The amyloid beta precursor protein (APP) gene encodes a transmembrane precursor protein that acts as a cell surface receptor. This protein is cleaved by secretase to form a polypeptide, part of which forms the protein basis for beta-amyloid plaques (Aβ) found in the brains of Alzheimer’s disease (AD) patients. Mutations in the APP gene are associated with autosomal dominant Alzheimer’s disease and cerebral amyloid angiopathy (CAA) ^[1]. The presenilin 1 (PS1) gene encodes presenilin, which regulates the processing of APP through its action on γ-secretase, a protease responsible for cleaving the APP precursor. Presenilin is also involved in the cleavage of Notch receptors. Mutations in the PS1 or APP genes are found in patients with hereditary Alzheimer’s disease (AD). These disease-associated mutations typically result in an increase in the longer form of β-amyloid protein, the main component of amyloid deposits found in the brains of AD patients ^[2]. 5xFAD mouse rapidly reproduces the main features of AD amyloid pathology and exhibits behavioral defects at different stages, presenting AD-like and progressive cerebral amyloid angiopathy (CAA)-like phenotypes. It is a useful model for studying Aβ42-induced neurodegeneration and amyloid plaque formation within neurons ^[3-4].

The Transferrin receptor (TFRC) gene encodes Transferrin Receptor 1 (TFR1), a protein that is expressed at low levels in most normal cells but shows increased expression in highly proliferative cells, such as basal epidermal cells, intestinal epithelium, and certain activated immune cells. Brain capillary endothelial cells, which constitute the blood-brain barrier (BBB), also express this receptor at high levels ^[5]. TFR1 plays a critical role in maintaining iron metabolism and homeostasis by facilitating receptor-mediated endocytosis of iron-bound transferrin (Tf) via Tf cycling, thereby promoting iron uptake ^[6]. Cellular iron deficiency can lead to apoptosis, while cellular transformation requires substantial iron to sustain proliferation, with iron overload contributing to tumor progression. The high expression of TFR1 in many tumors makes it a potential tumor marker, offering a target for therapies to inhibit tumor growth and metastasis ^[5]. Moreover, TFR1 is implicated in anemia and iron metabolism disorders. Studies have shown that elevated TFR1 expression in cardiomyocytes is associated with exacerbated inflammation in myocarditis patients ^[7]. As a target for antibody-mediated cancer therapy, TFR1 can be leveraged through two approaches: one involves the use of antibodies conjugated to anti-cancer drugs, which are indirectly internalized via receptor-mediated endocytosis; the other employs antibodies that directly disrupt receptor function or induce Fc effector functions such as antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), or complement-dependent cytotoxicity (CDC). Various clinical drugs targeting TFR1 are currently under development, including antisense oligonucleotides (ASOs), antibody-drug conjugates (ADCs), and antibody-oligonucleotide conjugates, applicable to diseases such as cancer, anemia, and neurodegenerative disorders. Research indicates that enhancing antibody transport across the blood-brain barrier via TFR1, by forming specific bispecific antibodies with anti-β-amyloid antibodies, can improve therapeutic outcomes in Alzheimer's patients ^[8-9]. As research progresses, TFR1 is expected to become an effective clinical target for multiple diseases and a synergistic target for drug delivery across the blood-brain barrier (BBB).

The B6-huTFRC/5xFAD mice are an Alzheimer's disease research model obtained by mating B6-huTFRC mice (catalog number: C001860) with 5xFAD mice (catalog number: C001541). This model can be used for the research of neurodegenerative diseases such as Alzheimer's disease (AD) and the development and efficacy evaluation of AD treatment strategies targeting TFRC.