amyloid-beta-peptides and Neurogenic-Inflammation

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.. 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.. 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.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Neuropathies; Amyloid Precursor Protein Secretases; Analysis of Variance; Animals; Animals, Newborn; Aspartic Acid Endopeptidases; Calcium-Binding Proteins; Cyclooxygenase 2; Disease Models, Animal; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Humans; Interleukin-1beta; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microfilament Proteins; Minocycline; Mutation; Neurogenic Inflammation; NFI Transcription Factors; Nitric Oxide Synthase Type II; Peptide Fragments