Minocycline corrects early,pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer's disease-like amyloid pathology

Background: a growing body of evidence indicates that inflammation is one of the earliest neuropathological events in alzheimer's disease. accordingly,we have recently shown the occurrence of an early,pro-inflammatory reaction in the hippocampus of young,three-month-old transgenic mcgill-thy1-app mice in the absence of amyloid plaques but associated with intracellular accumulation of amyloid beta petide oligomers. the role of such a pro-inflammatory process in the progression of the pathology remained to be elucidated.methods and results: to clarify this we administered minocycline,a tetracyclic derivative with anti-inflammatory and neuroprotective properties,to young,pre-plaque mcgill-thy1-app mice for one month. the treatment ended at the age of three months,when the mice were still devoid of plaques. minocycline treatment corrected the up-regulation of inducible nitric oxide synthase and cyclooxygenase-2 observed in young transgenic placebo mice. furthermore,the down-regulation of inflammatory markers correlated with a reduction in amyloid precursor protein levels and amyloid precursor protein-related products. beta-site amyloid precursor protein cleaving enzyme 1 activity and levels were found to be up-regulated in transgenic placebo mice,while minocycline treatment restored these levels to normality. the anti-inflammatory and beta-secretase 1 effects could be partly explained by the inhibition of the nuclear factor kappa b pathway.conclusions: our study suggests that the pharmacological modulation of neuroinflammation might represent a promising approach for preventing or delaying the development of alzheimer's disease neuropathology at its initial,pre-clinical stages. the results open new vistas to the interplay between inflammation and amyloid pathology. © 2012 ferretti et al; licensee biomed central ltd.