Comment regarding: Experimental Basis for Generating Nonhuman Primate Models of Frontotemporal Dementia and Alzheimer’s Disease

We read with great interest the review article by Morito et al. [1], which details their research teams’ efforts to develop enhanced preclinical models for tauopathies, including primary age-related tauopathy (PART), frontotemporal dementia (FTD), FTD with Parkinsonism linked to chromosome 17 (FTDP-17), amyotrophic lateral sclerosis (ALS), and Alzheimer’s disease (AD). These neurodegenerative disorders are characterized by the abnormal aggregation of the tau protein, leading to the formation of intracellular hyperphosphorylated neurofibrillary tangles (NFTs) that cause cell dysfunction and death [2]. Tau is encoded by the Microtubule Associated Protein Tau (MAPT) gene. Alternative spicing of the exon 10 in MAPT results in expression of six different tau isoforms, which differ on the presence of three-repeat (3R) and four-repeat (4R) microtubule-binding domains [2-3]. The predominant tau isoform found in NFTs differs across tauopathies, thus contributing to the classification and complexity of these disorders [4]. Therefore, there is a pressing need to develop model systems that express both 3R and 4R tau isoforms for a relevant study of human tauopathies.

In this review, the authors emphasize their successful creation of knock-in mouse models of FTDP-17 (Table 1), which may serve as the foundation for using non-human primate models (i.e., marmosets) to develop other knock-in models of tauopathies. Intriguingly, the authors claim the unnecessary nature of introducing intron 10+3 or S305N mutations in marmosets given their exclusive expression of 4R tau isoforms. This claim is primarily based on the authors’ earlier work [6], which reported that adult marmosets express only three tau isoforms, exclusively containing 4R repeats, compared to the six tau isoforms found in humans and macaques (Figure 1). Although there is considerable enthusiasm for non-human primates, particularly marmosets, as advantageous model systems for tauopathies, it is crucial to highlight that the authors overlooked a highly relevant recent publication substantiating the natural expression of 3R and 4R tau isoforms in adult marmoset brains [7]. This study conducted a comprehensive multi-modal characterization applying the most advanced and sensitive techniques, inclusive of the state-of- the-field mass spectrometry approaches currently used for human samples, confirming the expression of exon 10 inclusion and exclusion in the MAPT transcript and 3R and 4R tau protein isoforms across several unrelated adult marmosets of varying ages and in direct comparison to human brain tissue [7]. These data conclusively verify the natural expression of 3R and 4R tau isoforms in adult marmosets, contradicting the authors’ previous report [5]. Indeed, it would present an evolutionary paradox for adult marmosets to lack 3R tau given the exon 10 inclusion level in marmosets, which is conserved across other new world non-human primate species, as well as Old World macaques and humans [8]. Furthermore, primate species more phylogenetically distant from humans, such as adult mouse lemurs [9], express both 3R and 4R tau isoforms. Thus, while it remains interesting to perform genetic mutations in MAPT to model tauopathy in marmosets, it is erroneous to limit these approaches to 4R tauopathies given that marmosets naturally express all six tau isoform and could therefore serve as valuable models for 3R tauopathies, such as Pick’s disease and FTD, as well as mixed 3R/4R tauopathies, like AD, PART, and ALS.

The authors ultimate goal is to combine MAPT knock-in models (under development) with the authors’ previously developed marmoset AD models lacking exon 9 (PSEN1-Δ9) [5] to expedite the development of amyloid plaques and NFTs. The authors then highlighted the potential of genetic engineering approaches in marmosets, emphasizing the closer genetic homology between marmosets and humans for GWAS-identified AD risk genes compared to mice (Table 2) [1]. This increased homology is indeed one of the many advantages of marmoset models that should be leveraged for better study of human tauopathies. However, no references or methods for homology determination were provided for these GWAS and reference genome datasets, which will be crucial to include for future replicability studies.

In summary, there is great enthusiasm for developing marmoset models to study tauopathies, including FTD and AD. Similar to other known primate species, marmosets express 3R and 4R tau and exhibit natural and sporadic age-related progression of amyloid and tau [7], providing a strong foundation for translational studies. The significant advances in genetic engineering of risk mutations in marmosets, as highlighted by the author’s work in this review [1, 5] and other groups [10], continue to be crucial for understanding primate-specific mechanisms underlying disease progression and serve as model systems for investigating the therapeutic potential for halting, preventing, and treating these devastating diseases.

Hasi Huhe^1,2, Thais Rafael Guimaraes¹, Amantha Thathiah¹, Gregg E. Homanics³, Gregory W. Carter⁴, Afonso C. Silva^1,2, Stacey J. Sukoff Rizzo^1,2
1Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
²Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
³Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
⁴The Jackson Laboratory, Bar Harbor, Maine, USA

References
[1] Morito T, Watamura N, Sasaguri H, et al. Experimental basis for generating nonhuman primate models of frontotemporal dementia and Alzheimer’s disease. J Alzheimers Dis 2025; DOI: 10.1177/13872877251321116.
[2] Di Lorenzo D. Tau protein and yauopathies: Exploring tau protein-protein and microtubule interactions, cross-interactions and therapeutic strategies. ChemMedChem 2024; 19: e202400180.
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[4] Zhang Y, Wu KM, Yang L, et al. Tauopathies: new perspectives and challenges. Mol Neurodegener 2022; 17: 28.
[5] Sato K, Sasaguri H, Kumita W, et al. Production of a heterozygous exon skipping model of common marmosets using gene-editing technology. Lab Anim (NY) 2024; 53: 244–251.
[6] Sharma G, Huo A, Kimura T, et al. Tau isoform expression and phosphorylation in marmoset brains. J Biol Chem 2019; 294: 11433-11444.
[7] Huhe H, Shapley SM, Duong DM, et al. Marmosets as model systems for the study of Alzheimer's disease and related dementias: Substantiation of physiological tau 3R and 4R isoform expression and phosphorylation. Alzheimers Dement 2025; 21: e14366.
[8] Recinos Y, Bao S, Wang X, et al. Lineage-specific splicing regulation of MAPT gene in the primate brain. Cell Genom 2024; 4: 100563.
[9] Lam S, Petit F, Hérard AS, et al. Transmission of amyloid-beta and tau pathologies is associated with cognitive impairments in a primate. Acta Neuropathol Commun 202; 9: 165.
[10] Homanics GE, Park JE, Bailey L, et al. Early molecular events of autosomal-dominant Alzheimer's disease in marmosets with PSEN1 mutations. Alzheimers Dement 2024; 20: 3455-3471.