Mapt-KO Mouse

Mapt, encoding the microtubule-associated protein tau, is crucial for maintaining microtubule function and axonal transport. Tau is mainly expressed in neurons, participating in axonal transport and synaptic plasticity. Six major isoforms of tau are generated by alternative splicing of MAPT transcripts, which is regulated spatially and developmentally [2,3].

In mouse models, humanizing the entire murine Mapt gene (by replacing it with the human ortholog) created a platform to study human tauopathy. The double-knock-in mice (MAPT and App) exhibited higher tau phosphorylation. Tau humanization significantly accelerated cell-to-cell propagation of AD brain-derived pathological tau, with Aβ-amyloidosis intensifying tau accumulation [1]. Mutations in MAPT, like ∆K281, can cause Pick's disease, characterized by numerous inclusions of hyperphosphorylated 3R Tau in neurons and glial cells [5]. Also, MAPT haplotypes, such as H1G, are associated with an increased risk of dementia with Lewy bodies [4].

In conclusion, Mapt is essential for microtubule-related functions in neurons. Model-based research, especially the humanized Mapt mouse model, has revealed its role in tauopathy and neurodegenerative diseases like Alzheimer's, Pick's disease, and dementia with Lewy bodies. Understanding Mapt's functions and its genetic variations provides insights into the pathogenesis of these diseases, potentially guiding the development of targeted therapies.

References:

1. Saito, Takashi, Mihira, Naomi, Matsuba, Yukio, Trojanowski, John Q, Saido, Takaomi C. 2019. Humanization of the entire murine Mapt gene provides a murine model of pathological human tau propagation. In The Journal of biological chemistry, 294, 12754-12765. doi:10.1074/jbc.RA119.009487. https://pubmed.ncbi.nlm.nih.gov/31273083/

2. Corsi, Andrea, Bombieri, Cristina, Valenti, Maria Teresa, Romanelli, Maria Grazia. 2022. Tau Isoforms: Gaining Insight into MAPT Alternative Splicing. In International journal of molecular sciences, 23, . doi:10.3390/ijms232315383. https://pubmed.ncbi.nlm.nih.gov/36499709/

3. Ruiz-Gabarre, Daniel, Carnero-Espejo, Almudena, Ávila, Jesús, García-Escudero, Vega. 2022. What's in a Gene? The Outstanding Diversity of MAPT. In Cells, 11, . doi:10.3390/cells11050840. https://pubmed.ncbi.nlm.nih.gov/35269461/

4. Labbé, Catherine, Heckman, Michael G, Lorenzo-Betancor, Oswaldo, Dickson, Dennis W, Ross, Owen A. 2016. MAPT haplotype H1G is associated with increased risk of dementia with Lewy bodies. In Alzheimer's & dementia : the journal of the Alzheimer's Association, 12, 1297-1304. doi:10.1016/j.jalz.2016.05.002. https://pubmed.ncbi.nlm.nih.gov/27287057/

5. Schweighauser, Manuel, Garringer, Holly J, Klingstedt, Therése, Ghetti, Bernardino, Newell, Kathy L. 2023. Mutation ∆K281 in MAPT causes Pick's disease. In Acta neuropathologica, 146, 211-226. doi:10.1007/s00401-023-02598-6. https://pubmed.ncbi.nlm.nih.gov/37351604/