P2-374: Effects of anti-TNF therapy on amyloid pathology and neuroinflammation in 12-month-old arcAß transgenic mice

In 2008, Tobinick and colleagues demonstrated that Etanercept anti-TNF therapy could be used for the treatment of AD. Although this treatment approach has advanced to Phase II clinical trial the underlying therapeutic mechanisms remain unknown. To identify the mechanisms we launched an AD mouse model study, in which we infused Etanercept or vehicle control into the ventricles of arcAb mice over 28 days using ALZET osmotic minipumps; with an additional 15 non-treated transgenic and wildtype mice as a further controls. All mice underwent general health and neurological examination, as well as, cognitive assessment before they were sacrificed for further biochemical and histological analyses. Our findings demonstrated a treatment dependent improvement in cognitive performance in two hippocampus-dependent cognitive tests. Biochemical analyses suggested that the improvement in cognition was not associated with changes in soluble brain Abeta levels but rather a decrease in Formic acid insoluble Abeta levels. Histological analysis demonstrated a treatment-induced lowering of Abeta plaques and an increased clearance of Abeta plaques towards the vasculature.Stainings against GFAP and Iba1 further demonstrated a reduction in astrocytosis with parallel elevations in microglia activation. These findings suggest a neuroinflammatory and amyloid-lowering mechanism of anti-TNF therapy, in which Abeta is solubilized and cleared towards the vasculature.