AI Article Synopsis
- Alzheimer's disease (AD) is a leading cause of dementia that is fatal, and most treatments targeting amyloid beta have only limited success in slowing progression.
- Research into senescent cells (SC) and their harmful effects shows potential for new therapies, as treating aged monkeys with the senolytic drug navitoclax led to positive changes in biomarkers related to neuroinflammation and neuronal damage.
- Navitoclax was found to be safe and well tolerated in the study, suggesting its promise as a new therapeutic approach for addressing AD in humans.
Article Abstract
Alzheimer's disease (AD) is the most common global dementia and is universally fatal. Most late-stage AD disease-modifying therapies are intravenous and target amyloid beta (Aβ), with only modest effects on disease progression: there remains a high unmet need for convenient, safe, and effective therapeutics. Senescent cells (SC) and the senescence-associated secretory phenotype (SASP) drive AD pathology and increase with AD severity. Preclinical senolytic studies have shown improvements in neuroinflammation, tau, Aβ, and CNS damage; most were conducted in transgenic rodent models with uncertain human translational relevance. In this study, aged cynomolgus monkeys had significant elevation of biomarkers of senescence, SASP, and neurological damage. Intermittent treatment with the senolytic navitoclax induced modest reversible thrombocytopenia; no serious drug-related toxicity was noted. Navitoclax reduced several senescence and SASP biomarkers, with CSF concentrations sufficient for senolysis. Finally, navitoclax reduced TSPO-PET frontal cortex binding and showed trends of improvement in CSF biomarkers of neuroinflammation, neuronal damage, and synaptic dysfunction. Overall, navitoclax administration was safe and well tolerated in aged monkeys, inducing trends of biomarker changes relevant to human neurodegenerative disease.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11382177 | PMC |
| http://dx.doi.org/10.1016/j.heliyon.2024.e36483 | DOI Listing |
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