Bibliographic
In this study the authors investigated the therapeutic value of simvastatin in the A/T mouse model of AD,which displays cognitive deficits and cerebrovascular pathology. Using adult mice (3-month-old, tested after 3 and 6 months of treatment) the authors assessed the capacity of simvastatin (40 mg/kg/d) in rescuing spatial learning and memory in addition to cerebral arterial reactivity, astroglial and microglial activation, amyloidosis, and proteins regulating cerebrovascular structure and function. Previous studies testing simvastatin in Tg APP mouse models of AD reported normalization of several AD hallmarks such as impaired brain glucose metabolism, glial activation, cerebrovascular dysfunction and most importantly, memory deficits. Similar to Tg APP models simvastatin treatment of A/T mice significantly decreased insoluble Aβ peptide levels and Aβ plaque load despite no effect on BACE1 and Aβ-degrading enzyme neprilysin protein levels. However, in contrast to Tg APP models simvastatin failed to improve spatial learning and memory. It was anticipated that simvastatin would normalized cerebrovascular function in A/T mice. However, using some measures simvastatin aggravated cerebrovascular function. In addition, simvastatin did not reduce astrocytosis, microglial activation, eNOS or VEGF levels. The data indicate that simvastatin, in contrast to its high efficacy in APP Tg mice, has more limited benefits in A/T mice even after extended treatment (6 months). Together, these findings highlight the importance of testing potentially promising therapies in experimental models that recapitulate multiple facets of AD because they might better predict efficacy in a disease as complex as AD.