Simvastatin improves cerebrovascular function and counters soluble amyloid-beta, inflammation and oxidative stress in aged APP mice.
Cerebrovascular dysfunctions appear to contribute to Alzheimer's disease (AD) pathogenesis and the associated cognitive decline. Recently, it has been suggested that statins could be beneficial to AD patients independently from their cholesterol-lowering effects. Using 10 month-old amyloid precursor protein transgenic mice (APP mice), we sought to reverse cerebrovascular, neuronal and memory impairments with simvastatin (20 mg/kg/day, 8 weeks). Simvastatin improved reactivity of cerebral arteries, rescued the blood flow response to neuronal activation, attenuated oxidative stress and inflammation, and reduced cortical soluble amyloid-beta (Abeta) levels and the number of Abeta plaque-related dystrophic neurites. However, at such an advanced stage of the pathology, it failed to reduce Abeta plaque load and normalize cholinergic and memory deficits. These findings demonstrate that low-dose simvastatin treatment in aged APP mice largely salvages cerebrovascular function and has benefits on several AD landmarks, which could explain some of the positive effects of statins reported in AD patients.
Tong
Xin-Kang
XK
Laboratory of Cerebrovascular Research, Montreal Neurological Institute, 3801 University Street, Montréal, Québec H3A 2B4, Canada.
Nicolakakis
Nektaria
N
Fernandes
Priscilla
P
Ongali
Brice
B
Brouillette
Jonathan
J
Quirion
Rémi
R
Hamel
Edith
E
D000375:Aging; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000276:immunology; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy*; D006801:Humans; D007859:Learning Disabilities / Q000188:drug therapy; D008569:Memory Disorders / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015213:Neuroimmunomodulation / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects*; D058225:Plaque, Amyloid / Q000187:drug effects; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000235:genetics; D019821:Simvastatin / Q000008:administration & dosage / Q000627:therapeutic use*; D013028:Space Perception / Q000187:drug effects
C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018696:Neuroprotective Agents; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D019821:Simvastatin