Diet‐induced Alzheimer's‐like syndrome in the rabbit

Abstract

Introduction:Although mouse models of Alzheimer's disease (AD) have increased our understanding of the molecular basis of the disease, none of those models represent late-onset Alzheimer's Disease which accounts for >90% of AD cases, and no therapeutics developed in the mouse (with the possible exceptions of aduhelm/aducanumab and gantenerumab) have succeeded in preventing or reversing the disease. This technology has allowed much progress in understanding the molecular basis of AD. To further enhance our understanding, we used wild-type rabbit (with a nearly identical amino acid sequence for amyloid as in humans) to model LOAD by stressing risk factors including age, hypercholesterolemia, and elevated blood glucose levels (BGLs), upon an ε3-like isoform of apolipoprotein. We report a combined behavioral, imaging, and metabolic study using rabbit as a non-transgenic model to examine effects of AD-related risk factors on cognition, intrinsic functional connectivity, and magnetic resonance-based biomarkers of neuropathology.Methods: Aging rabbits were fed a diet enriched with either 2% cholesterol or 10% fat/30% fructose. Monthly tests of novel object recognition (NOR) and object location memory (OLM) were administered to track cognitive impairment. Trace eyeblink conditioning (EBC) was administered as a final test of cognitive impairment. Magnetic resonance imaging (MRI) was used to obtain resting state connectivity and quantitative parametric data (R 2 *).Results: Experimental diets induced hypercholesterolemia or elevated BGL. Both experimental diets induced statistically significant impairment of OLM (but not NOR) and altered intrinsic functional connectivity. EBC was more impaired by fat/fructose diet than by cholesterol. Whole brain and regional R 2 * MRI values were elevated in both experimental diet groups relative to rabbits on the control diet.Discussion: We propose that mechanisms underlying LOAD can be assessed by stressing risk factors for inducing AD and that dietary manipulations can be used to assess etiological differences in the pathologies and effectiveness of potential therapeuticsThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Genome-edited rabbit, a prospective alternative model for neurological diseases

“…Rabbits can be trained to learn basic skills (e.g., recall signals) through positive reinforcement [25] . Rabbits also have both short-and long-term memory [26,27] and can exhibit memory losses when mimicking NNDs such as AD [27] . Specifically, in an AD rabbit model constructed by drug induction, the results of novel object recognition (NOR) and object location memory (OLM) tests suggest that the model can track cognitive impairment [28] .…”

Brain activity studied with magnetic resonance imaging in awake rabbits

“…The natural tolerance of the rabbit to being swaddled for several hours, and its relatively smooth cortex allow good image acquisition and interpretation of results. Fan, J., Kitajima, S., Watanabe, T., Xu, J., Zhang, J., Liu, E., et al (2015) (2022). Applications in awake animal magnetic resonance imaging.…”

“…However, to understand functional aspects of dietary manipulations on learning and memory, and the involvement of neuronal networks in a rabbit model of AD, awake functional imaging is more appropriate. We recently reported the effects of either a high cholesterol diet (2% enrichment) or a combination of 10% saturated fat and 30% fructose on intrinsic functional connectivity and hippocampal dependent memory in the rabbit (Weiss et al, 2022 ). An independent component analysis (ICA) of 10 networks within the rabbit brain revealed a remarkable loss of functional connectivity among independent network components in rabbits on the cholesterol diet, as compared to rabbits on the control diet.…”

“…Stability has been achieved by instructing humans not to move, by anesthetizing experimental animal subjects to induce immobility, or by prolonged and repeated habituation sessions for awake animal subjects. Although mice and rats are common experimental subjects for neuroscience research, they do not tolerate restraint well without extensive habituation and with frequent rewards for immobility [although read the articles by Ferris (2022) and by Russo et al (2021) in this Research Topic for use of the rat in imaging research]. Non-human primates have been used after extensive habituation and training on goal directed tasks, but they are scarce and expensive to use.…”