TDP-43 Pathology and Prionic Behavior in Human Cellular Models of Alzheimer’s Disease Patients

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder for which there is currently no effective treatment. Despite advances in the molecular pathology of the characteristic histopathological markers of the disease (tau protein and β-amyloid), their translation to the clinic has not provided the expected results. Increasing evidences have demonstrated the presence of aggregates of TDP-43 (TAR DNA binding protein 43) in the postmortem brains of patients diagnosed with AD. The present research is focused on of the study of the pathological role of TDP-43 in AD. For this purpose, immortalized lymphocytes samples from patients diagnosed with different severity of sporadic AD were used and the TDP-43 pathology was analyzed against controls, looking for differences in their fragmentation, phosphorylation and cellular location using Western blot and immunocytochemical techniques. The results revealed an increase in TDP-43 fragmentation, as well as increased phosphorylation and aberrant localization of TDP-43 in the cytosolic compartment of lymphocytes of patients diagnosed with severe AD. Moreover, a fragment of approximately 25 KD was found in the extracellular medium of cells derived from severe AD individuals that seem to have prion-like characteristics. We conclude that TDP-43 plays a key role in AD pathogenesis and its cell to cell propagation.