bm-15766 and Alzheimer-Disease

Clinical, epidemiological, and laboratory studies suggest that cholesterol may play a role in the pathogenesis of Alzheimer's disease (AD). Transgenic mice exhibiting an Alzheimer's beta-amyloid phenotype were treated with the cholesterol-lowering drug BM15.766 and tested for modulation of beta-amyloid levels. BM15.766 treatment reduced plasma cholesterol, brain Abeta peptides, and beta-amyloid load by greater than twofold. A strong, positive correlation between the amount of plasma cholesterol and Abeta was observed. Furthermore, drug treatment reduced the amyloidogenic processing of the amyloid precursor protein, suggesting alterations in processing in response to cholesterol modulation. This study demonstrates that hypocholesterolemia is associated with reduced Abeta accumulation suggesting that lowering cholesterol by pharmacological means may be an effective approach for reducing the risk of developing AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Anticholesteremic Agents; Aspartic Acid Endopeptidases; Brain Chemistry; Cholesterol; Disease Models, Animal; Drug Evaluation, Preclinical; Endopeptidases; Enzyme Inhibitors; Female; Humans; Male; Membrane Proteins; Mice; Mice, Transgenic; Nerve Tissue Proteins; Oxidoreductases; Oxidoreductases Acting on CH-CH Group Donors; Piperazines; Presenilin-1; Protein Processing, Post-Translational; Serum Amyloid P-Component