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

Abstract

BackgroundA 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 resultsTo 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.ConclusionsOur 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.

Targeting Tumor Necrosis Factor Alpha for Alzheimer’s Disease

“…; 45 mg/kg/day for three weeks) to an Aβ 1- 4 2 -infused rat model and Tg2576 mice (knock in of human APPsw driven by the hamster prion protein promoter; 10 mg/kg/day minocycline, 5 days a week for 9 months) [112]. Importantly, minocycline (50 mg/kg/day) lowered brain inflammatory markers (COX-2, iNOS, and IL-1β), APP expression, and BACE1 activity when administered intraperitoneally for one month to young, pre-plaque McGill-Thy1-APP mice (knock in of human APPsw/ind driven by the murine Thy1.2 promoter) [113]. However, in the latter study the authors reported liver and peritoneal toxicity, which “precluded the completion of behavioral testing for learning and memory” [113].…”

“…Consequently, most anti-TNF-α drugs (including etanercept [121], infliximab [122], minocyclin [113], thalidomide [123], and celastrol [120]) were shown to reduce NF-κB phosphorylation (active state [48]) in various research models of inflammation. Interestingly, all these drugs reduced AD-like neuropathological features and, when assessed, improved cognitive measures (see references in sections 4.2.2.1–4 above).…”

Interactions between inflammation, sex steroids, and Alzheimer’s disease risk factors

“…Likewise, eliminating microglia prevents neuronal loss and neuroinflammation, and improves memory, without altering levels of Aβ (Spangenberg et al, 2016). Furthermore, administration of minocycline, a tetracyclic antibiotic that inhibits microglial activation, ameliorates AD-like pathology in transgenic mice and downregulates inflammatory markers, partially through inhibition of NFκB, and BACE-1 (Ferretti et al, 2012; Zemke and Majid, 2004). Shifting microglial activation states from the pro-inflammatory M1 to a more anti-inflammatory M2 phenotype has also proven to be effective.…”

Cytokines and Cytokine Receptors Involved in the Pathogenesis of Alzheimers Disease

“…Non-specific inhibitors of TNFα, such as thalidomide and minocycline, have been tested in AD treatment [7,191–193]. …”