Alzheimer’s disease is characterized by the buildup of toxic protein species in the brain. One of these proteins is tau. Tau normally is involved with stabilizing the cytoskeleton that gives neurons their structure. However, in people with Alzheimer’s disease, certain enzymes attach too many phosphate groups to tau. Molecules of this hyperphosphorylated tau can stick to each other to form tangles of fibers that accumulate inside of neurons.
It was originally assumed that these tau tangles contributed to neuronal death in Alzheimer’s disease. However, it has since been discovered that less than 17% of neurons in an Alzheimer’s brain contain tangles, even in the most advanced disease stages. Additionally, it was recently shown that the tangles are not associated with memory deficits or neuronal death in a mouse model. This has led some researchers to speculate that the soluble form of tau, which does not accumulate into tangles, might actually be the toxic species.
In a study published last week in Nature Medicine, researchers uncovered a possible mechanism for the toxicity of soluble tau. At the time, they were studying mice with a mutation that causes them to express high levels of tau. The researchers noticed that a particular fragment of tau called ∆tau314 (named so because it had been cleaved after the 314th amino acid) was more abundant in the mice that had greater memory impairment. They then looked at human brain tissue from 85 elderly subjects and found that tau fragments similar to ∆tau314 were present at significantly higher levels in cognitively impaired subjects compared to non-impaired controls. They demonstrated experimentally that this fragment was soluble and did not form the large tau tangles.
Subsequent experiments determined that an enzyme called caspase-2 was capable of cutting the ∆tau314 fragment from full-length tau. When they reduced the levels of caspase-2 in the brains of their Alzheimer’s mice, the levels of ∆tau314 decreased and the mice showed complete reversal of cognitive impairment.
The researchers were also able to determine the mechanism by which ∆tau314 leads to cognitive impairment. Previous studies had shown that in Alzheimer’s disease, tau improperly localizes to dendritic spines, the part of the neuron where it receives communicative inputs from other neurons. These communication sites can malfunction when too much tau is present. The researchers created mice expressing a form of tau that was resistant to cleavage at the 314th amino acid. They found that this form of tau did not localize to dendritic spines. Additionally, the mice did not experience any cognitive impairment or neurodegeneration, despite expressing high levels of this modified tau.
The main conclusion of this study was that in order for tau to induce the pathology of Alzheimer’s disease, it must first be cut at the 314th amino acid by caspase-2. This is an intriguing result, as it suggests that caspase-2 might be a useful therapeutic target for future drug research. In theory, if we can prevent caspase-2 from cutting tau, this could in turn prevent tau from causing malfunctions in dendritic spines. In addition, this study provides further support for the hypothesis that soluble tau, rather than insoluble tau tangles, is the more harmful species in Alzheimer’s disease.
An important caveat of this study is that it was performed almost exclusively on mice. These mice are only a simulation of human Alzheimer’s disease, and thus the same mechanisms may not translate to humans. Though significantly higher levels of ∆tau314 were found in cognitively impaired human brains, further research is needed to determine whether blocking caspase-2 cleavage of tau offers the same benefits in humans as it does in mice.
Additionally, the mice in question only simulated the tau pathology of Alzheimer’s. Tau is only one aspect of human Alzheimer’s disease. Other relevant pathologies include beta-amyloid plaques, neuropil threads, and neuroinflammation. Thus, it seems unlikely that eliminating the toxicity of tau could entirely reverse the disease in humans. A more likely scenario is that a caspase-2 drug therapy might be combined with other drugs that target the other pathological agents.
Despite these caveats, this paper represents an exciting development in Alzheimer’s disease research. Only time can tell whether it will translate to human drug candidates down the road.