Andrographolide recovers cognitive impairment in a natural model of Alzheimer's disease (Octodon degus)

Abstract

The social species Octodon degus (degu) is the only wild-type South American rodent that 38 develops Alzheimer’s-like pathology with age. Here, we evaluated the ability of a natural 39 product (Andrographolide, ANDRO), a diterpene of the labdane family obtained from the 40 Asian plant Andrographis paniculata, to recover the cognitive decline in this long-lived 41 animal model. We administered ANDRO to aged degus (56 months old) for 3 months. 42 Additionally, in two control groups (young degus: 12 months old and aged degus: 56 43 months old) we administrated saline solution as a vehicle. We evaluated cognitive 44 performance through several behavioral tests. We also performed a series of physiological 45 and biochemical analyses (e.g., electrophysiological and immunoblotting assessment) to 46 identify possible mechanisms underlying cognitive performance associated with age. Our 47 results suggest that there is an effect of aging on the loss of cognitive function, and this 48 decrease in cognitive function was also related to a decrease in the synaptic functions and 49 an increase in the main hallmarks of Alzheimer’s disease (AD). More importantly, ANDRO 50 treatments showed the following beneficial effects: (1) recovery of spatial memory and 51 learning performance; (2) recovery of synaptic basal transmission; (3) partial or complete 52 protection of certain synaptic proteins; and (4) a specific neuroprotective effect, including 53 the reduction of phosphorylated tau protein and Aβ aggregate maturation in aged degus. 54 Taken together, our results suggest that ANDRO could be used as a potential therapy for 55 AD and support the use of O. degus as a natural model in which to study both neural 56 damage associated with aging processes and the behavioral and neuropathological 57 hallmarks of aging-related diseases such as AD.