Cole SL, Grudzien A, Manhart IO, Kelly BL, Oakley H, Vassar R. Statins cause intracellular accumulation of amyloid precursor protein, beta-secretase-cleaved fragments, and amyloid beta-peptide via an isoprenoid-dependent mechanism. J Biol Chem. 2005 May 13;280(19):18755-70. PubMed.

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  1. This paper is most remarkable. The authors show that statin treatment, which has long been thought to be beneficial for Alzheimer disease patients, has two independent and diverging effects on APP processing. In a novel in-vitro system, the authors have been able to decipher the cholesterol-dependent and isoprenoid-dependent role of statins. The effects are surprisingly different. While low cholesterol reduced APP processing and Aβ generation, as expected, low isoprenoid levels enhanced intracellular accumulation of APP and its proteolytic products, including Aβ. Several recent studies have implicated a potential role of intraneuronal Aβ as an early pathological hallmark in AD patients. Together with recent reports that intracellular accumulation of Aβ is observed prior to neuronal death in APP/PS1 mouse models, one wonders whether statin treatment is indeed beneficial for Alzheimer disease patients.

    View all comments by Thomas Bayer

  2. Have you considered the possibility that a mechanism of statin action in AD may be related to its stimulatory effect on cerebral blood flow?

    View all comments by James Crawford

  3. The paper by Cole and colleagues is a very elegant manuscript because it provides important new insights into how statins might affect APP processing. The observation that inhibition of isoprenoid metabolism increases intracellular Aβ accumulation is surprising and important for the field to realize. However, the enzymes that drive isoprenoid synthesis have a very high affinity for their substrates, which means that isoprenoid synthesis remains intact even when cholesterol synthesis is partially blocked. Whether statins would actually cause this [Aβ accumulation] to occur in vivo remains an open question because statin treatment does not necessarily fully reduce cholesterol synthesis under the conditions used clinically (depending on the particular statin and dose utilized). This manuscript is also important because it elegantly defines careful methods for dissecting out the effects of cholesterol metabolism on the cell. By defining four treatment paradigms, the authors provide a roadmap for future studies into cholesterol biology.

    View all comments by Benjamin Wolozin

  4. Downregulation of clathrin-mediated intracellular transport; desensitization of receptor-mediated ester endocytosis, and RNAi antisense against cell synthesis of cholesterol could prove a powerful synergy of therapeutic treatment in this area. Decreased hydrolytic activity in lysosmes would further ensure less risk of bursting a cell (although targeting specific lysis may prove useful in overly active glial that cannot be suppressed or reverted back to inactive state).

    Isoprenoids that show a detrimental role to Alzheimers onset and progression might possibly show also show neuroprotective roles in future treatment modalities. Statins, although promising, are not the miracle some people belived they were.

    View all comments by Jacob Mack

  5. I find this paper encouraging to research in the area of statins and effects on various esters, their constituents and other biochmeical markers in Alzheimers. I am curious, though, how we may be able to maximize isoprenoid activity, lower cholesterol, (possibly through further clathrin downregulation), and block signal transduction cell receptors themselves. Maybe desensitize some and sensitize others in order to further find the efficacy of statins and new emerging delivery systems of them.

    Would it be fair to say that optimum lysosomal activity coupled with repressed cell uptake of cholesterol; and combined with cannabinoid-mediated lipid interference (arachidonic acid and others) of endocytotoxicity might in fact deal with many of the extra- and intracellular amyloid deposits. Then by using CB-2 mediated immune response we would partially suppress microglial activation. Then follow that up with a regiment of antioxidants, for we know that amyloid and immune cells oxidize (either immune system dependent/coupled with) so much cortical/subcortical matter, and, of course enzymes need their coenzymes. I read so much great research here at Alzforum, I would like to see more synergy among the various researchers.

    View all comments by Jacob Mack

  6. This excellent paper very elegantly untangled the differential and independent mechanisms by which Ab production is affected by isoprenoids and cholesterol. Unfortunately, the above discussion whether statin treatment in humans could increase intracellular Ab takes us away from the main and very important finding that the isoprenoid pathway is involved in Ab generation.

    As it has been pointed out in the paper and in the Q&A section above, it is experimentally possible to use statins in vitro at a concentration that shuts off HMG-CoA reductase activity. Only under these specific circumstances the isoprenoid pathway is shut down too. For a number of reasons such an approach would be incompatible with life. Animals need cholesterol to maintain functional membranes, cells continuously shed cholesterol from the plasma membrane and this cholesterol must be replenished. Contrary to popular belief, cells produce most of their cholesterol needs themselves by de-novo synthesis, only a minor part is hepatocyte- or diet-derived.

    Notwithstanding the perilous consequences of isoprenoid depletion, without HMG-CoA reductase activity the animal would sooner or later run out of cholesterol stores and die. Similar statin brain concentrations (0.25µM) as the minimal concentration used in the elegant in-vitro studies by Vassar had been reported in mice by Gibson Wood. These high levels were achieved by feeding 50 times the maximum clinical dose, could be maintained only for brief periods of time and steady state levels were considerably lower.

    Cell-culture studies define mechanisms, not therapeutic strategies. In light of the existing data, this part of the discussion is difficult to comprehend. The necessary statin dosage would have to be enormously above clinical standards before harmful accumulation of intracellular Ab occurs. That the patient would be dead by that time for other reasons shows only how unrealistic this discussion is. Like Robert Vassar, I don’t see any evidence that clinical statin dosages could possibly cause relevant intracellular Ab accumulation. In a way, millions of patients on statins give living confirmation for this year by year.

    View all comments by Tobias Hartmann

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