The main hallmark of Alzheimer’s disease is the accumulation of toxic protein species in the brain. These toxic deposits include senile plaques (made of the amyloid-beta protein) and neurofibrillary tangles (made of the tau protein). In general, recent drug development research for Alzheimer’s has focused on targeting amyloid-beta. This is because previous research suggested that amyloid-beta is responsible for initiating a set of chemical reactions that lead to the phosphorylation of tau. This p-tau (phosphorylated tau) is then more prone to sticking to itself and forming tangles. Thus, the thinking was that if we could get rid of amyloid-beta, tau would no longer form tangles, allowing us to eliminate both toxic proteins at once.
However, a study published this week in the journal Science may completely change how we think about amyloid-beta and tau. Researchers from Australia looked at enzymes of the p35 family, which are believed to mediate amyloid-beta’s ability to initiate p-tau formation. They focused on a member of this protein family called p35-delta (p35D), after determining that it was the only p35 protein that localized to synapses (the communication junctions between neurons.)
The exciting part of this study came when the researchers generated Alzheimer’s mice that lacked the gene for p35D. These mice experienced exacerbated symptoms of Alzheimer’s disease, including worsened excitotoxicity, memory loss, and premature death. The researchers determined experimentally that these worsened symptoms were dependent on p35D’s ability to create p-tau. In other words, it seems that the presence of p35D (and in turn, the presence of p-tau) was actually protecting the mice from more severe symptoms of Alzheimer’s disease.
This study is big news in the field of neuroscience because it suggests that the formation of tangles by the p-tau protein may be helpful rather than harmful. Whereas in the past scientists have viewed tangles as a harmful side effect of amyloid-beta plaques, these new results indicate that p-tau may actually be a beneficial reaction to the plaques which keeps their toxicity in check. This is consistent with additional data from the study showing that humans with Alzheimer’s disease have reduced expression of p35D. The authors of the paper suggested that a decline in p35D expression, and in turn a decline in p-tau levels, may be a major contributor to the development of Alzheimer’s disease.
Alzheimer’s researchers around the world are very excited about this paper and the ramifications it could have for future studies. Where previously we had been trying to deplete toxic p-tau, this strategy may actually worsen the disease. Rather, perhaps we should be trying to increase levels of p35D and/or p-tau in early Alzheimer’s patients in order to prevent disease progression. It’s possible that this study may also help explain why approximately 1 in 5 elderly adults contain the signature pathology of Alzheimer’s in their brains and yet do not experience any cognitive deficits. Perhaps these individuals benefit from higher expression of p35D which helps fight of the toxicity of amyloid-beta. Future studies will investigate whether this is indeed the case.
As always, we must interpret these results with caution. Since this study was based in mice, a lot of additional research will be needed to determine whether similar neurochemical pathways occur in humans and, if so, whether these can be utilized to design a preventative treatment for Alzheimer’s. Only time can tell how far-reaching the impacts of this study will be.