[P‐211]: Chronic Γ Secretase Inhibition Can Reduce Amyloid Load Without Evidence of Notch Related Pathology in the Tg2576 Mouse

The body of evidence indicating that β-amyloid peptides (Aβ) are critical factors in the onset and development of Alzheimer's disease (AD) has become over whelming. Reducing the production of Aβ through inhibition of the secretase enzymes that cleave Aβ from the amyloid precursor protein (APP) is identified as a key point for therapeutic intervention and is being pursued aggressively. To demonstrate that chronic treatment with a γ secretase inhibitor attenuates the appearance of amyloid lesions in the Tg2576 mouse model of Alzheimer's disease (AD). Investigate any consequent changes in reactive gliosis and aberrant Tau phosphorylation. To examine peripheral target organs for evidence of pathology induced by activity at alternative substrates, such as the Notch family of receptors. Mice were treated for 91 days then brains were subjected to detailed morphometric and histological evaluation using a variety of procedures including immunohistochemistry, stereology and ligand binding. Biochemical measures of Aβ (40) and (42), reactive gliosis (GFAP) and aberrant tau phosphorylation were made from samples of cortex. Peripheral organs were collected for histopathological evaluation. The data indicate that the prolonged blockade of amyloid production by a γ secretase inhibitor will significantly and dose dependently decrease the rate at which amyloid deposits form, attenuating both vascular and parenchymal lesions to the same degree. The consistency of average deposit volume across treatment groups indicates that lowering amyloid concentrations at these levels does not significantly alter deposit growth once initiated. Reactive gliosis is reduced in concert with plaque pathology. Plaque numbers also correlate significantly with the appearance of aberrant tau phosphorylation. Further, we demonstrate that these beneficial effects can be achieved at levels of γ secretase inhibition which do not appear to induce histopathological changes in selected target organs as a consequence of activity at alternative substrates, such as the Notch family of receptors. This important data may help allay a key concern in the development of this therapeutic approach to AD.