Changes in cognition and amyloid-β processing with long term cholesterol reduction using atorvastatin in aged dogs.
Human studies suggest either a protective role or no benefit of statins against the development of Alzheimer's disease (AD). We tested the hypothesis that statin-mediated cholesterol reduction in aged dogs, which have cognitive impairments and amyloid-β (Aβ) pathology, would improve cognition and reduce neuropathology. In a study of 12 animals, we treated dogs with 80 mg/day of atorvastatin for 14.5 months. We did not observe improvements in discrimination learning; however, there were transient impairments in reversal learning, suggesting frontal dysfunction. Spatial memory function did not change with treatment. Peripheral levels of cholesterol, LDLs, triglycerides, and HDL were significantly reduced in treated dogs. Aβ in cerebrospinal fluid and brain remained unaffected. However, β-secretase-1 (BACE1) protein levels and activity decreased and correlated with reduced brain cholesterol. Finally, lipidomic analysis revealed a significant decrease in the ratio of omega-6 to omega-3 essential fatty in temporal cortex of treated aged dogs. Aged beagles are a unique model that may provide novel insights and translational data that can predict outcomes of statin use in human clinical trials. Treatment with atorvastatin may be beneficial for brain aging by reducing BACE1 protein and omega6:omega3 ratio, however, the potential adverse cognitive outcomes reported here should be more carefully explored given their relevance to human clinical outcomes.
Murphy
M Paul
MP
Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 405360230, USA. mpmurp3@email.uky.edu
Morales
Jacqueline
J
Beckett
Tina L
TL
Astarita
Giuseppe
G
Piomelli
Daniele
D
Weidner
Adam
A
Studzinski
Christa M
CM
Dowling
Amy L S
AL
Wang
Xiaohong
X
Levine
Harry
H
Kryscio
Richard J
RJ
Lin
Yushun
Y
Barrett
Edward
E
Head
Elizabeth
E
D000375:Aging / Q000097:blood / Q000187:drug effects*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000378:metabolism*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D000069059:Atorvastatin; D002784:Cholesterol / Q000097:blood*; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D004193:Discrimination Learning / Q000187:drug effects / Q000502:physiology; D004285:Dogs; D005260:Female; D006538:Heptanoic Acids / Q000494:pharmacology*; D008297:Male; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D011597:Psychomotor Performance / Q000187:drug effects* / Q000502:physiology; D011758:Pyrroles / Q000494:pharmacology*; D011897:Random Allocation; D013997:Time Factors
D016229:Amyloid beta-Peptides; D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D011758:Pyrroles; D002784:Cholesterol; D000069059:Atorvastatin