A potential target for dementia therapy

One of my favorite things about diving into scientific literature is the feeling of drawing connections between observations from different papers, allowing you to close any gaps that remain in your thinking. This happened to me recently, as my interest in neurodegenerative disease markedly increased given the nature of my work. For those who have been asking what kind of research I do in the Doudna Lab after my recent post, I generally focus on methods of safe and precise gene editing in the brain.

In one of my projects, we’re attempting to use gene editing to knock down levels of a cell structural protein called tau, which has been heavily implicated in several neuropathologies. While I’ve always known that dysfunctional tau can be a “harmful” protein in the brain, I’ve always assumed its mechanism of harm to purely be aggregate formation (accumulation of the protein) and subsequent mechanical obstruction of neuronal pathways, instigation of immune responses, etc. I had never considered that tau might interfere with specific components of metabolic pathways in the brain, and that disruptions in those pathways could actually be leading to dementia and diseases like Alzheimer’s.

It’s imperative to first put things in perspective: this is still very much a controversial topic in the field. Though protein aggregation is a consistent observation in diseases of the brain, and many neuroscientists subscribe to the hypothesis of protein aggregation causing disease, others believe it may just be a symptom and not necessarily pathological in itself. Having heard murmurs of the latter hypothesis, I became especially curious to dig into the literature regarding tau, as it pertained to the clinical relevance of my research.

In doing this, a few months ago I came across the work of Drs. Francisco Gonzalez-Lima and Jack de la Torre, professors in the Department of Psychology at the University of Texas, Austin. Through some clever experiments involving low doses of mitochondrial toxins, they demonstrated that a key component of dementia in the brain was the inhibition of cytochrome c oxidase, otherwise known as Complex IV of the electron transport chain (ETC). Now, this actually ties into my post from a while back on Dr. Navdeep Chandel’s views on the mitochondria as a signaling organelle. One established form of mitochondrial signaling triggers apoptosis (programmed cell death) via the release of cytochrome c: another ETC component which donates an electron to cytochrome c oxidase (Complex IV). As it turns out, when cytochrome c oxidase is inhibited in neurons during dementia, cytochrome c cannot properly transfer this electron, is deemed “dysfunctional,” and signals for the neuron to die by apoptosis.

The question then becomes, what causes the inhibition of cytochrome c oxidase to kick off this pathway of neuronal death? There are several hypotheses, which are probably all correct; this may be one reason why there are so many different variations of dementia. The vascular hypothesis of dementia suggests that chronic low blood flow to the brain, often caused by cardiovascular disease, high blood pressure, or head trauma, may be responsible (perhaps why these causes are among the biggest risk factors for dementia). Being a key enzyme in respiration, cytochrome c oxidase is inducible by oxygen. With low oxygen levels in the brain as a result of a lack of blood flow, cytochrome c oxidase could be chronically inhibited, and initiate the process of neuronal death.

Figure 1: Role of tau in activation of the PI3K-AKT-mTOR pathway. Normal arrows signal activation, and T-shaped arrows signal inhibition. Note that, in the context of this paper, mTOR activity was found to promote behaviors of autism spectrum disorder (ASD). (Image: Modi et al., 2020)

In literature searches for my own work, I came across this paper which (among other things) mentioned that ablation (removal) of tau protein in certain neurons “reduced overactivation of the PI3K-AKT-mTOR pathway.” I believe I’ve only alluded to mTOR–the mechanistic target of rapamycin–before in the contexts of metformin and fasting. However, this is a major metabolic pathway in our cells in so many respects, so seeing this immediately caught my attention. After further investigation, I saw that tau was actually a relatively established activator of this pathway. Activation of the mTOR pathway can lead to downstream production of nitric oxide (NO), a small molecule which functions as a reversible inhibitor of cytochrome c oxidase. The ability of NO to modulate cytochrome c oxidase activity may contribute to this apoptotic cell death signaling.

While this is all still speculation on the mechanism of action, it was incredible to think that I may have closed at least one loop on tau’s role in dementia. Certain mutations or accumulations of tau allow it to chronically stimulate the PI3K-AKT-mTOR pathway, which over time can increase levels of nitric oxide and subsequent inhibition of cytochrome c oxidase to kickstart the pathway towards dementia. Perhaps chronic stimulation of this pathway is also why we see associations between cognitive decline and key markers of metabolic disease like obesity and insulin resistance, as well as aging. All of these things tend to chronically increase activity of this pathway, which is why we will undoubtedly return to it in the future in different contexts. For now, though, I certainly believe there could be promise in targeting tau therapeutically for dementia.

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