Quantitative 3D histochemistry reveals region-specific amyloid-β reduction by the antidiabetic drug netoglitazone

Abstract

A hallmark of Alzheimers disease (AD) is the extracellular aggregation of toxic amyloid-beta (A{beta}) peptides in form of plaques. Here, we identify netoglitazone, an antidiabetic compound previously tested in humans, as an A{beta} aggregation antagonist. Netoglitazone improved cognition and reduced microglia activity in a mouse model of AD. Using quantitative whole-brain three-dimensional histology (Q3D), we precisely identified brain regions where netoglitazone reduced the number and size of A{beta} plaques. We demonstrate the utility of Q3D in preclinical drug evaluation for AD by providing a high-resolution brain-wide view of drug efficacy. Applying Q3D has the potential to improve pre-clinical drug evaluation by providing information that can help identify mechanisms leading to brain region-specific drug efficacy. Significance statementAlzheimers disease (AD) is the most prevalent neurodegenerative disease. Its primary symptom is progressive cognitive decline, which impairs executive brain functions and deprives patients of their autonomy in life. Experimental and clinical evidence points to the critical pathophysiological role of the amyloid-beta (A{beta}) peptide. Despite some limited successes in AD immunotherapy targeting A{beta}, AD is still incurable. Here, we use an innovative pipeline for accurate whole-brain measurements of A{beta} load to test the efficacy of the antidiabetic compound, netoglitazone. We found that netoglitazone decreases A{beta} burden in certain brain areas but not in others. Region-specific assessment of anti-A{beta} efficacy may be useful in the development of effective drugs against Alzheimers disease.