Investigating the Effects of Tau Overexpression in Perineurial Glia in Drosophila melanogaster

Abstract

Neurodegenerative diseases comprise a complex group of disorders defined by progressive neuronal loss and protein abnormalities, notably tauopathies, which are characterized by the accumulation of hyperphosphorylated tau. In disease cases, such as Alzheimer’s, progressive supranuclear palsy, and chronic traumatic encephalopathy, this tau protein forms aggregates, which accumulate within neurons and, in many cases, also in surrounding glial cells. While the blood-brain barrier is maintained by glia and its dysfunction accelerates neurodegeneration, the impact of glial tau pathology on CNS function and disease progression remains poorly understood. This project addresses this gap by investigating the impact of tau overexpression specifically within barrier-associated perineurial glial (PG) cells in the model organism Drosophila melanogaster (fruit fly). Genetically modified flies were analyzed to determine if PG-specific tau overexpression causes cell death and organismal dysfunction. We found that the overexpression of tau in PG cells resulted in developmental lethality, and the co-expression of a histone-RFP construct, along with tau in PG cells, rescued this lethality. Additional analysis of these flies, however, demonstrated tau-induced toxicity was present when expressed in PG cells. These results demonstrate that tau overexpression in perineurial glia induces toxicity, identifying these barrier-associated cells as a critical factor in neurodegenerative disease progression.