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 Aβ1–42 in the rat motor cortex led to an increase in TDP-43 pathology, including up-regulation of the mature ~ 44 kDa protein, identical to the pathological changes seen in AD. Furthermore, expression of Aβ1–42 was associated with TDP-43 phosphorylation and accumulation in the cytosol. Clearance of Aβ 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 Aβ, independent of Tau. Increased levels of casein kinase (CK1 and CK2), which are associated with TDP-43 phosphorylation, were also observed in Aβ1–42 expressing brains. These data indicate an overlap in TDP-43 pathology between AD and ALS-FTLD and suggest that Aβ triggers modifications of TDP-43.

Research highlights
► We observe over-expression of TDP-43 in autopsies of AD patients.
► TDP-43 pathology was observed in Aβ expressing models independent of Tau.
► Clearance of Aβ with parkin eliminated TDP-43 pathology.
► TDP-43 was not observed in α-Synuclein expressing models.
► Aβ may trigger TDP-43 pathology independent of Tau.