The Secreted β-Amyloid Precursor Protein Ectodomain APPsα Is Sufficient to Rescue the Anatomical, Behavioral, and Electrophysiological Abnormalities of APP-Deficient Mice

• DOI: 10.1523/jneurosci.1026-07.2007
• Publication Date: 2007-07-18T17:28:28Z
• Authors: Sabine Ring; Sascha W. Weyer; Susanne B. Kilian; Elaine Waldron; Claus U. Pietrzik; Mikhail A. Filippov; Jochen Herms; Christian Buchholz; Christopher B. Ec...; Martin Korte; David P. Wolfer; Ulrike C. Müller
• Keywords: 0301 basic medicine; Analysis of Variance; Amyloid beta-Peptides; Behavior, Animal; Hand Strength; Body Weight; Long-Term Potentiation; Action Potentials; Brain; Spatial Behavior; Mice, Transgenic; In Vitro Techniques; Motor Activity; Peptide Fragments; Cell Line; Amyloid beta-Protein Precursor; Mice; 03 medical and health sciences; Gene Expression Regulation; Animals; Amyloid Precursor Protein Secretases; Sequence Deletion

It is well established that the proteolytic processing of the β-amyloid precursor protein (APP) generates β-amyloid (Aβ), which plays a central role in the pathogenesis of Alzheimer's disease (AD). In contrast, the physiological role of APP and of its numerous proteolytic fragments and the question of whether a loss of these functions contributes to AD are still unknown. To address this question, we replaced the endogenous APP locus by gene-targeted alleles and generated two lines of knock-in mice that exclusively express APP deletion variants corresponding either to the secreted APP ectodomain (APPsα) or to a C-terminal (CT) truncation lacking the YENPTY interaction motif (APPΔCT15). Interestingly, the ΔCT15 deletion resulted in reduced turnover of holoAPP, increased cell surface expression, and strongly reduced Aβ levels in brain, likely because of reduced processing in the endocytic pathway. Most importantly, we demonstrate that in both APP knock-in lines the expression of APP N-terminal domains either grossly attenuated or completely rescued the prominent deficits of APP knock-out mice, such as reductions in brain and body weight, grip strength deficits, alterations in circadian locomotor activity, exploratory activity, and the impairment in spatial learning and long-term potentiation. Together, our data suggest that the APP C terminus is dispensable and that APPsα is sufficient to mediate the physiological functions of APP assessed by these tests.