Atorvastatin and pitavastatin reduce oxidative stress and improve IR/LDL-R signals in alzheimer's disease

Objectives: To examine and compare the pleiotropic effects on oxidative stress and metabolic signaling pathways of atorvastatin and pitavastatin in mouse model of Alzheimer's disease (AD). Methods: We gave the transgenic (Tg) mice either atorvastatin or pitavastatin from 5-20 months (M) of age, and performed immunohistological analysis [4-hydroxy-2-nonenal (4-HNE)-positive, advanced glycation end products (AGEs), low-density lipoprotein receptor (LDL-R)-positive neurons, apolipoprotein E (ApoE)- positive senile plaque (SP), and insulin receptor (IR)-positive endothelium], and biochemistry analysis (adiponectin and leptin). Results: The numbers of 4-HNE- and AGE-positive neurons and the sum of ApoE-positive SP size progressively increased with age in amyloid precursor protein (APP)-Tg mice, while the amount of IR- positive endothelium and the number of LDL-R-positive neurons decreased. Adiponectin and leptin serum levels were lower in APP-Tg mice than in non-Tg mice. Treatment with statins reduced the number of AGE- positive neurons from as early as 10 M, preserved the numbers of 4-HNE- and LDL-R-positive neurons and the amount of IR-positive endothelium at 15 M, and reduced the sum of ApoE-positive SP size and adiponectin serum level at 20 M. Discussion: Atorvastatin and pitavastatin reduced the level of oxidative stress, as revealed by the presence of 4-HNE and AGE, in AD mouse brains, and that treatment with statins improves insulin signaling and LDL- R/ApoE systems. The beneficial effects of these statins may be associated with direct pleiotropic effects on AD mouse brains, indirect effects through improving the serum adiponectin/leptin balance, or both.