Statins have therapeutic potential for the treatment of Alzheimer's disease, likely via protection of the neurovascular unit in the AD brain.
Structural and functional abnormalities in the neurovascular unit (NVU) have been recently observed in Alzheimer's disease (AD). Statins, which are used clinically for reducing cholesterol levels, can also exert beneficial vascular actions, improve behavioral memory and reduce senile plaque (SP). Thus, we examined cognitive function, the serum level of lipids, senile plaque (SP), and the protective effects of statins on NVU disturbances in a mouse AD model. Amyloid precursor protein (APP) transgenic (Tg) mice were used as a model of AD. Atorvastatin (30 mg/kg/day, p.o.) or pitavastatin (3mg/kg/day, p.o.) were administered from 5 to 20 months of age. These 2 statins improved behavioral memory and reduced the numbers of SP at 15 and 20 M without affecting serum lipid levels. There was a reduction in immunopositive staining for N-acetyl glucosamine oligomer (NAGO) in the endothelium and in collagen IV in the APP vehicle (APP/Ve) group, with collagen IV staining most weakest near SP. There was also an increase in intensity and numbers of glial fibrillary acidic protein (GFAP) positive astrocytes, particularly around the SP, where MMP-9 was more strongly labeled. Double immunofluorescent analysis showed that astrocytic endfeet had detached from the capillary endothelium in the APP/Ve group. Overall, these data suggest that statins may have therapeutic potential for AD by protecting NVU.
Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikatacho, Kitaku, Okayama 700-8558, Japan.
Tomoko
T
Kurata
Hiromi
H
Kawai
Kazunori
K
Miyazaki
Miki
M
Kozuki
Nobutoshi
N
Morimoto
Yasuyuki
Y
Ohta
Yoshio
Y
Ikeda
Koji
K
Abe
D000367:Age Factors; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D000069059:Atorvastatin; D002784:Cholesterol / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005944:Glucosamine / Q000378:metabolism; D006538:Heptanoic Acids / Q000627:therapeutic use*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D008747:Methylcellulose / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D011758:Pyrroles / Q000627:therapeutic use*; D011804:Quinolines / Q000627:therapeutic use*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000924:Anticholesteremic Agents; D024141:Collagen Type IV; D005904:Glial Fibrillary Acidic Protein; D006538:Heptanoic Acids; D011758:Pyrroles; D011804:Quinolines; D008747:Methylcellulose; D002784:Cholesterol; D000069059:Atorvastatin; D020780:Matrix Metalloproteinase 9; C108475:pitavastatin; D005944:Glucosamine