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

Abstract

It is well established that the proteolytic processing of the ␤-amyloid precursor protein (APP) generates ␤-amyloid (A␤), 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 (APPs␣) or to a C-terminal (CT) truncation lacking the YENPTY interaction motif (APP⌬CT15). Interestingly, the ⌬CT15 deletion resulted in reduced turnover of holoAPP, increased cell surface expression, and strongly reduced A␤ 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 APPs␣ is sufficient to mediate the physiological functions of APP assessed by these tests.

Loss of γ-Secretase Function Impairs Endocytosis of Lipoprotein Particles and Membrane Cholesterol Homeostasis

“…Transgenic mice expressing human PS1 WT or ⌬E9 mutant have been described previously . Mice with APP-and APLP2-deficient alleles (von Koch et al, 1997; Heber et al, 2000) and APPs␣ knock-in (APPs␣-KI) (Ring et al, 2007) were described earlier. APLP2-deficient mice with APPs␣-KI alleles (DKI) were generated by breeding APPs␣-KI with APLP2-deficient animals.…”

Regulation of the Physiological Function and Metabolism of AβPP by AβPP Binding Proteins

“…Substitutions of residues in the GYENPTY motif with Ala also result in impaired internalization of APP and decreased secretion A peptides in cultured cells [49]. In the knock-in mice, in which endogenous APP is replaced with truncated APP lacking residues around the GYENPTY motif, turnover of APP and Alevels are strongly reduced in brain [50]. These results suggest that the interaction of proteins with the GYENPTY motif of APP is important for the regulation of APP metabolism.…”

“…In contrast, the roles of APP binding proteins to regulate the metabolism of APP are well analyzed. Without protein interactions through the cytoplasmic domain, the intracellular trafficking or proteolytic cleavages of APP is not disrupted completely but severely disturbed both in vitro and in vivo [47,48,50]. Recent gene ablation studies support the model that X11 and FE65 family proteins are involved in the regulation of APP metabolism [72-74, 93, 94].…”

The Circadian System in Alzheimer’s Disease: Disturbances, Mechanisms, and Opportunities

“…In the TgCRND8 model diurnal organization of behavior was altered, with more daytime activity and lessened levels of nocturnal activity, suggesting rhythm fragmentation, and these effects are noted before the appearance of A-b neuropathology (64). Modifications of diurnal patterns of activity in APP knockout animals can be rescued by the secreted b-amyloid precursor protein ectodomain APPsa (65). The 3xTg mouse model, which displays both A-b and t pathology, did not display abnormalities in free-running period or photic phase-shifting but did display markedly reduced activity levels after the onset of A-b pathology (66).…”