Diet-induced Alzheimer's-like syndrome in the rabbit.

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 therapeutics against LOAD. In addition, non-invasive MRI in awake, non-anesthetized rabbits further increases the translational value of this non-transgenic model to study AD.
Competing Interests: Grazia Aleppo is partially supported by Novo‐Nordisk, Eli‐Lilly, and Insulet/Dexcom. Payments to William L. Klein were made to organize a meeting for Acumen Pharmaceuticals. William L. Klein has founders’ shares in Acumen Pharmaceuticals and is a member of the scientific advisory board of Acumen. ACU193 was a gift from Acumen Pharmaceuticals. NU2 was developed with support from NIH Grants RO1AG18877 and RO1AG22547 to Northwestern University. Support paid to Northwestern University from NIH R01 AG063903, NIH‐R21 AG060203‐01, NIH‐R43OD023025‐01A1 (subcontract from Virscio, Inc). Imaging partially supported by the Rice Foundation. John F. Disterhoft supported by NIH R01 NS113804, R01 MH114923, R25 GM121231, T32 AG20506‐16‐20, RF1 AG017139, R37 AG008796‐28S1, R21 AG060267. John F. Disterhoft received payment from Brain Research Foundation for grant review service, and received payment from International Bordeaux Neurocampus Aging Meeting (2018). John F. Disterhoft is an unpaid member of Chicago Methodist Senior Services Board. Craig Weiss, Nicola Bertolino, Daniele Procissi, Quinn C. Smith, Kirsten L. Viola, Samuel C. Bartley have no disclosures.
(© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)