A protein named tau, which has been highly implicated in the world's No. 1 cause of dementia — Alzheimer's disease — and several other neurodegenerative disorders, may spur these diseases in a way that differs greatly from the pathological pathway usually ascribed to it.
Tau's molecular malfeasance is increasingly viewed as one of the strongest instigators of Alzheimer's disease for a few reasons. First, the appearance of telltale forms of the protein in cerebrospinal fluid or in the bloodstream strongly predicts impending Alzheimer's symptoms. Second, neuroimaging studies and postmortem inspections indicate the presence of neurofibrillary tangles — long filaments largely composed of tau — inside Alzheimer's patients' nerve cells. And third, in its healthier manifestation, tau is believed to play a role in stabilizing so-called microtubules: skeletal structures in nerve cells that are critical to these cells' proper operation.
Neurofibrillary tangles and other aspects of tau's misbehavior — notably, a tendency to rack up chemical modifications that shift that protein's disposition and destination to the dark side — have been sighted in Parkinson's and Huntington's diseases and in other, rarer conditions such as frontotemporal dementia and progressive supranuclear palsy. Neuroscientists lump these disorders together under the catch-all term "tauopathies."
Tauopathies share another common pathology: deteriorating performance on the part of the tiny intracellular powerpacks that populate and produce energy in almost every cell in our bodies. These nano-batteries, called mitochondria, may number in the dozens or in the tens of thousands within a single cell, depending on its energy needs. Nerve cells have especially high mitochondria demand.
Nobody has nailed down the reason for this connection between tau weirdness and powerpack pathologies — until now. In a study to be published online Aug. 6 in Neuron, Stanford Medicine scientists have shown that wayward tau molecules, juiced by acquired enzymatic tweaks, can wander into mitochondria and gum up their internal energy-production lines, initiating a vicious cycle of pathological events within mitochondria and the nerve cells that harbor them.
Bingwei Lu , PhD, professor of pathology, is the study's senior author. Lead authorship is shared by basic life research scientists Wen Li, PhD, and Suman Rimal, PhD.
"This is the first demonstration of exactly what tau does inside mitochondria," Lu said. "Our discovery of a whole new mechanism driving tauopathies renders these disorders amenable to new therapeutic interventions."
Tau story
Tau molecules do indeed spend some of their time sitting on microtubules, straddling those structures' identical subunits. So, not unreasonably, the consensus is that tau's perch on microtubules helps keep them from falling apart.
But tau molecules spend even more of their time detached from their seats on microtubules. During this downtime, a free-floating tau molecule becomes especially prone to confrontations such as the stapling of a chemical cap onto its exposed parts by neighborhood enzymes.
These modifications predispose tau molecules to clumping with one another, potentially aggregating into neurofibrillary tangles. A single tau molecule can acquire numerous chemical caps along its length, all the more pumping up its potential for mischief. More often than not, the chemical cap that gets attached is what chemists call a phosphate group. (A single tau molecule can accommodate as many as 80 separate phosphate-group additions, or phosphorylations.) Tau "hyperphosphorylation" is a uniting feature linking all tauopathies.
The newly discovered pathological pathway is entirely independent of both neurofibrillary-tangle formation and microtubule instability. Instead, it involves a switch in the directionality of mitochondria's energy-production line, with a resulting disruption of mitochondria's primary function: the conversion of calories from glucose or fat to energy by what's known as the electron-transport chain. This multiple-component complex passes electrons, conveyor-belt-style, from one to the next of its components, the last of which converts a precursor molecule into ATP, our cells' universal energy currency. (Analogous to a tiny cannister of gasoline, ATP pours its stored energy into our hard-working proteins.)
The new study shows that when the hyperphosphorylated tau molecule interacts with a key mitochondrial component, it jams up the conveyor belt, causing electrons to flow backward.
Aptly named "reverse electron transport," this snarl produces large amounts of highly reactive, noxious chemicals, with accompanying inflammation and damage to proteins. That's bad for cells.
Reverse electron transport
Reverse electron transport is an area of intense recent interest in biology. Although it was first discovered in the 1960s, there's still no clear evidence that it serves any constructive physiological role.
"In healthy cells, very little reverse electron transport is happening," Lu said.
The new study shows reverse electron transport is activated under stress. It may initially serve some beneficial function — for example, providing short-term adaption to that stress — but nothing like that has been proven.
Lu and his associates carried out an extensive series of experiments in fruit flies, mice, human brain tissue and cultured human nerve cells that in some cases contained mutated genes for tau identical to those found in tauopathy patients. They also employed lab-generated nerve cells carrying a well-studied gene duplication that promotes accelerated acquisition of Alzheimer's disease.
The researchers proved that reverse electron transport was occurring in animal models of tauopathy as well as in tauopathy-afflicted human brain tissues. Healthy nerve cells, largely spared of hyperphosphorylated tau's malevolent presence, showed no sign of reverse electron transport or its downside effects.
Next, they showed how reverse electron transport is activated: Tau molecules enter mitochondria — although only when they're phosphorylated. There, they can bind to a component of the electron-transport chain called NDUSF3, warping that protein's shape. When this happens, electrons drop off the conveyor belt and start flowing backward.
Genetically or pharmacologically depleting tau halted this defection. An experimental drug called CPT prevented hyperphosphorylated tau from binding to NDUSF3, blocking reverse electron transport without impairing normal electron flow.
Experimental animals, genetically altered so that they produced no or little tau, suffered none of the cognitive or other behavioral deficits or brain pathophysiology that tau-producing, but otherwise genetically identical, animals did under stress conditions.
Deleting the gene for tau, for instance, protected fruit flies from the severe, life-shortening nervous-system damage that normally results from prolonged exposure to elevated temperatures. (These flies also lived longer than tau-producing normal flies do.) CPT treatment of the tau-producing normal flies not only protected them against heat stress but extended their lifespan.
With mice engineered to not produce tau, it was the same story. These mice's cognition was protected by CPT treatment from the detrimental effect of heat stress. CPT also protected tau-producing normal mice subjected to heat stress.
Tau hyperphosphorylation proved critical for promoting reverse electron transport. Only tau molecules that had undergone particular phosphorylation events could get inside mitochondria, bind to NDUFS3 and induce reverse electron transport.
In tauopathy mice with severe cognitive deficiencies, an extended CPT regimen inhibited reverse electron transport in the mice's brain mitochondria. That significantly improved the mice's performance on a wide range of behavioral tests and prevented nerve-cell inflammation as well as several characteristic markers of neurodegeneration, such as diminished cortical thickness and total brain volumes.
Breaking up a vicious circle
Reverse electron transport is a textbook example of a vicious circle, Lu said. The massive release of highly reactive chemicals dramatically boosts the odds that individual tau molecules will get hyperphosphorylated, leading to additional activation of reverse electron transport.
"Once this gets started, it can become self-perpetuating," he said.
Reverse-electron-transport inhibition holds promise as a therapeutical strategy for tauopathies and, potentially, other maladies characterized by aberrant tau phosphorylation and mitochondrial dysfunction, such as brain tumors, stroke and traumatic brain injuries, Lu said.
"The main results we observed in our animal models were also seen in patient brain tissues and in the laboratory generated nerve-cell models we derived from tauopathy-patients' cells," he said. "This suggests that what we learned from this study is applicable to the human nervous system."
"In fly and mouse models of tauopathy, CPT treatment rescues behavioral deficits, reduces neuroinflammation and mitigates neurodegeneration. In hiPSC-derived neurons carrying pathogenic tau mutations, CPT protects against stress-induced cellular abnormalities."
But these are early days for this compound's clinical development, he added. "Much more work remains to be done before it can undergo clinical trials."
Lu is co-founder and sits on the advisory board of Cerapeut, Inc., a company that is developing CPT as a therapeutic drug for the treatment of neurodegenerative diseases.
Researchers from the University of California, San Francisco, contributed to the work.
The study was funded by the National Institutes of Health (grants R21AG083863, R01NS084412, R01AG089752, R37NS083417 and R01NS120219).
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