The Tau Infection

A while back, I think it was in November, I spent a few journals analyzing and explaining the argument between two theories of Alzheimer's Disease pathogenesis - the Amyloid Hypothesis and the Oxidative Stress Theory. It might be helpful to go back and read this group of journals starting from the post entitled "I've Got it!" but let's quickly review the definitions for each theory. The Amyloid Hypothesis suggests that flaws in the processes governing production, accumulation or disposal of beta-amyloid are the primary cause of Alzheimer’s - the initiation of the disease's pathogenesis. On the other hand, the Oxidative Stress Theory proposes that the primary driving factor in Alzheimer’s is a reduction in the capacity of neurons in specific regions to harness energy from glucose which would occur long before plaque deposition. The Oxidative Stress theory has been largely synonymized with a diabetes-like dysfunction of the brain and is often associated with cases of Alzheimer's in people who suffered from diabetes earlier in life.

Although analyzing that particular argument in the Alzheimer's world was quite nuanced, it seems another theory has entered the scene. Yesterday, a study was published in the neurology journal Brain titled Tau burden and the functional connectome in Alzheimer’s disease and progressive supranuclear palsy. So you already know what Alzheimer's Disease is but most people likely have never heard of Progressive Supranuclear Palsy (PSP). Similar to Alzheimer's disease, PSP is a neurological disease associated with neurodegeneration. The activity at nerve synapses becomes weak and neurons are damaged, eventually destroyed. Unlike Alzheimer's disease however, PSP is not necessarily associated with plaques of the protein Beta-Amyloid. In this study by Thomas Cope et al, 17 human subjects with Alzheimer's Disease, 17 patients with PSP, and 12 controls were assessed by in vivo PET imaging and resting functional MRIs to take a look at tau protein pathologies and neuronal connectivity, the two factors being studied independently of one another. This setup alone is quite groundbreaking for the neuroscience world. Usually, as I have discussed numerous times here, brain research is restricted to model organisms due to its often invasive and dangerously ambiguous nature. But the fact that this particular study utilized non-invasive techniques and was able to study human brain activity in vivo eliminates a large amount of variance consideration and that's kind of huge. Granted, results were from brain scans which may not have provided the most extensive amount of data but nonetheless, the question being asked did not necessarily warrant the usual dissections.

Anyway, since the team was looking at common neurodegenerative ground between Alzheimer's and PSP, they explored the trans-neuronal spread of Tau proteins. Regarding this gradual spread, it was concluded that areas of dense neural connectivity had a higher concentration of Tau. (A note about tau - tau deposits are found inside a neuron which is different from Amyloid deposits which are found outside the neurons.) This finding suggested to the researchers that "tau may spread in a way analogous to influenza during an epidemic, when people with the most social contacts will be at greatest risk of catching the disease." This theory, although in its elementary stages due to the extremely small sample size of the study, has been coined the Transneuronal Spread Hypothesis.

Upon my first read of the paper, I was a little confused as to how this theory differed from the Amyloid Hypothesis or even the Oxidative Stress Theory. They all seemed to be rooted in a fundamental sense of contagion. The Oxidative Stress Theory was all about how people with diabetes saw their neurons catch the glucose-rejecting disease. The Amyloid Hypothesis also rifts off the fact of gradual buildup and spreading of plaques. I thought, why is the Transneuronal Spread Hypothesis any different? Upon a closer analysis of the results then, I realized that the basis of this theory lied in the differences in tau concentration between various regions of the brain. In areas with lots of connection and lots of activity, there was more tau deposits. But in regions of less connection and less activity, there was less tau deposits. When I understood this my next question became well, isn't it just proportional then? If there are less neuronal connections, it makes sense that there are less deposits. But what I had failed to consider is that the study focused on dense vs. sparse connections, not more vs. less neurons. So theoretically, what was being said is that the amount of tau in an individual neuron depended largely upon the extent of connections it had with other neurons. It's small, but the difference is certainly there.

The more I come across and read about all of these different theories, the more I feel like they're all part of one huge explanation for such complicated diseases. Everywhere you look, there's evidence for each opinion and sometimes it's really quite overwhelming the ambiguity of this disease's origins. One other interesting thing about this particular study was that the same theory of disease pathogenesis was found to hold true in mouse brains but this study was the first to illustrate the same trend in human brains. The sample size, however, is of substantial concern. In reading different publications that interpreted this study, almost all of the science news outlets mentioned how the team openly acknowledged this flaw with their project. Certainly though, that's not a knock against the study - it's definitely nothing to sneeze at. Research with less invasive methods is starting to appear throughout neuroscience and that's really important because for the longest time, mice, rats, pigs, and don't forget C. elegans (!), have been the go-to organisms for brain studies. Now, although sample sizes must be smaller and studies more careful, we're seeing a shift towards human brain research in order to confirm what all of these helpful organisms have taught us.