huAPOE4/hutau-P301S Mouse

Apolipoprotein E (APOE) is a critical apolipoprotein involved in lipid transport mediated by lipoproteins. As a core component of plasma lipoproteins, APOE facilitates the transport of lipids through plasma and interstitial fluid between organs, and it plays a pivotal role in the generation, conversion, and clearance of lipoproteins. In humans, the APOE gene has three isoforms (E2, E3, E4) associated with atherosclerosis and Alzheimer’s disease (AD), with the E4 allele present in approximately 14% of the population ^[1]. The ApoE4 isoform is a major genetic risk factor for late-onset Alzheimer’s disease (AD), exacerbating neurodegeneration. ApoE4-associated damage to vascular systems in the brain could have a key role in AD pathogenesis ^[2]. Beyond AD, APOE4 is linked to cardiovascular diseases due to its influence on lipid homeostasis ^[3].

The tau protein, a microtubule-associated protein encoded by MAPT, is primarily localized to neuronal axons and plays a critical role in microtubule stability and assembly. By binding to microtubules, the tau protein helps to maintain neuronal cell shape. Mutations in MAPT can promote tau aggregation, leading to pathological tau protein accumulation and death of glutamatergic cortical neurons ^[4]. Additionally, certain MAPT mutations can affect pre-mRNA exon splicing, altering the ratio of 3R to 4R tau protein isoforms and increasing the relative production of 4R-tau protein, which is more prone to fibril formation. Common mutations include P301L, P301S, and Intron10+3 G>A ^[5]. Research indicates that the P301S mutation significantly reduces the ability of recombinant tau protein to promote microtubule assembly. Patients with this mutation exhibit clinical heterogeneity ^[6-7]. Similar to the P301L mutation, the P301S mutation also leads to pathological aggregation of the tau protein, resulting in neurodegenerative diseases. Therapies targeting the MAPT gene primarily consist of small molecule drugs and monoclonal antibodies, with indications including Alzheimer’s disease (AD) and Frontotemporal Dementia (FTD). MAPT is the earliest discovered and most frequently implicated gene in FTD. Mutations in the MAPT gene are detectable in roughly 30% of familial FTD cases ^[8].

The huAPOE4/hutau-P301S mouse is a dual-gene humanized model obtained by crossing the huAPOE4 mouse (Catalog No.: C001867) with the hutau-P301S mouse (Catalog No.: C001836). The huAPOE4/hutau-P301S mouse can be utilized for the screening, pharmacodynamic evaluation, safety assessment, and mechanism of action studies of dual-target therapeutics targeting APOE4 and MAPT (tau), for investigating how APOE4 exacerbates tauopathy and neurodegeneration. It serves as an ideal preclinical research platform for developing innovative therapies for Alzheimer's disease (AD) and other neurodegenerative diseases.