B6-htau*P301S Mouse
Product Name
B6-htau*P301S Mouse
Product ID
C001836
Strain Name
C57BL/6JCya-Mapttm3(hMAPT*P301S)/Cya
Backgroud
C57BL/6JCya
Note
One of Cyagen’s HUGO-GTTM (Humanized Genomic Ortholog for Gene Therapy) Strains
Status
When using this mouse strain in a publication, please cite “B6-htau*P301S Mouse (Catalog C001836) were purchased from Cyagen.”
Product Type
Age
Genotype
Sex
Quantity
Gene Name
Gene Alias
TAU, MSTD, PPND, DDPAC, MAPTL, MTBT1, MTBT2, tau-40, FTDP-17, PPP1R103, Tau-PHF6
NCBI ID
Chromosome
Chr 17
MGI ID
Datasheet
Strain Description
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 [1].
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 [2]. 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 [3]. Common mutations include P301L, P301S, and Intron10+3 G>A [4]. 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 [10-12]. 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 AD and FTD. Transgenic mice are frequently used in drug development, and the utilization of humanized animal models helps advance potential MAPT-related therapies toward clinical trials [5-9]. This strain is a mouse Mapt gene humanized model carrying the P301S mutation and can be used for research on FTD and AD. The homozygous B6-htau*P301S mice are viable and fertile. In addition, based on the independently developed TurboKnockout fusion BAC recombination technology, Cyagen can also generate other hot mutation models (e.g., B6-htau*P301L mice, Catalog Number: C001835) and provide customized services for specific mutations.
Reference
Bang J, Spina S, Miller BL. Frontotemporal dementia. Lancet. 2015 Oct 24;386(10004):1672-82.
Strang KH, Golde TE, Giasson BI. MAPT mutations, tauopathy, and mechanisms of neurodegeneration. Lab Invest. 2019 Jul;99(7):912-928.
Lisowiec J, Magner D, Kierzek E, Lenartowicz E, Kierzek R. Structural determinants for alternative splicing regulation of the MAPT pre-mRNA. RNA Biol. 2015;12(3):330-42.
Molecular Genetics Department, University of Antwerp. AD Mutations.
Andorfer C, Kress Y, Espinoza M, de Silva R, Tucker KL, Barde YA, Duff K, Davies P. Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem. 2003 Aug;86(3):582-90.
Easton A, Jensen ML, Wang C, Hagedorn PH, Li Y, Weed M, Meredith JE, Guss V, Jones K, Gill M, Krause C, Brown JM, Hunihan L, Natale J, Fernandes A, Lu Y, Polino J, Bookbinder M, Cadelina G, Benitex Y, Sane R, Morrison J, Drexler D, Mercer SE, Bon C, Pandya NJ, Jagasia R, Ou Yang TH, Distler T, Grüninger F, Meldgaard M, Terrigno M, Macor JE, Albright CF, Loy J, Hoeg AM, Olson RE, Cacace AM. Identification and characterization of a MAPT-targeting locked nucleic acid antisense oligonucleotide therapeutic for tauopathies. Mol Ther Nucleic Acids. 2022 Aug 4;29:625-642.
DeVos SL, Miller RL, Schoch KM, Holmes BB, Kebodeaux CS, Wegener AJ, Chen G, Shen T, Tran H, Nichols B, Zanardi TA, Kordasiewicz HB, Swayze EE, Bennett CF, Diamond MI, Miller TM. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci Transl Med. 2017 Jan 25;9(374):eaag0481.
Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, Maeda J, Suhara T, Trojanowski JQ, Lee VM. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 2007 Feb 1;53(3):337-51.
Arvinas. (2021). Arvinas 2021 Investor Day Presentation.
Barghorn S, Zheng-Fischhöfer 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.
Bugiani O, Murrell JR, Giaccone G, Hasegawa M, Ghigo G, Tabaton M, Morbin M, Primavera A, Carella F, Solaro C, Grisoli M, Savoiardo M, Spillantini MG, Tagliavini F, Goedert M, Ghetti B. Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau. J Neuropathol Exp Neurol. 1999 Jun;58(6):667-77.
Yasuda M, Nakamura Y, Kawamata T, Kaneyuki H, Maeda K, Komure O. Phenotypic heterogeneity within a new family with the MAPT p301s mutation. Ann Neurol. 2005 Dec;58(6):920-8.
Strain Strategy
The mouse Mapt gene was replaced with the human MAPT gene carrying the P301S mutation by gene editing technology.
Figure 1. Gene editing strategy of B6-htau*P301S mice.
Application Area
Research on Frontotemporal dementia (FTD);
Research on Alzheimer's disease (AD);
Research on other neurodegenerative diseases.
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