hAPP-NL-F Mouse

The APP gene encodes the Amyloid Precursor Protein, a type I transmembrane glycoprotein that is ubiquitously expressed but reaches its highest levels in the central nervous system, particularly in the cerebral cortex and hippocampus. Following translation, the APP protein is proteolytically processed via two primary pathways: the non-amyloidogenic pathway, which prevents Aβ formation, and the amyloidogenic pathway, where sequential cleavage by β-secretase (BACE1) and γ-secretase releases amyloid-beta (Aβ) peptides ^[1]. While its precise physiological role remains an area of active research, APP is known to function in synaptic formation and repair, anterograde neuronal transport, and cell-to-cell adhesion ^[2]. Pathological mutations or duplications of the APP gene are primary drivers of Alzheimer’s Disease (AD) and Cerebral Amyloid Angiopathy (CAA), characterized by the extracellular accumulation of Aβ plaques and vascular deposits that lead to neurodegeneration and cognitive decline ^[3].

Pathogenic point mutations in the APP gene typically disrupt these proteolytic pathways, favoring the production or aggregation of neurotoxic peptides. The p.K670N/p.M671L (Swedish) double mutation (AAGATG to AATCTG) occurs at the β-secretase cleavage site, significantly increasing the production of total Aβ by enhancing BACE1 affinity ^[4]. In contrast, the p.I716F (Iberian) mutation (ATC to TTC), located near the γ-secretase cleavage site, shifts the cleavage precision to increase the ratio of the highly aggregate-prone Aβ42 isoform over Aβ40, thereby facilitating early-onset amyloid plaque deposition ^[5].

The hAPP-NL-F mouse is an Alzheimer's disease research model generated by replacing the region from downstream of the mouse App signal peptide-coding sequence through part of intron 1 with the "Mutant Human APP CDS-3'UTR of Human APP-WPRE-BGH pA" cassette, while retaining the mouse App signal peptide-coding sequence. In addition, the following point mutations were introduced into the mutant human APP CDS: p.K670N/p.M671L (AAGATG→AATCTG) and p.I716F (ATC→TTC). This model can be used for research on Alzheimer's disease and other neurodegenerative diseases, as well as for the development and efficacy evaluation of AD therapeutic strategies targeting APP.