TY - JOUR
T1 - Progressive neurovascular disturbances in the cerebral cortex of Alzheimer's disease-model mice
T2 - Protection by atorvastatin and pitavastatin
AU - Kurata, T.
AU - Miyazaki, K.
AU - Kozuki, M.
AU - Morimoto, N.
AU - Ohta, Y.
AU - Ikeda, Y.
AU - Abe, K.
N1 - Funding Information:
This work was partly supported by a Grant-in-Aid for Scientific Research (B) 21390267 and the Ministry of Education, Culture, Sports, Science and Technology of Japan , and by Grants-in-Aid from the Research Committee of CNS Degenerative Diseases (Nakano I), and grants (Itoyama Y, Imai T, Sobue G, and Mizusawa H) from the Ministry of Health, Labour and Welfare of Japan .
PY - 2011/12/1
Y1 - 2011/12/1
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Astrocyte
KW - Collagen IV
KW - Microglia
KW - Neurovascular unit
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U2 - 10.1016/j.neuroscience.2011.09.030
DO - 10.1016/j.neuroscience.2011.09.030
M3 - Article
C2 - 21955601
AN - SCOPUS:82855175132
VL - 197
SP - 358
EP - 368
JO - Neuroscience
JF - Neuroscience
SN - 0306-4522
ER -