P021 - USING INTRACEREBRAL MICRODIALYSIS TO PROBE THE PHARMACOKINETICS OF ALZHEIMER’S DISEASE DRUG CANDIDATES (ID 1680)
Abstract
Aims
All disease-targeting drug trials completed to date have failed to meet the clinical endpoint of significantly slowing cognitive decline in Alzheimer’s disease patients. Even the recently approved drug, Aducanumab, has proven effective in removing amyloid-β, but does not reduce cognitive nor functional decline. This emphasizes the urgent need for novel therapeutic approaches that reduce several AD neuropathologies simultaneously, eventually leading to improved cognitive performance.
Methods
In this study we have repurposed two drugs, Fasudil and Lonafarnib, with the potential to target several aspects of AD pathology at once. Furthermore, these drugs are already approved for other medical causes in patients, and their safety confirmed by previous studies.
Results
Using intracerebral microdialysis for the simultaneous infusion of disease-modifying drugs and collection of cerebrospinal fluid, we found that Fasudil reduces intracellular amyloid-β in young animals, and amyloid plaques and cerebrospinal fluid amyloid-β in old animals, while Lonafarnib reduces tau neuropathology and cerebrospinal fluid tau biomarkers in young and old animals. However, an unexpected finding was that Lonafarnib treatment increased amyloid plaques and cerebrospinal fluid amyloid-β in old animals, suggesting that activating the endosomal-lysosomal system may inadvertently increase amyloid-β pathology if administered too late in AD. Co-infusion of both drugs appears to attenuate contextual memory deficits, compared to mice receiving a vehicle.
Conclusions
Taken together, these findings lend support to the application of repurposed drugs to attenuate Alzheimer’s disease neuropathology at various time points in preclinical models to probe potential biochemical events that result in Alzheimer’s disease.
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