Affiliations: [a] Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada | [b] Abital Pharma Pipeline Ltd., Tel Aviv, Israel
Correspondence:
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Correspondence to: Dr. A. Claudio Cuello, Department of Pharmacology and Therapeutics, McGill University, 3655 Sir-William-Osler Promenade, Room 1210, Montreal, Quebec, H3G 1Y6, Canada. Tel.: +1 514 398 3618; Fax: +1 514 398 8317; claudio.cuello@mcgill.ca
Note: [1] These authors contributed equally to this work.
Abstract: Current therapies for Alzheimer’s disease (AD) offer partial symptomatic relief and do not modify disease progression. There is substantial evidence indicating a disease onset years before clinical diagnosis, at which point no effective therapy has been found. In this study, we investigated the efficacy of a new multi-target drug, M30, at relatively early stages of the AD-like amyloid pathology in a robust rat transgenic model. McGill-R-Thy1-APP transgenic rats develop the full AD-like amyloid pathology in a progressive fashion, and have a minimal genetic burden. McGill rats were given 5 mg/kg M30 or vehicle per os, every 2 days for 4 months, starting at a stage where the transgenic animals suffer detectable cognitive impairments. At the completion of the treatment, cognitive functions were assessed with Novel Object Location and Novel Object Recognition tests. The brains were then analyzed to assess amyloid-β (Aβ) burden and the levels of key inflammatory markers. Long-term treatment with M30 was associated with both the prevention and the reversal of transgene-related cognitive decline. The effects on cognition were accompanied by a shift of the Aβ-immunoreactive material toward an amyloid plaque aggregated molecular form, diminished molecular signs of CNS inflammation and a change in microglia morphology toward a surveying phenotype. This study is the first to demonstrate the therapeutic potential of M30 in a rat model of the AD amyloid pathology. It provides a rationale for further investigations with M30 and with potential multi-target approaches to delay, prevent or reverse the progression the AD pathology at early disease-stages.
