Cell Type and Regional Vulnerability in Frontotemporal Dementia - Project Summary/Abstract A key question in tauopathy research is why some brain cell populations are significantly affected while others are relatively spared. The long-term goal of this study is to understand this differential cell vulnerability and use the knowledge to develop therapies that protect neural cells from tauopathy-related degeneration. Mutations in the MAPT gene that encodes Tau commonly cause extensive pathology in the forebrain, with significant loss of frontal and temporal lobe cerebral cortical cells leading to behavioral, language and cognitive deficits. However, a subset of MAPT mutations also cause significant degeneration of midbrain dopaminergic neurons in the substantia nigra contributing to a parkinsonism phenotype. Furthermore, these cells are connected: midbrain dopaminergic neurons widely innervate the prefrontal cortex and are reciprocally innervated via cortico-striatal-nigral circuits. Why specific MAPT mutations significantly affect the midbrain in addition to cortex while others do not, and how connectivity between these regions with the potential for pathological tau spread may be involved, represent significant gaps in knowledge that we will address in this proposed study. Over the past few years, we have helped create a large iPSC line collection from patients with familial dementia due to mutations in the MAPT gene, including isogenic controls. Phenotypic analyses show MAPT mutant and control iPSC-derived cerebral cortical cells are initially phenotypically similar but develop differences with maturation that include increased tau aggregation, tau hyperphosphorylation and vulnerability to several stressors, associated with the mutation. However, to date, studies comparing forebrain and midbrain cell population responses to MAPT mutations that differentially affect these brain regions have not been done. Such comparisons have the potential to reveal common and unique molecular mechanisms that underlie cell vulnerability. Our approach is to use human iPSC-derived 3D organoids, which recapitulate complex cell-cell interactions in a human cell system and enable long-term culture over several months. We will create cortical and midbrain organoids from two MAPT mutations that primarily affect cortex and two that affect both cortex and midbrain, versus respective isogenic controls. In Aim 1 we will examine the impact of these MAPT mutations on cell populations and gene expression over time using single cell transcriptomics to define how diverse cell types respond to each mutation. In Aim 2, we will create assembloids of cortical and midbrain organoids to model the circuitry between the regions and determine whether this connectivity alters patterns of cell vulnerability and enables the spread of pathological tau from one region to another, depending on specific MAPT mutation. In Aim 3 we will probe the impact of stimulating tau degradation on differential cell vulnerability in cerebral cortex and midbrain.
