Advertisement
Research Article

Modulation of Statin-Activated Shedding of Alzheimer APP Ectodomain by ROCK

  • Steve Pedrini equal contributor,

    equal contributor Contributed equally to this work with: Steve Pedrini, Troy L Carter

    Affiliation: Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America

    X
  • Troy L Carter equal contributor,

    equal contributor Contributed equally to this work with: Steve Pedrini, Troy L Carter

    Affiliation: Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America

    X
  • George Prendergast,

    Affiliation: Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, United States of America

    X
  • Suzana Petanceska,

    Affiliation: Nathan S. Kline Institute for Psychiatric Research, Department of Psychiatry, New York University School of Medicine, Orangeburg, New York, United States of America

    X
  • Michelle E Ehrlich,

    Affiliation: Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America

    X
  • Sam Gandy

    Affiliations: Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America, Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, United States of America

    X
  • Published: January 11, 2005
  • DOI: 10.1371/journal.pmed.0020018

Reader Comments (2)

Post a new comment on this article

An Enigma Wrapped in a Conundrum

Posted by plosmedicine on 30 Mar 2009 at 23:39 GMT

Author: Sam Gandy
Position: Professor and Director
Institution: Farber Institute for Neurosciences of Thomas Jefferson University
E-mail: samgandy@earthlink.net
Submitted Date: February 02, 2005
Published Date: February 3, 2005
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

We appreciate Dr Koudinov's note. In our opinion, no model has yet been presented that plausibly accounts for all the data on statins, cholesterol, amyloid, and Alzheimer's. In our paper, we present evidence that the isoprenoid pathway contributes to statin-activated shedding of the APP ectodomain in cultured cells. We would not yet know which (if any) other "cholesterol-related" Alzheimer phenomena are also attributable to modulation of isoprenoids, Rho, or ROCK.

Previously, conventional wisdom held that A-beta load and hypercholesterolemia were directly related, based on the observation that high-fat diet aggravates amyloid pathology in plaque-forming mice. (Refolo et al., 2000). Refolo LM, Malester B, LaFrancois J, Bryant-Thomas T, Wang R, Tint GS, Sambamurti K, Duff K, Pappolla MA. Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol Dis. 2000 Aug;7(4):321-31). More recently, however, the formulation that statins act simply via cholesterol-lowering fails to account for several observations that cannot immediately be reconciled, either with the original dogma or with each other:

First, Fagan et al. (Fagan AM, Christopher E, Taylor JW, Parsadanian M, Spinner M, Watson M, Fryer JD, Wahrle S, Bales KR, Paul SM, Holtzman DM. ApoAI deficiency results in marked reductions in plasma cholesterol but no alterations in amyloid-beta pathology in a mouse model of Alzheimer's disease-like cerebral amyloidosis. Am J Pathol. 2004 Oct;165(4):1413-22.2004), questioned the role of cholesterol as the final common pathway in A-beta load specification, since, in their experiments, low cholesterol per se apparently had no impact on brain A-beta load in plaque-forming transgenic mice. Pharmacological data are equally puzzling. Atorvastatin has recently been shown to lower brain amyloid load and A-beta levels, but brain cholesterol levels were unaffected (Petanceska S, Papolla M, Refolo L. Modulation of Alzheimer's amyloidosis by statins. Curr Med Chem 2003 3, 233-243). In an apparent complete contradiction with the original dogma, now, some investigators have been able to demonstrate an inverse relationship between cholesterol and A-beta in some situations, with low neuronal cholesterol increasing A-beta generation (Abad-Rodriguez J, Ledesma MD, Craessaerts K, Perga S, Medina M, Delacourte A, Dingwall C, De Strooper B, Dotti CG. Neuronal membrane cholesterol loss enhances amyloid peptide generation.J Cell Biol. 2004 Dec 6;167(5):953-60), and vice versa (George AJ, Holsinger RM, McLean CA, Laughton KM, Beyreuther K, Evin G, Masters CL, Li QX. APP intracellular domain is increased and soluble Abeta is reduced with diet-induced hypercholesterolemia in a transgenic mouse model of Alzheimer disease. Neurobiol Dis. 2004 Jun;16(1):124-32).
These newer observations are extremely puzzling, and the explanation is not at all clear.

For those readers seeking an update on this challenging area, we would direct your attention to the AlzForum.org website

(http://www.alzforum.org/n...)

where you will find an excellent review of the literature as well as a series of evaluations of how our data fit into existing scenarios and models regarding cholesterol, statins, cerebral amylodosis, and the cognitive failure of Alzheimer's disease.

No competing interests declared.