B6-htau*P301L Mice

Catalog Number: I001181

Strain Name: C57BL/6JCya-Mapttm2(hMAPT*P301L)/Cya

Genetic Background: C57BL/6JCya

Reproduction: Homozygote x Homozygote

One of Cyagen’s HUGO-GTTM (Humanized Genomic Ortholog for Gene Therapy) Strains

 

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, 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. Common mutations include P301L, P301S, and Intron10+3 G>A [4]. 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 [11-12].

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. This strain is a mouse Mapt gene humanized model carrying P301L mutation and can be used for research on FTD and AD. The homozygous B6-htau*P301L 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*P301S mice) and provide customized services for specific mutations.

Strain Strategy

Figure 1. Gene editing strategy of B6-htau*P301L mice. The mouse Mapt gene was replaced with the human MAPT gene carrying the P301L mutation by gene editing technology.

Application

  • Research on Frontotemporal dementia (FTD);
  • Research on Alzheimer's disease (AD);
  • Research on other neurodegenerative diseases.

Validation Data

1. Expression of human MAPT gene and mouse Mapt gene


Figure 2. RT-qPCR detection of human MAPT gene and mouse Mapt gene expression in the liver, cerebral cortex, and kidney of 6-week-old female B6-htau*P301L mice (hMAPT*P301L), B6-htau (hMAPT) and wild-type (WT) mice. The results indicate that B6-htau*P301L mice and B6-htau mice significantly express the human MAPT gene in the liver, cerebral cortex, and kidney, while not expressing the mouse Mapt gene. In contrast, WT mice only exhibit expression of the mouse Mapt gene and do not show expression of the human MAPT gene.

(ND: Not detected)

Expanded Information: The Rare Disease Data Center (RDDC)

1. Basic information about the MAPT gene

 

2. MAPT clinical variants

3. Disease introduction

Frontotemporal Dementia (FTD) is the second most prevalent form of early-onset dementia, following Alzheimer’s disease (AD). FTD typically exhibits an autosomal dominant inheritance pattern. Pathologically and radiographically, FTD is characterized by 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.

4. MAPT gene and mutations

The human MAPT gene is located on chromosome 17 and encodes the microtubule-associated tau protein. Tau protein is primarily localized to neuronal axons and plays a critical role in microtubule stability and assembly. Mutations in MAPT can lead to pathological tau protein accumulation and neuronal death in glutamatergic cortical neurons. These mutations, typically occurring in exons 9-12 and adjacent intronic regions, fall into two main categories: The first type affects protein expression, altering the protein’s structure and stability. Deletion of the MAPT gene may impair its function and exacerbate abnormal tau protein aggregation, consistent with the acquisition of cytotoxic effects. Similarly, mutations at specific sites can increase the propensity of tau protein to aggregate. The second type affects 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 MAPT mutations include P301L, P301S, and Intron10+3 G>A, among others [4]. Unlike the P301S mutation, P301L does not affect the splicing of 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 [11-12]. This leads to abnormal tau protein aggregation, resulting in neurofibrillary tangles—a characteristic feature of neurodegenerative diseases. Similar to the P301L mutation, the P301S mutation also causes pathological tau protein aggregation. Research indicates that recombinant tau proteins carrying the P301S mutation significantly impair microtubule assembly [13], and patients with this mutation exhibit clinical heterogeneity [14].

5. Function of non-coding DNA sequences

According to the publications, the pathogenic Intron10+3 G>A mutation in the MAPT intron can result in an increased proportion of 4R isoforms. Treatment with the oligonucleotide drug ASO-001933, which targets the 3’UTR region of MAPT, has been shown to effectively reduce tau protein expression in mice [5], non-human primates, and primary cultures of human neurons [6].

6. MAPT-targeted gene therapy

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. The ASO drug ISIS-814907 from Ionis targets and reduces MAPT gene expression to treat disease. Preclinical research for this drug candidate utilized transgenic humanized PS19 mice, in which the human MAPT gene carrying the P301S mutation was randomly inserted [7-8]. ASO-001933 targets the 3’UTR region of MAPT and effectively reduces its expression, In one study, a humanized disease model obtained by crossing transgenic mice (randomly inserting cDNA of the human wild-type MAPT gene) with MAPT-KO mice was used to pharmacologically analyze [5]. This study was funded by Roche [6]. Additionally, Arvinas’ ASO molecule and monoclonal antibody drug targeting the MAPT gene are currently in preclinical research [9].

7. Summary

The MAPT gene is a crucial pathogenic gene associated with frontotemporal dementia (FTD). Currently, gene therapy primarily focuses on antisense oligonucleotides (ASOs) and utilizes humanized mouse models for preclinical drug testing. Notably, MAPT gene humanized mice from Cyagen, along with popular mutation disease models (such as B6-htau*P301L and B6-htau*P301S mice), can be applied in preclinical research for FTD gene therapy. Cyagen also offers customized services for different mutations.

 

 

References
[1]Bang J, Spina S, Miller BL. Frontotemporal dementia. Lancet. 2015 Oct 24;386(10004):1672-82.
[2]trang KH, Golde TE, Giasson BI. MAPT mutations, tauopathy, and mechanisms of neurodegeneration. Lab Invest. 2019 Jul;99(7):912-928.
[3]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.
[4]Molecular Genetics Department, University of Antwerp. AD Mutations. http://www.molgen.vib-ua.be/ADMutations
[5]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.
[6]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.
[7]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.
[8]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.
[9]Arvinas. (2021). Arvinas 2021 Investor Day Presentation. https://ir.arvinas.com/static-files/e04cc75d-eaf0-4b83-8b7a-68537fe79dc8
[10]Boyarko B, Hook V. Human Tau Isoforms and Proteolysis for Production of Toxic Tau Fragments in Neurodegeneration. Front Neurosci. 2021 Oct 21;15:702788.
[11]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.
[12]Alzforum. (2021). MAPT P301L Mutation. Retrieved from https://www.alzforum.org/mutations/mapt-p301l
[13]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.
[14]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.