A novel humanized Tau‐FAD mice represent a robust model for studying AD‐related dysfunction

Abstract

AbstractBackgroundFamilial AD (FAD) mice expressing mutant forms of the Amyloid β protein (Aβ) precursor (APP) and presenilin‐1 (PS1) have been key models for AD research. While other studies combined FAD and the Tau protein, none, except 3xTgAD, have been made freely available or characterized well. As APP and Tau are linked in 3xTgAD mice, one cannot evaluate their contribution. This study combined the popular hTau strain lacking mouse Mapt and expressed human wild‐type MAPT with FAD.MethodWe generated HTAP by crossing hTau mice in C57BL6/J (JAX #005491) with FAD mutant APP‐PS1 (MMRRC #034833‐JAX) and HTAP2 with 5xFAD (#032882‐JAX). While hTau hyperphosphorylates Tau at 3 mo, the FAD models deposit Aβ after 5 mo. We compared mouse spatial memory with either a radial arm water maze or a Barnes maze. We also compared the levels of norepinephrine in the hippocampus, cortex, and striatum of HTAP2 with the parental C57BL6/J mice by HPLC analysisResultHTAP and HTAP2 mice deposit plaques similar to parental FAD mice and hTau hyperphosphorylated Tau. The combined HTAP mice showed hyperphosphorylated Tau, but the structures appeared distorted. We noted that after 7 months of age, HTAP mice performed poorly in the radial arm water maze compared to wild‐type, FAD, and hTau mice. We observed a similar deficit in HTAP2 in the Barnes Maze. HTAP2 mice showed a significant drop in norepinephrine in all evaluated brain regions, reminiscent of early AD‐related changes.ConclusionHTAP/2 mice have exacerbated behavioral deficits, suggesting that it is a more robust model for studying AD‐related dysfunction. However, these mice still perform well in activities of daily living, such as grooming and feeding. Such novel tau mice, which contain the human MAPT gene, would accelerate our ongoing studies on human microRNAs that target human 3'UTR MAPT mRNA without interference from the host Mapt gene. We propose that this system may better represent the behavioral deficits in AD.