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: Ectodomain; Alpha secretase; Gene knockin

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