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]. The P301L mutation affects the 4R-tau isoforms without affecting splicing in exon 10. This mutation accelerates the formation of paired helical filaments in tau proteins, reduces microtubule interactions and stability, and promotes β-sheet folding during the aggregation process. This leads to abnormal tau protein aggregation, resulting in neurofibrillary tangles—a characteristic feature of neurodegenerative diseases ^[6-7]. 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 in FTD. Mutations in the MAPT gene are detectable in roughly 30% of familial FTD cases ^[8].

The B6-APOE4/htau*P301L mouse is a model generated by crossing B6-APOE4 mice with B6-htau*P301L mice. It can be used to study the pathogenic mechanisms and therapeutic approaches of neurodegenerative diseases such as Alzheimer’s disease (AD), frontotemporal dementia (FTD), and cerebral amyloid angiopathy (CAA), as well as cardiovascular diseases such as atherosclerosis.