Building a proposal for testing resilience against neurodegeneration

Abstract

Protective drugs effective against age-related Alzheimer’s disease (AD)-like neurodegeneration in animal models, generally failed when tested in humans where processes are much more complex and involving irreparable cell death. Animal models for testing prevention efficacy would help to set up treatments for increasing brain resilience in the population at risk. We hypothesize that the activation of molecular pathways of survival and/or neuroprotection inducing a protective effect against age-related memory loss and neurodegeneration, might also have a preventive effect by increasing brain resilience that can be tested. The antiaging compounds resveratrol and melatonin protected against AD-like symptoms and pathology after a chronic food supplementation in AD transgenic mice. Both compounds activate the SIRT1 pathway of longevity and neuroprotection. Similarly, a chronic treatment of proinsulin, which activates the Akt pathway of neuroprotection, was effective against memory loss in the senescence and early AD mouse model SAMP8. Remarkably, these treatments also induced beneficial changes in the brain cells and the behavior and cognitive responses of the control healthy mice. In the changes shown, to highlight decreases of inflammatory markers that suggest a protection against inflammaging, increase of proteolytic mechanisms against aberrant proteins, and improved responses in the non-cognitive and cognitive behaviour indicative of wellbeing and neural circuitry strengthening. Therefore treated healthy mice showed up-regulation of the pathways that maintain nerve cell homeostasis against age-related deleterious changes. We propose the joint analysis of healthy mice and disease models to define the most significant markers for setting up mouse models of brain resilience against AD and other age-related neurodegenerative diseases.