B6-hTFRC/htau*P301S Mice

Catalog Number: C001688

Strain Name: C57BL/6N;6JCya-Tfrctm1(hTFRC)Mapttm3(hMAPT*P301S)/Cya

Genetic Background: C57BL/6N;6JCya

Reproduction: Homozygous B6-hTFRC(CDS) mice x Homozygous B6-htau*P301S mice

 

Strain Description

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 [1]. 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 [2]. 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 [1]. 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 [3]. 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 [4-5]. 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 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, 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 [6]. 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 [6]. 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 [7].Frontotemporal Dementia (FTD) is the second most prevalent form of early-onset dementia, following Alzheimer’s disease (AD). This condition is distinguished by the selective degeneration of the frontal and temporal lobes, resulting in personality and behavioral changes, language impairments, and executive dysfunction. Approximately 40%-50% of FTD cases have a familial component, with known causative genes including MAPT, FUS, and TARDBP. Of these, 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-hTFRC/htau*P301S mouse model is a humanized model obtained by breeding B6-hTFRC(CDS) mice (Catalog No.: C001584) with B6-htau*P301S mice (Catalog No.: I001182). This model can be used for research on Alzheimer's disease (AD), Frontotemporal dementia (FTD), neurodegenerative diseases, and tumor development, aiding in the research of TFRC/MAPT-targeted drugs.

 

Strain Strategy

  • Construction strategy for B6-hTFRC(CDS) mice: Partial coding region of mouse Tfrc exon 2 sequences was replaced with the TFRC chimera CDS-WPRE-BGH pA cassette. Gene-editing techniques were employed to knock out exons 10-13 (~3.9 kb) of the mouse Tfrc gene.



  • Construction strategy for B6-htau*P301S mice: The mouse Mapt gene was replaced with the human MAPT gene carrying the P301S mutation by gene editing technology.



Application

  • Research on Alzheimer's disease (AD), Frontotemporal dementia (FTD), neurodegenerative diseases, and tumor development;
  • Development, screening, and efficacy evaluation of TFRC/MAPT-targeted therapies;
  • Research and evaluation of drug delivery across the blood-brain barrier (BBB).



References
[1]Candelaria PV, Leoh LS, Penichet ML, Daniels-Wells TR. Antibodies Targeting the Transferrin Receptor 1 (TfR1) as Direct Anti-cancer Agents. Front Immunol. 2021 Mar 17;12:607692.
[2]Xu W, Barrientos T, Mao L, Rockman HA, Sauve AA, Andrews NC. Lethal Cardiomyopathy in Mice Lacking Transferrin Receptor in the Heart. Cell Rep. 2015 Oct 20;13(3):533-545.
[3]Kobak KA, Franczuk P, Schubert J, Dzięgała M, Kasztura M, Tkaczyszyn M, Drozd M, Kosiorek A, Kiczak L, Bania J, Ponikowski P, Jankowska EA. Primary Human Cardiomyocytes and Cardiofibroblasts Treated with Sera from Myocarditis Patients Exhibit an Increased Iron Demand and Complex Changes in the Gene Expression. Cells. 2021 Apr 6;10(4):818.
[4]Bray, Natasha. "Transferrin'bispecific antibodies across the blood–brain barrier." Nature Reviews Drug Discovery 14.1 (2015): 14-15.
[5]Pardridge, William M. "Blood–brain barrier drug delivery of IgG fusion proteins with a transferrin receptor monoclonal antibody." Expert opinion on drug delivery 12.2 (2015): 207-222.
[6]Strang KH, Golde TE, Giasson BI. MAPT mutations, tauopathy, and mechanisms of neurodegeneration. Lab Invest. 2019 Jul;99(7):912-928.
[7]Barghorn S, Zheng-Fischöfer Q, Ackmann M, Biernat J, von Bergen M, Mandelkow EM, Mandelkow E. Structure, microtubule interactions, and paired helical filament aggregation by tau mutants of frontotemporal dementias. Biochemistry. 2000 Sep 26;39(38):11714-21.
[8]Bang J, Spina S, Miller BL. Frontotemporal dementia. Lancet. 2015 Oct 24;386(10004):1672-82.