseases. P7C3 compounds also have been shown to protect animals from developing depression-like behavior in response to stress-induced killing of nerve cells in the hippocampus, a brain region critical to mood regulation and cognition.
The researchers tested the P7C3 compound in a well-established rat model of Alzheimer's disease. As these rats age, they develop learning and memory problems that resemble the cognitive impairment seen in people with Alzheimer's disease. The new study, however, revealed another similarity with Alzheimer's patients. By 15 months of age, before the onset of memory problems, the rats developed depression-like symptoms. Developing depression for the first time late in life is associated with a significantly increased risk for developing Alzheimer's disease, but this symptom has not been previously seen in animal models of the disease.
Over a three-year period, researchers tested a large number of male and female Alzheimer's and wild type rats that were divided into two groups. One group received the P7C3 compound on a daily basis starting at six months of age, and the other group received a placebo. The rats were tested at 15 months and 24 months of age for depressive-type behavior and learning and memory abilities. At 15 months of age, all the rats - both Alzheimer's model and wild type, treated and untreated - had normal learning and memory abilities. However, the untreated Alzheimer's rats exhibited pronounced depression-type behavior, while the Alzheimer's rats that had been treated with the neuroprotective P7C3 compound behaved like the control rats and did not show depressive-type behavior.
At 24 months of age (very old for rats), untreated Alzheimer's rats had learning and memory deficits compared to control rats. In contrast, the P7C3-treated Alzheimer's rats were protected and had similar cognitive abilities to the control rats. The team also examined the brains of the rats at the 15-month and 24-month time points. They found the traditional hallmarks of Alzheimer's disease - amyloid plaques, tau tangles, and neuroinflammation - were dramatically increased in the Alzheimer's rats regardless of whether they were treated with P7C3 or not. However, significantly more neurons survived in the brains of Alzheimer's rats that had received the P7C3 treatment.