Progressive neurovascular disturbances in the cerebral cortex of Alzheimer's disease-model mice: protection by atorvastatin and pitavastatin

Abstract

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. Thus, we examined 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 (3 mg/kg/day, p.o.) were administered from 5 to 20 months of age. Changes in the NVU, including the endothelium and basement membrane, as well as astrogliosis and matrix metalloproteinase-9 (MMP-9) activation, were assessed. 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 senile plaques (SPs). There was also an increase in intensity and number 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. Treatment with atorvastatin or pitavastatin ameliorated the activation of MMP-9. Overall, these data suggest that statins may have therapeutic potential for AD by protecting NVU.