A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer's 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.
Refolo
L M
LM
Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York 10962, USA. refolo@nki.rfmh.org
Pappolla
M A
MA
LaFrancois
J
J
Malester
B
B
Schmidt
S D
SD
Thomas-Bryant
T
T
Tint
G S
GS
Wang
R
R
Mercken
M
M
Petanceska
S S
SS
Duff
K E
KE
D000544:Alzheimer Disease / Q000097:blood / Q000188:drug therapy / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000032:analysis*; D016564:Amyloid beta-Protein Precursor / Q000032:analysis; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016282:Aspartic Acid Endopeptidases; D001923:Brain Chemistry / Q000187:drug effects*; D002784:Cholesterol / Q000032:analysis / Q000097:blood / Q000502:physiology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D010450:Endopeptidases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000032:analysis; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000032:analysis*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D053764:Presenilin-1; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology; D000683:Serum Amyloid P-Component / Q000032:analysis
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C508853:PSEN1 protein, human; D010879:Piperazines; D053764:Presenilin-1; D000683:Serum Amyloid P-Component; C047457:BM 15766; D002784:Cholesterol; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse