Transgenic AD Mouse Models and Gamma-Secretase Inhibitor Treatment

3xTgAD (harboring PS1_M146V, βAPP_swe, and Tau_P301L transgenes) and non-transgenic (nonTg) mice [37 (link)] were generated from breeding pairs provided by Dr. LaFerla (Irvine, USA). 2xTgAD (PS1wt, βAPP_swe and Tau_P301L) were produced by crossing 3xTgAD with nonTg mice, as described [38 (link)]. For AAV-mediated in vivo delivery, 1-day-old C57BL6 mice (Janvier Labs., France) were injected with 4 µl of AAV virus (5.5 × 10¹² vg/ml (viral genomes per ml)) into the left lateral ventricle, as described [21 (link)] and mice were analyzed at 2 months post-AAV delivery. 5-month-old nonTg and 3xTgAD males or 2-month-old AAV-infected mice (males and females) were treated daily for 12 or 30 days with the γ-secretase inhibitor ELND006, referred to as D6 hereafter (30 mg/kg, Elan Pharmaceuticals, San Francisco, USA) [9 , 45 (link)] or with vehicle alone (methylcellulose/polysorbate 80, Sigma) via oral gavage, as described [24 (link)]. All experimental procedures were in accordance with the European Communities Council Directive of 24 November 1986 (86/609/EEC) and local French legislation.