An HIV-drug to correct cholesterol metabolism in Alzheimer’s disease


Rik van der Kant and colleagues report that accumulation of cholesterol in Alzheimer’s disease (AD) neurons drives early Tau- and Amyloid pathology, and can be reversed by existing cholesterol-targeting drugs. Published in Cell Stem Cell.

Using induced pluripotent stem cell-derived (iPSC) neurons from AD patients, Rik van der Kant reports that cholesteryl esters (CE) — the storage product for excess cholesterol within cells — act as regulators of tau. Through screening of more than 1,600 Food and Drug Administration-approved drugs they found that low doses of the anti-HIV drug efavirenz lowered CE through activation of the neuronal enzyme “CYP46A1”, thereby reducing tau in the AD-patient neurons.

The accumulation of amyloid beta (Aβ) plaques and tangles of a protein called tau in the brain are hallmarks of Alzheimer’s disease (AD). Much effort has focused on the former, with many attempts made to prevent, slow or even reverse the presence of Aβ, and thus ameliorate the development of AD. To date, results have been mixed. In a new paper, published in the January 24, 2019 online issue of Cell Stem Cell , Rik van der Kant in collaboration with the University of California San Diego School of Medicine, focused on the alternative therapeutic target: tau.

Using induced pluripotent stem cell-derived (iPSC) neurons from AD patients, the researchers report that cholesteryl esters (CE) — the storage product for excess cholesterol within cells — act as regulators of tau. Importantly, through screening of more than 1,600 Food and Drug Administration-approved drugs they found that low doses of the anti-HIV drug efavirenz lowered CE through activation of the neuronal enzyme “CYP46A1”, thereby reducing tau in the AD-patient neurons.

The findings reveal that CE inhibit the proteasomal degradation of pTau, causing it to accumulate in the neurons of AD patients. Drugs that reduced CE also reduced pTau levels in all AD neurons tested.  The researchers also confirmed previous reports that CE drive the formation of amyloid. However, while the effect of CE on amyloid was highly correlated with the effect of CE on pTau, the study found the effect of CE on both pathologies were mediated by two independent downstream pathways. “These findings show that cholesterol metabolism is upstream of both amyloid and tau pathology and provide a novel new drug target for the treatment of AD” says Rik van der Kant.

Previous work by multiple AD investigators has suggested that cholesterol-lowering drugs, such as statins, may reduce AD incidence. However, the effect of statins in clinical trials were limited, possibly due to poor blood-brain barrier permeability or low potency. Efavirenz is highly brain permeable and affects neuronal cholesterol at doses hundreds of times lower than those administered to HIV-patients. “We believe low-dose efavirenz could be an effective treatment for AD” says Rik van der Kant. “Together with the VUmc Alzheimer center we are currently applying for funding to perform clinical trials with efavirenz for AD”. As efavirenz is already an FDA/EMA approved medicine, the researchers are hopeful human clinical trials can be completed with the next few years and will tell whether low-dose efavirenz is indeed an effective new treatment for AD.

van der Kant R, Langness VF, Herrera CM, Williams DA, Fong LK, Leestemaker Y, Steenvoorden E, Rynearson KD, Brouwers JF, Helms JB, Ovaa H, Giera M, Wagner SL, Bang AG, Goldstein LSB. Cholesterol Metabolism Is a Druggable Axis that Independently Regulates Tau and Amyloid-β in iPSC-Derived Alzheimer's Disease Neurons.

Funding for this research came, in part, from the Alzheimer Netherlands Fellowship, ERC Marie Curie International Outgoing Fellowship, the National Institutes of Health (5T32AG000216-24), the National Institute of Aging (IRF1AG048083-01) and the California Institute for Regenerative Medicine (RB5-07011).