huAPP-Aβ-NL-G-F-I 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.E693G (Arctic) mutation (GAA to GGA) is located within the Aβ sequence itself; it does not increase peptide quantity but dramatically accelerates the formation of protofibrils ^[5]. Mutations near the γ-secretase cleavage site, such as p.I716F (Iberian) (ATC to TTC) and p.V717I (London) (GTC to ATC), shift the cleavage precision to increase the ratio of the highly aggregate-prone Aβ42 isoform over Aβ40, thereby facilitating early-onset amyloid plaque deposition ^[6].

The huAPP-Aβ-NL-G-F-I mouse is an Alzheimer's disease research model generated by replacing the sequence from upstream of exon 16 to downstream of exon 17 in the murine App gene with the corresponding sequence from the human APP gene. Simultaneously, the p.K670N/p.M671L (AAGATG to AATCTG), p.I716F (ATC to TTC), p.E693G (GAA to GGA) and p.V717I (GTC to ATC) point mutations were introduced into exon 16 and exon 17 of human APP gene. This model is suitable for studying neurodegenerative diseases such as Alzheimer's disease (AD), as well as for the research, development, and efficacy evaluation of AD therapeutic strategies targeting APP.