Laura Pancrazi, Italy
Istituto di Neuroscienze Consiglio Nazionale delle Ricerche, CNRAuthor Of 1 Presentation
GENE EXPRESSION OF DISEASE-RELATED GENES IN ALZHEIMER’S DISEASE IS IMPAIRED BY TAU AGGREGATION
Abstract
Aims
Neuronal hyperexcitability linked to an increase in glutamate signalling is a peculiar trait of the early stages of Alzheimer's disease (AD) and tauopathies, however, a progressive reduction in glutamate release follows in advanced stages. We recently reported that in the early phases of the neurodegenerative process, soluble, non-aggregated Tau accumulates in the nucleus and modulates the expression of disease-relevant genes directly involved in glutamatergic transmission, thus establishing a link between Tau instability and altered neurotransmission.
Methods
We investigated, at cellular level, Tau aggregation mechanism in the nuclear compartment, and we evaluated the impact on disease-related gene expression.
Moreover, we evaluated the glutamatergic synapse function in PFC of DA patients by GSEA.
Results
Here we report that while the nuclear translocation of Tau in cultured cells is not impaired by its own aggregation, the nuclear amyloid inclusions of aggregated Tau abolish Tau-dependent increased expression of the glutamate transporter. Remarkably, we observed that in the prefrontal cortex (PFC) of AD patient brain, the glutamate transporter is upregulated at early stages and is downregulated at late stages.
Conclusions
The Gene Set Enrichment Analysis indicates that the modulation of Tau-dependent gene expression along the disease progression can be extended to all protein pathways of the glutamatergic synapse. Together, this evidence links the altered glutamatergic function in the PFC during AD progression to the newly discovered function of nuclear Tau.