CONSEQUENCES OF ASTROCYTE-SPECIFIC MODULATION OF TAGLN3 EXPRESSION AND RELEVANCE FOR ALZHEIMER’S DISEASE

Our lab identified TAGLN3, a central nervous system member of the transgelin family, as downregulated inhuman iPSC-astrocytes from APOE ε4 carriers, a major genetic risk factor for sporadic Alzheimer’s Disease (AD), linked to a pro-inflammatory phenotype. In an unrelated study TAGLN3 levels were found elevated in the cerebrospinal fluid (CSF) of AD patients and showed significant correlation with CSF tau levels. Although TAGLN3 is relatively understudied, other transgelin isoforms have been linked to peripheral inflammation. Thus, TAGLN3 is an intriguing protein potentially involved in astrocyte–neuron communication, neuroinflammatory regulation, and Alzheimer’s pathology. We hypothesize that TAGLN3 acts as a mediator of AD-related cellular dysregulation and aim to test this by genetically modulating its expression and assessing the impact on AD-related pathology.
We are generating genetic tools allowing for TAGLN3 modulations in hiPSC-derived astrocytes and neurons. The effects of astrocytic TAGLN3 modulations are assessed using integrated proteomic, genomic, and functional assays, focusing on astrocyte reactivity and AD-related pathologies. TAGLN3 expression and cellular distribution are further examined in hiPSC-astrocytes and neurons, and mouse models using immunostaining and hybridization. TAGLN3 knockout lines are validated; calcium imaging confirmed functional hiPSC-astrocytes; RNAscope confirmed astrocytic TAGLN3 expression in mice.
From its modulation in different models, we aim to establish TAGLN3 as a functional mediator of AD by defining its cell-type–specific role in AD-associated cellular dysfunction. By applying genetic modulation in human iPSC-derived brain cells, this study seeks to validate TAGLN3 as a relevant, druggable target influencing brain function in health and neurodegenerative disease.