As trials of agents attacking amyloid plaque have been disappointing for Alzheimer's disease (AD) researchers, they're turning more to tau, a key driver in the progression of certain neurodegenerative diseases, including AD.
A special issue of Alzheimer's & Dementia is devoted entirely to various areas of tau-related research. It features nine articles on topics ranging from how tau may lead to brain cell death to the latest in tau therapeutic strategies.
In one paper, Kurt R. Brunden, PhD, director of drug discovery, and professor, research faculty, Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, and colleagues outlined the state of the art for therapeutic approaches targeting tauopathies, that is, neurodegenerative diseases in which tau plays a role.
One of the most promising approaches, according to Dr Brunden, is tau immunotherapy, either active immunization through vaccines or passive immunization using antibodies. Two candidate vaccines (Axon Neuroscience and AC Immune/Janssen) are being tested in phase 1 clinical trials, as are two different antibodies (Bristol-Myers Squibb and AbbVie).
"I think we will see multiple immunotherapy approaches from pharma companies in the next year or two, in addition to these ones," said Dr Brunden.
Dr Brunden is perhaps even more enthusiastic about a phase 1 trial of a microtubule stabilizer (Cortice Biosciences). Microtubule stabilizers (MTs) are the architecture or scaffolding that help shape neurons and are important in many cellular processes.
As noted by Dr Brunden and colleagues in their paper, MT deficits have been observed in animal models of tauopathy, and there's evidence of MT alterations in the brains of patients with AD. However, long-term safety is an issue with this therapeutic approach.
The prevailing hypothesis in AD involves the "amyloid cascade" whereby amyloid plaques develop years before symptoms and trigger a series of events that lead to tau pathology.
It's the tau pathology that ultimately causes neuron death. "Amyloid may be a trigger, but tau may actually be the executioner," is how Dean Hartley, PhD, director of science initiatives, medical and scientific relations, Alzheimer's Association, put it. "Those tangles you see in brain show the best correlation to cognitive impairment; in other words, the more tangles, the worse the brain is in terms of cognition."
Whereas amyloid-β (αβ) levels probably plateau a decade before symptoms, tau changes seem to still be occurring as the disease progresses, said Dr Brunden.
"So if you can stop the tau pathology from getting worse, then you might have an impact, even in patients who already have some signs of the disease."
However, it's more difficult to target tau than amyloid. For one thing, the process of tau formation is less well understood than that of αβ.
As Dr Brunden explained, researchers have "a clear understanding" of the role of the amyloid precursor protein (APP) in the development of AD and have identified enzymes that cleave APP to release αβ (?-secretase and β-secretase).
"We know that if you could block those enzymes, and block αβ production, you would reduce plaques."
One of most exciting drugs in advanced clinical trials is a β-secretase inhibitor (BACE inhibitor) being tested by Merck, said Dr Brunden.
"So far, inhibiting β-secretase looks like it's relatively safe, and you can definitely reduce αβ levels to almost nothing by inhibiting that enzyme."
On the other hand, inhibiting ?-secretase is proving to be more problematic; because this enzyme is linked to other functions, this may cause unacceptable side effects.
But while there are "classic druggable targets" for amyloid, researchers aren't sure which enzymes are key in processing tau, said Dr Brunden.
"Tau does get cleaved, but there are half a dozen or more enzymes that are implicated. It's not even clear that they are necessary to cause neurofibrillary tangles. They might slightly speed the process by cleaving tau, but which one to attack is unclear."
Another approach to targeting tau is inhibiting its aggregation. A phase 3 clinical trial of LMTX (TauRx Therapeutics), an agent that inhibits tau fibrillization, found some statistically significant benefit on cognitive and functional outcomes and slowing of brain atrophy in patients taking the agent as monotherapy. However, the study failed in its primary endpoint of slowing the rate of cognitive decline overall in people with mild to moderate AD.
"My lab has looked at that approach as well, without much success," commented Dr Brunden "Our group showed that the methylene blue, which is kind of the prototype compound that LMTX was based on, acts by a nonspecific mechanism. It didn't surprise me that it didn't work in the clinic."
Dr Hartley also felt there were "methodologlcal problems" related to the LMTX study, although he said "it does not diminish the enthusiasm for a tau or tangle therapy."
Several other methods of tackling tau are being investigated, but many appear to be even less promising. One of these involves improving cellular proteostasis.
"These are cellular degradation systems that play critical roles in cells, and so whether they can truly be modulated in a way that's safe and effective is unknown at this point," said Dr Brunden.
Another challenging approach is inhibition of kinases that catalyze tau phosphorylation. There's some uncertainly as to which kinase or kinases are most relevant to tau phosphorylation in neurons. And there are safety challenges associated with prolonged inhibition of kinases, such as GSK-3β, that modify multiple proteins and cellular pathways, according to Dr Brunden and his colleagues.
A related strategy is the modulation of tau O-glycosylation. An area gaining interest is the role of O-GlcNAcylation, the posttranslational modification of intracellular proteins by O-linked b-N-acetylglucosamine (O-GlcNAc).
According to a review article by Cheng-Xin Gong and colleagues included in the special issue, numerous brain proteins, including tau, APP, and many synaptic proteins, are modified by O-GlcNAc. Recent studies suggest that deregulation of brain O-GlcNAcylation may mediate the molecular mechanism by which decreased brain glucose metabolism contributes to neurodegeneration in AD.
Combining therapeutic approaches might prove to be the best route to take when it comes to treating AD. "No one therapy is probably going to be totally sufficient to eradiate or slow the disease process," as neurodegenerative diseases, including AD, involve multiple pathologies, said Dr Brunden.
In AD, that may mean targeting Aβ and tau and/or microglial inflammation.
Another topic tackled in the special issue was the growing awareness that tau might act like a prion-like protein spreading from cell to cell in AD.
"As the proteins abnormally fold and get packaged in small vesicles, they're able to be transported to another cell — kind of what a virus would do, but in no way is it infectious in that way," said Dr Hartley.
With this knowledge, researchers are keen to stop that transfer of "cargo" through a very specific therapeutic target aimed at these vesicles, according to Dr Hartley. In fact, he said, antibodies that are being tested to inhibit tau aggregation "may actually be interrupting this process."
Why Tau Now?
Tau is emerging as a research target in AD for several reasons. One is that because amyloid plaques begin to develop years before symptoms, it's difficult for a targeted drug to be of much use.
"Even if you had a drug that's perfect...it's unclear if giving it to a patient who already has got a head full of plaque is going to be beneficial; you probably need to give it much earlier," he said.
This might help explain why therapies that theoretically should work have failed. "The rethinking has been that it may not have been the wrong therapies but they may be given at the wrong time," said Dr Hartley.
That realization has spurred AD prevention trials. The Alzheimer's Association is funding three such trials to the tune of over $20 million.
Another reason for the keen interest in tau is further evidence that the presence of tau tangles correlates much better with the extent of dementia than the αβ load.
"For many years, we have believed that tau is the killer, and this has just been further reinforced by new imaging and biomarker studies," said Dr Brunden.
Alzheimers Dement. October 2016 issue. Contents