Ipsc-based model to study frontotemporal dementia due to mapt mutation - our goal is to generate and validate a novel, cellularly complex model of frontotemporal dementia (FTD) due to mutations in the…

The National Institute of Neurological Disorders and Stroke (NINDS) awarded $1.54M to Regenerative Research Foundation under the Extramural Research Programs in the Neurosciences and Neurological Disorders (CFDA 93.853) program on June 1, 2025, for a 24-month project period concluding May 31, 2027. The award funds the development and validation of a novel induced pluripotent stem cell (iPSC)-based model to study frontotemporal dementia (FTD) caused by MAPT gene mutations. The primary deliverable is a cellularly complex, axon-connected three-dimensional organoid system that integrates cerebral cortex, striatum, and midbrain regions with multiple cell types including neurons, astrocytes, oligodendrocytes, and microglia to more comprehensively model the disease pathology and neural circuitry affected in FTD-tau. This integrated model will demonstrate improved construct and face validity compared to existing single-region models and will capture the vulnerability of interconnected forebrain-midbrain neurons implicated in tau pathology development and progression.

The foundation will produce validated disease modeling tools and associated characterization data through Aim 1, which focuses on developing and optimizing production and connectivity of the multi-region organoid system. These research products will advance understanding of FTD-tau mechanisms and provide a robust platform for future therapeutic development and drug screening efforts. The work addresses a gap identified by the NINDS 2022 Alzheimer's Disease and Related Dementias Summit Report for improved human cellular models that capture the complexity of multiple affected brain regions in FTD-tau disease.

Ipsc-based model to study frontotemporal dementia due to mapt mutation - our goal is to generate and validate a novel, cellularly complex model of frontotemporal dementia (FTD) due to mutations in the mapt gene that encodes TAU (FTD-TAU). The ninds 2022 adrd summit report describes the need for such a model. Over 50 mutations in mapt cause FTD-TAU, which manifests by abnormal TAU accumulation in subsets of cerebral cortical neurons, astrocytes, and oligodendrocytes. This leads to cellular dysfunction and death, primarily in the frontal and temporal cortical regions, leading to deficits in executive function, language, and behavioral responses. Mapt mutation carriers frequently also have significant degeneration of subcortical areas, including the striatum and the midbrain dopaminergic substantia nigra (SNC) and midbrain ventral tegmental area (VTA) neurons, contributing to parkinsonism and behavioral changes. Hence there is need to model multiple brain areas to more fully capture brain cell vulnerability. Furthermore, there are extensive connections between these midbrain and forebrain area neurons that are affected in FTD- TAU, which implicates this circuitry in pathology development and spread. Prior 3D human cell models of FTD- TAU have focused on the cerebral cortex neurons and glia, which demonstrate key features of cortical tauopathy, including accumulation of abnormally phosphorylated TAU and degeneration of glutamatergic neurons. Here, we propose to build a model of axon-connected 3D cerebral cortex, striatum, and midbrain organoids that incorporates the major cell types and reconstructs key elements of the forebrain-midbrain circuity affected in FTD-TAU. To further advance the model and include critical cell types implicated in FTD-TAU, IT will incorporate microglia. The goal is a human cell model of affected brain regions that exhibits improved construct and face validity over existing models. In aim 1 we will develop and optimize production and connectivity of the cortical- striatal-midbrain (cost-MB) model. In aim 2 we will generate cost-MB models from different mapt mutations VS isogenic control lines. We will deeply phenotype the models and compare them to patient brain samples with mapt mutations in face and construct validation studies. Quantitative metrics will be used to assess reproducibility of the model and its phenotypic resemblance to patient forebrain and midbrain pathology. We will demonstrate independent replication of the model in more than one institution lab to demonstrate robustness. Transparent sharing of detailed protocols and data will aid adoption of the cost-MB FTD-TAU model. The model will be generated using our collection of human induced pluripotent stem cell (ipsc) lines with mapt mutations in coding and non-coding regions that affect both forebrain and midbrain pathology and crispr-corrected isogenic control lines; these lines are fully available to other researchers. The cost-MB model can be used in the future to study disease mechanisms and develop therapeutics to combat FTD-TAU and potentially other tauopathies or related neurodegenerative diseases that cause multi-region brain cell loss.