Seminar #3. Rik can der Kant. Cholesterol and apoe4. Prof. van der Kant specializes in cholesterol metabolism and is applying this apoe4 models. He began by discussing how human cells can be converted in stem cells, then into almost any other type of cells - which is useful for making apoe4 populations of neurons, astrocyctes, and microglia. (see his Nature Reviews Neuroscience 2019 review paper for more information). When these cells are created from AD patients they product high levels of amyloid beta (AB40) and hyperphosphorylated tau (p-tau) - hallmarks of the disease. They used this system to test 1684 potential drugs to see if they would lower either AB or p-tau in these cell lines. They IDed 160 promising compounds, 42 of which seemed like they could be safe and/or effective. Interestingly, all stains tested were effective. (I also noticed some SSRIs on the list, but that slide went by fast). Refer to his 2019 Cell Stem Cell paper for more information on this. He mentioned that in large studies statins have been shown to reduce AD risk - an interesting point, given the debate we often have here, but I have read these studies and came away convinced that statins can have a small risk reduction, at least in these study populations. In their cell cultures, statins consistently reduced p-tau accumulation in a dosage dependent manner, with atrovastatin standing our as being just a bit better than the others in this regard. Probing the system further it seemed that cholesterol itself was not the key, rather it was cholesterol esters (CEs), a storage and transport form of the molecule. They found that lowering CEs using statins - again in cells cultures from AD patients - lowers AB and p-tua production, separately by independent mechanisms. One interesting finding is that the amyloid precursor protein (APP; the cell surface protein that can be cleaved to form AB) has a site that binds cholesterol. Eliminating this binding site prevented statins from lowering AB levels but p-tau was still reduced. So, more evidence that statins do this two good things separately, at the same time. Here's an important point from the seminar, however. Prof. van der Kant pointed out that statins don't work to reduce AD in patients because they don't reach the brain in high enough concentrations and because statins can be toxic to astrocytes. I feel like I could ask a lot of questions about this. But I suppose he's right: while some studies show statins reduce AD risk slightly in population studies, they don't cure anyone of of the disease. Anyway, they have identified a drug that seems to work better, at least in cell culture. It is Efavirnez. It is "sold under the brand names Sustiva among others, is an antiretroviral medication used to treat and prevent HIV/AIDS." It crosses teh BBB and is specific to an enzyme found in neurons. It reduces CEs. He pointed out that accumulation of "lipid droplets" is a characteristic of AD first observed by A. Alzheimer in the early 1900s.....and that these droplets could be accumulations of CEs. apoe4 seems to encourage lipid droplet accumulation, as can other risk genes. They (or others) tried it in mice, and it worked - see papers by Pikuleva et al. He hypothesized, therefore, that treatments lowering CE over-production could actually help apoe4s MORE than apoe3s with LOAD. They are hoping to continue on to clinical trials with this already-FDA approved drug. The drug has some side effects, of course, so it remains to be seen if it is well tolerated. I found the seminar to be fascinating and encouraging.
Four relatives with AD. Concerned, but hopeful. Introverted, but will talk about science.