An HIV drug to cure Alzheimer’s disease?
Patients with AD all share a common trait: the accumulation of amyloid-beta protein plaques in the brain. But scientists’ attempts to prevent or remove amyloid in AD-patients’ brain have so far failed to cure the disease. This, says Dr Rik van der Kant, researcher at VU Amsterdam, suggests that future investigations should rather focus on another change known to predate AD: Tau pathology. This process sees proteins form into neurofibrillary tangles, starting in the areas of the brain important for memory then spreading throughout the rest of the brain. “We believe that Tau could be a better target as it is more closely associated with neuronal death and cognitive decline,” he explains. Although it’s been known to play a key role in AD, Tau pathology is actually much harder to study than amyloid-beta accumulation. Whilst amyloid is generated by all cells in our body, Tau is only expressed in neurons and mice develop a different type of Tau pathology that does not occur in patients with AD. Only tests on a human brain can help understand the mechanisms at play, and Dr van der Kant has found a way. “We used a novel stem cell technique that received the Nobel prize in 2012: skin cells from patients or healthy subjects are reprogrammed using a genetic trick to a stem-cell like state, at which stage these cells are called induced pluripotent stem cells (iPSC). These iPSCs can then be used to generate any cell type, including an unlimited supply of neurons. Interestingly enough, these neurons retain the characteristics of the patient they were derived from and, in iPSC-derived neurons from AD patients, accumulation of phosphorylated Tau (characteristic of AD Tau pathology) can be observed,” he explains. APPTOTAU’s research consisted in using these AD iPSC-neurons to screen a library of over 1 600 drugs. More than 40 of them were found to effectively reduce early stage Tau pathology in iPSC-derived neurons. These included a number of statins – cholesterol-lowering drugs that are currently prescribed for hypercholesteremia. “Cholesterol has previously been implicated in the AD disease process, but only related to Amyloid pathology. Our finding that cholesterol also regulates Tau pathology was highly unexpected,” Dr van der Kant explains. “By reducing the levels of cholesterol through statin treatment, we could enhance the degradation of phosphorylated Tau in all AD-patient iPSC-derived neurons that we tested.” Another important finding was that the effect of cholesterol on Tau pathology was correlated with, but independent from, the effect of cholesterol on Amyloid pathology. “This implicates that changes in cholesterol metabolism known to occur in AD can drive Tau pathology even in the absence of Amyloid pathology. This means that simply removing amyloid from the brain would not suffice to halt the progression of Tau pathology.” A therapeutic approach to normalize cholesterol metabolism, on the other hand, could effectively prevent the occurrence of both Amyloid and Tau pathology. Unlike other statins tested in previous research, Dr van der Kant found that efavirenz, an HIV drug, is specific to brain cholesterol and would be a good candidate drug for AD. “The fact that efavirenz is already a marketed drug has the major advantage that it can be directly repurposed for AD. We are currently in the process of designing such drugs and applying to research grant and clinical trials,” he concludes.
