TDP-43 interacts with amyloid-β, inhibits fibrillization, and worsens pathology in a model of Alzheimer's disease

TDP-43 inclusions are found in many Alzheimer's disease (AD) patients presenting faster disease progression and greater brain atrophy. Previously, we showed full-length TDP-43 forms spherical oligomers and perturbs amyloid-beta (A beta) fibrillization. To elucidate the role of TDP-43 in AD, here, we examined the effect of TDP-43 in A beta aggregation and the attributed toxicity in mouse models. We found TDP-43 inhibited A beta fibrillization at initial and oligomeric stages. A beta fibrillization was delayed specifically in the presence of N-terminal domain containing TDP-43 variants, while C-terminal TDP-43 was not essential for A beta interaction. TDP-43 significantly enhanced A beta 's ability to impair long-term potentiation and, upon intrahippocampal injection, caused spatial memory deficit. Following injection to AD transgenic mice, TDP-43 induced inflammation, interacted with A beta, and exacerbated AD-like pathology. TDP-43 oligomers mostly colocalized with intracellular A beta in the brain of AD patients. We conclude that TDP-43 inhibits A beta fibrillization through its interaction with A beta and exacerbates AD pathology. TDP-43 inclusions are observed in Alzheimer's disease. Here the authors show that TDP-43 interacts with amyloid-beta and inhibits fibrillization in vitro and exacerbates Alzheimer's disease pathology in animal models.