RARE‐LacZ Mice as a Model to Study of Retinoic Acid Signaling in Alzheimer’s Disease

Background Disrupted balance between amyloidogenic and non‐amyloidogenic pathways leads to cognitive decline in Alzheimer’s disease (AD). Evidence suggests vitamin A (VA) supplementation favors the non‐amyloidogenic pathway through upregulation of α‐secretase. Originally used to map embryonic retinoic acid (RA) signaling, RARE‐LacZ mice possess multiple LacZ genes controlled by retinoic acid response elements (RAREs). We crossed RARE‐LacZ mice with AD mouse models to determine their suitability for quantitative studies into the effects of VA on dentate gyrus (DG) RA signaling and learning in AD. Methods Relative LacZ gene copy ratio was determined by qPCR of LacZ in gDNA, normalized to ultra‐conserved region 329. Dietary intervention compared VA supplemented (20 IU/g) AIN‐93M to standard AIN‐93M (4 IU/g VA). Mice were tested at postnatal day (P)125 via water T‐maze (WTM, 9 simple discrimination, 9 reversal trials). PFA‐fixed sections (40µm) were immunostained for LacZ, doublecortin, and/or calbindin, confocally imaged, and analyzed using ImageJ. Results RARE‐lacZ mice were first crossed with C57BL/6J, ‐NJ, and CD1 mice (wildtype strains of J20, hAβ‐KI, and RARE‐LacZ mice, respectively). The relative LacZ gene copy ratio was ∼2.6:1 between RARE‐LacZ mice (N = 12) and crosses (N = 34). Values for 32/34 offspring fell within ±50% of the mean. Strain affected latency to platform on WTM during simple discrimination and reversal (N = 11‐12, p