Prevention of Amyloid-β and Tau Pathologies, Associated Neurodegeneration, and Cognitive Deficit by Early Treatment with a Neurotrophic Compound.

Abstract

To date, neither any effective treatment nor prevention of Alzheimer's disease (AD), a major dementia causing disorder, are available. Herein, we investigated the secondary prevention of neurodegeneration, amyloid-β (Aβ) and tau pathologies with a neurotrophic compound P021 in 3xTg-AD mice. Previous work found that P021 can rescue at mild to moderate stages Aβ and tau pathologies in 3xTg-AD mice. To determine its potential clinical application, we sought to test the preventive effect of P021 on Aβ and tau pathologies by starting the treatment during the period of synaptic compensation several months before the appearance of any overt pathology in 3xTg-AD mice. We started a continuous treatment with P021 in 3-month-old female animals and followed its effect at 9-, 15- and 18-months post-treatment. Neurodegeneration at the above time points was studied using Fluorojade C staining, and tau and Aβ pathologies both immunohistochemically and by Western blots. Cognitive performance was studied by assessing episodic memory with Novel Object Recognition task at 16-17-months post-treatment. We found that P021 treatment initiated during the synaptic compensation period can prevent neurodegeneration, Aβ and tau pathologies, rescue episodic memory impairment, and markedly reduce mortality rate. These findings for the first time show effective prevention of AD changes with a neurotrophic compound that targets neurogenesis and synaptic plasticity, suggesting that improving the health of the neuronal network can prevent AD.