This seminar was presented by Dr. Rik van der Kant, a Research Associate in both the Faculty of Science, (Functional Genomics) and Amsterdam Neuroscience (Neurodegeneration) at Vrije Universiteit Amsterdam.\u00a0 He is an expert on cholesterol metabolism and is studying how apoe4 contributes to LOAD.\u00a0 The title of his seminar was \u201cCholesterol metabolism as a dual driver of neuronal AD pathology\u201d.\u00a0 He described his recent work that was published (open access) here:<\/p>\n
van der Kant, R.; Langness, V. F.; Herrera, C. M.; Williams, D. A.; Fong, L. K.; Leestemaker, Y.; Steenvoorden, E.; Rynearson, K. D.; Brouwers, J. F.; Helms, J. B.; Ovaa, H.; Giera, M.; Wagner, S. L.; Bang, A. G.; Goldstein, L. S. B. Cholesterol Metabolism Is a Druggable Axis That Independently Regulates Tau and Amyloid-\u03b2 in IPSC-Derived Alzheimer\u2019s Disease Neurons. Cell Stem Cell 2019, 24 (3), 363-375.e9. https:\/\/doi.org\/10.1016\/j.stem.2018.12.013<\/a>.<\/p>\n Dr. van der Kant began by reviewing how human cells can be converted in stem cells, then into almost any other type of cells.\u00a0 This is useful for making populations of neurons, astrocyctes, and microglia carrying apoe4 genes.\u00a0 This work is described in another recent article, found here:<\/p>\n van der Kant, R.; Goldstein, L. S. B.; Ossenkoppele, R. Amyloid-\u03b2-Independent Regulators of Tau Pathology in Alzheimer Disease. Nat. Rev. Neurosci.<\/em> 2020<\/strong>, 21<\/em> (1), 21\u201335. https:\/\/doi.org\/10.1038\/s41583-019-0240-3.<\/p>\n He explained that when such cells are created from patients with LOAD they produce high levels of amyloid beta (A\u03b240<\/sub>) and hyperphosphorylated tau (p-tau) – hallmarks of the disease.<\/p>\n Recall that amyloid beta is a peptide fragment of the large amyloid precursor protein (APP), which occurs on many types of cells. APP is cleaved by the enzymes beta secretase and gamma secretase to yield A\u03b2.\u00a0 Amyloid beta fragments can be 36 to 43 amino acids long, with A\u03b240 <\/sub>and A\u03b242<\/sub> the mostly commonly studied forms. These fragments can exist as a single monomer unit, or combine to form larger oligomers, fibrils and plaques.\u00a0 Misfolded oligomer fragments can act as \u201cseeds\u201d inducing other amyloid beta fragments to misfold and aggregate, a process akin to a prionic infection.<\/p>\n (This is easily imagined by recalling the Slinky, a once-popular children\u2019s toy \u2013 essentially a coil of wire which \u201cwalked down stairs, alone or in pairs\u201d until becoming a tangled mess. \u00a0Imagine placing a tangled Slinky (a \u201cseed\u201d) into the drawer of new, perfectly-coiled Slinkys.\u00a0 The inevitable outcome is a drawer full of \u201cmisfolded and aggregated\u201d toys.)<\/em><\/p>\n Tau proteins are essential components of cell cytoskeletons, specifically the assembly of microtubules.\u00a0 However, tau proteins that have become hyperphosphorylated \u2013 covered in extra phosphate groups \u2013 also tend to misfold and stick together, becoming insoluble aggregates called neurofibrillary tangles.<\/p>\n Dr. van der Kant\u2019s group used these populations of human cells grown in culture to test 1684 potential drugs to determine if they could lower either A\u03b240<\/sub> or p-tau. \u00a0They identified 160 promising compounds, including 42 of which might be safe and\/or effective in patients.<\/p>\n Interestingly, all statin drugs they tested were effective.\u00a0 This is explained more fully in their article published in the journal Cell Stem Cell.<\/em> He mentioned that in previous studies statins have been shown to reduce AD risk. In their cell cultures, several statins consistently reduced p-tau accumulation in a dosage dependent manner. \u00a0He noted that atorvastatin stood out as being just a bit better than the others in this regard.<\/p>\n This has also been noted in previous studies, including:<\/p>\n \u201cResults of this analysis revealed that statin users had better cognitive scores than nonusers; and this effect was somewhat more evident with the use of some lipophilic statins (atorvastatin and lovastatin).\u201d<\/em>\u00a0 Geifman, N., Brinton, R.D., Kennedy, R.E. et al. Evidence for benefit of statins to modify cognitive decline and risk in Alzheimer\u2019s disease. Alz Res Therapy 9, 10 (2017). https:\/\/doi.org\/10.1186\/s13195-017-0237-y<\/a><\/p>\n However, other studies reporting that statins reduced the risk of developing LOAD found no clear differences between the various hydrophilic and lipophilic statins; for example:<\/p>\n Haag, M. D. M.; Hofman, A.; Koudstaal, P. J.; Stricker, B. H. C.; Breteler, M. M. B. Statins Are Associated with a Reduced Risk of Alzheimer Disease Regardless of Lipophilicity. The Rotterdam Study. Journal of Neurology, Neurosurgery & Psychiatry 2009, 80 (1), 13\u201317. https:\/\/doi.org\/10.1136\/jnnp.2008.150433<\/a>.<\/p>\n Probing the system further Dr. van der Kant\u2019s group found that cholesterol itself was not the critical link to A\u03b2 and p-tau accumulation in the brain.\u00a0 Rather they found that levels of cholesterol esters (CEs), a storage and transport form of the molecule, was key.<\/p>\n Cholesterol is an essential building block of animal cell membranes, and can be obtained from the diet or synthesized by cells.\u00a0 It is required for the synthesis of steroid hormones and vitamin D. \u00a0It is not a water-soluble molecule and it is transported in blood within bubble-like lipoprotein particles.\u00a0 The brain is a cholesterol hog.\u00a0 It possesses 20% of the bodies cholesterol, by weight.<\/p>\n When cholesterol is bound to a fatty acid chain by an ester bond, cholesterol esters are formed.\u00a0 Most cholesterol in our diets and in circulating lipoprotein particles are in this form.<\/p>\n These researchers found that lowering CE concentrations using statins – again in cells cultures from AD patients – lowers A\u03b2 and p-tau levels.\u00a0 These two effects seem to occur separately, by independent mechanisms.<\/p>\n Statin drugs inhibit the HMG CoA reductase enzyme, the rate limiting step in cholesterol production.<\/p>\n One interesting finding is that the amyloid precursor protein (APP; the cell surface protein that can be cleaved to form A\u03b2) has a molecular site that binds strongly to cholesterol.\u00a0 Dr. van der Kant pointed out that eliminating this binding site prevented statins from lowering A\u03b2 levels but that in this case p-tau was still reduced. \u00a0This is more solid evidence that statins reduce A\u03b2 and p-tau in different ways, but at the same time.<\/p>\n Here Dr. van der Kant made an important point. He stressed that despite their ability to reduce LOAD incidence, to a modest degree, in large population studies, statins don’t generally work to treat LOAD in individual patients.\u00a0 He suggested this is because statins either don’t reach the brain in high enough concentrations or because statins can be toxic to astrocytes, brain cells which nurture and protect neurons. He shared data to demonstrate this occurring in cell culture.<\/p>\n Similar statin toxicity has been observed previously.\u00a0 For example:<\/p>\n \u201cHowever, there are data indicating that statins can have toxic effects on brain neural cells\u2026.In general, what distinguishes the studies on protective effects of statins versus toxic effects are the drug concentrations used in the different studies.\u201d<\/em>\u00a0 Wood, W. G.; Eckert, G. P.; Igbavboa, U.; Muller, W. E. Statins and Neuroprotection: A Prescription to Move the Field Forward. Annals of the New York Academy of Sciences 2010, 1199 (1), 69\u201376. https:\/\/doi.org\/10.1111\/j.1749-6632.2009.05359.x<\/a>.<\/p>\n A review of the positive and negative effects of statins for LOAD is:<\/p>\n Schultz, B. G.; Patten, D. K.; Berlau, D. J. The Role of Statins in Both Cognitive Impairment and Protection against Dementia: A Tale of Two Mechanisms. Translational neurodegeneration 2018, 7 (1), 5\u201311. https:\/\/doi.org\/10.1186\/s40035-018-0110-3<\/a>.<\/p>\n In short, while large population studies sometimes find that long-term statin is associated with modest reduction in the incidence of LOAD, suggesting a potential preventative role, statins do not cure individual patients with Alzheimer\u2019s disease and at high levels can be toxic to important brain cell types.<\/p>\n Dr. van der Kant\u2019s group identified a different drug that seems to be effective, without harming astrocyctes.<\/p>\n Efavirnez, sold under the brand name Sustiva (among others), is an antiretroviral medication used to treat and prevent HIV\/AIDS. \u00a0The researchers found that it crosses the blood brain barrier and binds specifically to an enzyme found primarily in neurons to effectively reduce CE levels.\u00a0 This is an encouraging dataset.<\/p>\n He pointed out that accumulation of “lipid droplets” is a characteristic of AD first observed by Dr. Alois Alzheimer and suggested that these droplets could have been accumulations of excess CEs in the brains of LOAD patients.\u00a0 This observation seems to fit with the theory that reducing CE over-production could reduce the accumulation of A\u03b2 and p-tau.<\/p>\n Recall that the apoe4 risk gene seems to increase lipid droplet accumulation.<\/p>\n For more information about lipid droplets, apoe4, and LOAD, see the summary of Dr. Lance Johnson\u2019s seminar from March 26.<\/p>\n Dr. van der Kant\u2019s group \u2013 and others \u2013 have tested Efavirnez in mice and found it effective.\u00a0 He suggested these previous, related studies focusing on this drug:<\/p>\n Mast, N.; Li, Y.; Linger, M.; Clark, M.; Wiseman, J.; Pikuleva, I. A. Pharmacologic Stimulation of Cytochrome P450 46A1 and Cerebral Cholesterol Turnover in Mice. J. Biol. Chem. 2014, 289 (6), 3529\u20133538. https:\/\/doi.org\/10.1074\/jbc.M113.532846<\/a>.<\/p>\n