Optical Redox Imaging of Ex Vivo Hippocampal Tissue Reveals Age-Dependent Alterations in the 5XFAD Mouse Model of Alzheimer’s Disease

Abstract

A substantial decline in nicotinamide adenine dinucleotide (NAD) has been reported in brain tissue homogenates or neurons isolated from Alzheimer’s disease (AD) models. NAD, together with flavin adenine dinucleotide (FAD), critically supports energy metabolism and maintains mitochondrial redox homeostasis. Optical redox imaging (ORI) of the intrinsic fluorescence of reduced NAD (NADH) and oxidized FAD yields cellular redox and metabolic information and provides biomarkers for a variety of pathological conditions. However, its utility in AD has not been characterized at the tissue level. We performed ex vivo ORI of freshly dissected hippocampi from a well-characterized AD mouse model with five familial Alzheimer’s disease mutations (5XFAD) and wild type (WT) control littermates at various ages. We found (1) a significant increase in the redox ratio with age in the hippocampi of both the WT control and the 5XFAD model, with a more prominent redox shift in the AD hippocampi; (2) a higher NADH in the 5XFAD versus WT hippocampi at the pre-symptomatic age of 2 months; and (3) a negative correlation between NADH and Aβ42 level, a positive correlation between Fp and Aβ42 level, and a positive correlation between redox ratio and Aβ42 level in the AD hippocampi. These findings suggest that the ORI can be further optimized to conveniently study the metabolism of freshly dissected brain tissues in animal models and identify early AD biomarkers.

Keywords

• NAD redox
• FAD-containing flavoproteins
• redox ratio
• amyloid-β
• redox shift