β-Amyloid triggers ALS-associated TDP-43 pathology in AD models

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with loss of motor neurons in the brain and spinal cord. ALS is occasionally diagnosed with frontotemporal lobar dementia with ubiquitin-positive inclusions (FTLD-U). Alzheimer's disease (AD) is the most common type of age-associated dementia. Abnormal levels of aggregated Tar-DNA binding protein-43 (TDP-43) are detected in the majority of patients with ALS, FTLD and AD. We observed a significant increase (200%) in the levels of TDP-43 in cortical autopsies of late stage AD patients. Lentiviral expression of A beta(1-42) in the rat motor cortex led to an increase in TDP-43 pathology, including up-regulation of the mature similar to 44 kDa protein, identical to the pathological changes seen in AD. Furthermore, expression of A beta(1-42) was associated with TDP-43 phosphorylation and accumulation in the cytosol. Clearance of A beta with parkin prevented TDP-43 pathology. TDP-43 modifications were also observed in 3xTransgenic AD (3xTg-AD) compared to wild type mice, but these changes were attenuated in parkin-injected hippocampi, even in the presence of Tau pathology, suggesting that TDP-43 pathology is triggered by As, independent of Tau. Increased levels of casein kinase (CK1 and CK2), which are associated with TDP-43 phosphorylation, were also observed in A beta(1-42) expressing brains. These data indicate an overlap in TDP-43 pathology between AD and ALS-FTLD and suggest that A beta triggers modifications of TDP-43. Published by Elsevier B.V.