Presenilin‐2 Mutation Causes Early Amyloid Accumulation and Memory Impairment in a Transgenic Mouse Model of Alzheimer′s Disease

Abstract

In order to clarify the pathophysiological role of presenilin-2 (PS2) carrying the Volga German Kindred mutation (N141I) in a conventional mouse model of Alzheimer's disease (AD) expressing amyloid precursor protein (APP) with the Swedish mutation (Tg2576 line), we generated a double transgenic mouse (PS2Tg2576) by crossbreeding the PS2 mutant with Tg2576 mice. Here, we demonstrate that the PS2 mutation induced the early deposition of amyloid β-protein (Aβ) at 2-3 months of age and progressive accumulation at 4-5 months of age in the brains of the mutant mice. The PS2 mutation also accelerated learning and memory impairment associated with Aβ accumulation at 4-5 months of age in Tg2576 mice. These results suggest that the PS2 mutation causes early cerebral amyloid accumulation and memory dysfunction. PS2Tg2576 mice are a suitable mouse model for studying amyloid-lowering therapies.

SOD1 (Copper/Zinc Superoxide Dismutase) Deficiency Drives Amyloid β Protein Oligomerization and Memory Loss in Mouse Model of Alzheimer Disease

“…Indeed, there are the differences of distribution for plaque depositions in several hAPP transgenic mice. In preliminary experiments, we investigated the variance of plaque distribution using several lines (Tg2576 (20), J20 (28), and PS2Tg2576 (27)); Tg2576 and PS2Tg2576 had almost no preference in the plaque areas, whereas the plaque deposits was frequently found in the hippocampus of J20, as Mucke et al (28) also previously described. Therefore, we carried out the biochemical analysis using the whole brain lysates of mice crossed with Tg2576.…”

“…Tissue Preparation and Western Blotting-The procedure was based on the method of previous works (23)(24)(25)(26)(27). In brief, human brain tissue (0.1-0.2 g) was homogenized in 10 volumes (w/v) of 50 mM TBS (Tris-HCl buffer (pH 7.6) containing 150 mM NaCl, a mixture of protease and phosphatase inhibitors (Complete TM ; Roche Diagnostics) supplemented with 0.7 g/ml pepstatin A and 1 mM phenylmethylsulfonyl fluoride).…”

“…Morris Water Maze-Memory impairment was assessed using the Morris water maze test, as described previously (25)(26)(27). The water maze pool (Muromachi Kikai, Tokyo), diameter 120 cm, contained opaque water (20°C) with a platform (10 cm in diameter) submerged 2 cm below the surface.…”

“…Immunohistochemistry-The procedure was basically adopted based on the method of the previous works (23)(24)(25)(26)(27). In brief, the sections (5 m) were deparaffinized, rehydrated, and washed in phosphate-buffered saline (PBS) before being treated briefly with formic acid in the case of A␤ staining.…”

An Update of Animal Models of Alzheimer Disease with a Reevaluation of Plaque Depositions

“…However, transgenic mice carrying FAD mutant forms of presenilins or gene-targeted mice carrying FAD-mutant PS1 (PS1 P264L/P264L ) do not develop plaques, although when crossed with plaque-forming APP lines (eg., Tg2576), the presenilin FAD mutations produce elevated levels of Aβ42 and cause earlier and more extensive plaque deposition [38-41]. …”