Efficacy of Low Dose of Dihydroquercetin (DHQ) in Two Genetic Models of Neurodegeneration: Insights from FUS[1-359]-Tg and APPswe/PS1dE9 Paradigms

Abstract

Dihydroquercetin (DHQ), a powerful antioxidant and regulator of cellular metabolism, was proposed for therapy of neurodegenerative disorders. Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS) are serious neurodegenerative disorders with oxidative stress as an overlapping feature and unmet therapeutic needs. To date, few studies have explored the efficacy of DHQ in animal models of genetically driven neurodegeneration. Here, APPswe/PS1dE9 (APP/PS1) mice and their wild-type (WT) littermates were orally administered DHQ (0.6 mg/kg/day) for four months, starting at eight months of age. At the age of 12 months, behavioral evaluation was performed, followed by brain staining with Congo red for amyloid plaque scoring and immunohistochemical analysis of GFAP-positive cells for the assessment of astrogliosis. Malondialdehyde (MDA) levels in the prefrontal cortex were studied as a marker of oxidative stress. Second, two-month-old FUS[1-359]-Tg mice, which recapitulate the hallmarks of ALS, received DHQ for 1.5 months and were investigated for general physiological parameters, the onset of paralysis, motor functions, and density of motor neurons in the spinal cord. DHQ-treated APPswe/PS1dE9 mutants displayed a decrease in amyloid plaque density of small size (≤100 μm) in the cortex and thalamus, had normalized MDA levels, improved conditioned taste aversion and Y-maze learning, and ameliorated anxiety measures, whereas their hippocampus-dependent step-down and pellet displacement performance remained impaired. In the second study, DHQ-treated FUS[1-359]-Tg mice showed rescued density of spinal cord neurons, normalized liquid and diet intake, and improved coat state, while the onset of paralysis and motor scores were not significantly ameliorated. Thus, chronic administration of low doses of DHQ exerted neuroprotective effects in both AD and ALS genetic models, which partially translated to reduced manifestations of these diseases.