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Biological Chemistry

Study Strengthens Alzheimer's Link To Cholesterol

Findings on the mechanism of a cholesterol metabolism pathway could aid development of new therapeutics

by Stuart A. Borman
February 8, 2010 | A version of this story appeared in Volume 88, Issue 6

Findings on the molecular mechanism of a cholesterol metabolism pathway could aid development of a new class of Alzheimer’s disease therapeutics, according to a research report. Cholesterol metabolism is known to play a role in the accumulation of amyloid β, a peptide associated with Alzheimer’s. Dora M. Kovacs of Harvard Medical School and coworkers previously showed that inhibitors of acyl-coenzyme A:cholesterol acyltransferase (ACAT) reduce amyloid β accumulation in cell and animal tests, but the way the inhibitors work has been unclear. Now, Ta-Yuan Chang of Dartmouth Medical School and coworkers find that genetic inactivation of ACAT1, one form of ACAT, in a mouse model of Alzheimer’s boosts levels of a cholesterol metabolite, 24(S)-hydroxycholesterol. Chang and colleagues propose that this biochemical response leads to a reduction in amyloid precursor protein and therefore amyloid β (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.0913828107). The study confirms the potential of ACAT1 as a therapeutic target for treating certain forms of Alzheimer’s disease, the researchers write. Kovacs says the work supports her group’s previous findings. Samuel E. Gandy of Mt. Sinai School of Medicine, in New York City, an expert in lipid-based Alz­hei­mer’s therapy, adds, “I believe that this work has major clinical implications.”


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