Alzheimers Dement. 2024 Dec;20 Suppl 6:e086492. doi: 10.1002/alz.086492.
ABSTRACT
BACKGROUND: Alzheimer’s disease (AD) is a progressive neurodegenerative disease associated with neuroinflammation and heightened production of reactive oxygen species (ROS) in the brain from overactive NADPH Oxidase 2 (NOX2). The current study examines whether administration of a novel, brain-penetrant NOX2 inhibitor (CPP11G & CPP11H) reduces amyloid plaque load and improves AD-associated vascular dysfunction in a male APP-PS1 mouse model of AD.
METHOD: Intraperitoneal injections of CPP11G (n = 1) or CPP11H (n = 2) three times per week began at 9-10 months of age in the treatment APP-PS1 group (15 mg/kg). The control group of age-matched APP-PS1 mice received no treatment (n = 7). All mice were implanted with a 5mm cranial window for awake optical imaging at least 2 weeks prior to onset of treatment. Two-photon microscopy was performed to assess longitudinal changes in amyloid plaque deposition after weekly Methoxy-04 administration (1 mg/kg). Changes in plaque load were quantified weekly and averaged monthly. Additionally, wide-field optical imaging at 620nm was performed with a 90s, 8% CO2 hypercapnic challenge. This imaging wavelength is sensitive to changes in blood oxygenation (OIS-BOLD) to capture changes in vascular reactivity over time.
RESULT: Treatment with CPP11G/H shows a trend toward reduction in cortical plaque load when compared to an untreated cohort (Fig. 1). OIS-BOLD results for vascular reactivity studies show a slight trend of improved vascular function over time with CPP11G/H treatment (Fig. 2).
CONCLUSION: Our preliminary findings show a strong trend in amyloid plaque reduction with ongoing CPP11G/H treatment in older-aged AD mice and improved vascular function. Ongoing studies to increase the size of the treated cohort will reveal the reliability and statistical significance of CPP11G/H’s therapeutic benefits. We are also examining the impact of treatment on microglia activation and gliosis in APP-PS1::CX3CR1-GFP mice (Fig. 3).
PMID:39782524 | DOI:10.1002/alz.086492
