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

A hallmark of Alzheimer’s disease (AD) is the extracellular aggregation of toxic amyloid-beta (Aβ) peptides in form of plaques. Here, we identify netoglitazone, an antidiabetic compound previously tested in humans, as an Aβ 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 Aβ 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 statement Alzheimer’s 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 (Aβ) peptide. Despite some limited successes in AD immunotherapy targeting Aβ, AD is still incurable. Here, we use an innovative pipeline for accurate whole-brain measurements of Aβ load to test the efficacy of the antidiabetic compound, netoglitazone. We found that netoglitazone decreases Aβ burden in certain brain areas but not in others. Region-specific assessment of anti-Aβ efficacy may be useful in the development of effective drugs against Alzheimer’s disease.

• Publication year

  2024

• Venue

  bioRxiv

• Publication date

  2024-08-17

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1101/2024.08.15.608042PMID 39185170PMCID 11343181
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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