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CHOLESTEROL METABOLISM: A THERAPEUTIC TARGET FOR ALZHEIMER’S DISEASE.

Dr. Larry Refolo,

Scientific Director, The Institute of the Study of Aging, New York, USA.

Cerebral accumulation of Amyloid b (Ab) peptides is an early event in establishing of Alzheimer’s disease pathology.  Based on epidemiological studies pointing to a link between cholesterol metabolism and Alzheimer’s disease (AD) as well as experimental evidence implicating cholesterol in the process of Ab production and accumulation it is now believed that cholesterol-lowering therapies will be of value for AD prevention and/or treatment.

Epidemiological studies have revealed that the use of statins for the treatment of hypercholesterolemia- and hyperlipidemia–related, coronary arterial disease is associated with a decreased prevalence or a decreased risk of developing AD. However, these observations  require both preclinical and clinical validation.

The former involves testing statins in one or more animal models of AD in order to establish which disease features are affected by statin treatment, the relative efficacy with which different statins modify these features and the mechanism(s) by which statins affect AD phenotypes.

Here we discuss the results of a preclinical study aimed at determining the effects of atorvastatin (Lipitor^R) on brain Ab deposition in the PSAPP transgenic mouse model of Alzheimer’s disease. The atorvastatin-induced hypocholesterolemia was associated with a marked reduction in brain Ab deposition and was also accompanied with a reduction in brain ApoE content.

Based on our findings and the observations of others regarding the effects of statins on Ab metabolism and taking into account the current knowledge of the various activities of statins, we propose a working hypothesis of the mechanisms by which statins modulate brain amyloidosis

Lorenzo M. Refolo Ph.D.

Institute for the Study of Aging, 767 Fifth Avenue, Suite 4600, New York, NY 10153

Graduating in Biology at the University of Connecticut, he did a Ph.D. in Molecular Genetics at the University of Medicine and Dentistry of New Jersey Department of Microbiology and Molecular Genetics Newark. NJ

POSTDOCTORAL TRAINING

1986 - 1987 Post-doctoral, Fellow, Laboratory of Neurobiology Rockefeller University, NY, NY.

1987-1989 Post-doctoral Fellow Department of Psychiatry and Neurobiology Center Mount Sinai School of Medicine, NY, NY.

ACADEMIC APPOINTMENTS

1989-1994 Research Assistant Professor Department of Psychiatry and Fishberg Center for Neurobiology Mount Sinai School of Medicine, NY, NY.

1995 Visiting Scientist Department of Pathology University of Texas Medical Center Houston, TX.

1995-1998 Associate Consultant/Assistant Professor Aizheimer's Disease Center Mayo Clinic, Jacksonville, FL.

1998-2001 Research Assistant Professor Nathan S. Kline Institute, Orangeburg, NY. Department of Psychiatry New York University New York, NY

Since August 2001 he has been Scientific Director of The Institute for the Study of Aging, New York, NY.

Recent Publications:

            1.         Fillit HM, O'Connell AW, Refolo LM. Strategies for drug discovery for cognitive aging and Alzheimer's disease. J Mol.Neurosci. 2002;19:1-3.

            2.         Petanceska SS, DeRosa S, Olm V, Diaz N, Sharma A, Thomas-Bryant T et al. Statin therapy for Alzheimer's disease: will it work? J Mol.Neurosci. 2002;19:155-61.

            3.         Pappolla MA, Smith MA, Bryant-Thomas T, Bazan N, Petanceska S, Perry G et al. Cholesterol, oxidative stress, and Alzheimer's disease: expanding the horizons of pathogenesis. Free Radic.Biol.Med. 2002;173-81.

            4.         Eckman CB, Mehta ND, Crook R, Perez-tur J, Prihar G, Pfeiffer E et al. A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of A beta 42(43). Hum.Mol.Genet. 1997;6:2087-9.

            5.         Zhao J, Paganini L, Mucke L, Gordon M, Refolo L, Carman M et al. Beta-secretase processing of the beta-amyloid precursor protein in transgenic mice is efficient in neurons but inefficient in astrocytes. J Biol.Chem. 1996;271:31407-11.