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Changes in cognition and amyloid-β processing with long term cholesterol reduction using atorvastatin in aged dogs
M Paul Murphy1, Jacqueline Morales, Tina L Beckett
1Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 405360230, USA. mpmurp3@email.uky.edu
Journal of Alzheimer'S Disease : JAD
|September 18, 2010
Summary
Atorvastatin did not improve cognitive function in aged dogs with Alzheimer's disease (AD) pathology. While it lowered cholesterol and reduced BACE1, transient cognitive impairments suggest potential adverse effects warranting further study.
Area of Science:
- Neuroscience
- Pharmacology
- Gerontology
Background:
- Human studies on statins and Alzheimer's disease (AD) show conflicting results regarding their protective effects.
- Aged dogs exhibit cognitive impairments and amyloid-beta (Aβ) pathology, making them a relevant model for AD research.
- Cholesterol reduction via statins is hypothesized to impact AD progression.
Purpose of the Study:
- To investigate the effects of atorvastatin on cognitive function and neuropathology in aged dogs.
- To determine if statin-mediated cholesterol reduction impacts amyloid-beta (Aβ) pathology and related biomarkers.
- To assess the translational relevance of aged dogs as a model for statin use in human AD trials.
Main Methods:
- Aged dogs (n=12) were treated with atorvastatin (80 mg/day) for 14.5 months.
- Cognitive functions including discrimination and reversal learning, and spatial memory were assessed.
- Cerebrospinal fluid (CSF) and brain tissues were analyzed for Aβ, β-secretase-1 (BACE1) activity, and lipid profiles.
Main Results:
- Atorvastatin significantly reduced peripheral cholesterol, LDLs, triglycerides, and HDL.
- No improvement in discrimination learning or spatial memory was observed; transient reversal learning impairments suggested frontal dysfunction.
- Brain Aβ levels remained unaffected, but BACE1 protein and activity decreased, correlating with reduced brain cholesterol.
- Lipidomic analysis showed a decreased omega-6 to omega-3 essential fatty acid ratio in the temporal cortex.
Conclusions:
- Atorvastatin treatment in aged dogs did not improve cognitive function and induced transient impairments.
- The drug reduced BACE1 protein and activity, and altered brain lipid profiles, suggesting potential neuroprotective mechanisms.
- Aged dogs offer a valuable translational model for exploring statin effects in human AD, highlighting the need to investigate potential adverse cognitive outcomes.
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