OO220 - TDP-43 PROMOTES AMYLOID-Β OLIGOMERIZATION VIA INTERACTION AND WORSENS PATHOLOGY IN A MODEL OF ALZHEIMER’S DISEASE (ID 1413)
Abstract
Aims
TDP-43 inclusions are found in more than half of the 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-β (Aβ) fibrillization.
Methods
To elucidate the role of TDP-43 in AD, here, we examined the effect of TDP-43 in Aβ aggregation and the attributed toxicity in mouse models as well as the interaction between TDP-43 and Aβ.
Results
We found TDP-43 inhibited Aβ fibrillization at initial and oligomeric stages. Aβ fibrillization was delayed specifically in the presence of N-terminal domain containing TDP-43 variants, while C-terminal TDP-43 was not essential for Aβ interaction. TDP-43 significantly enhanced Aβ’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 Aβ, and exacerbated AD-like pathology. TDP-43 oligomers mostly colocalized with intracellular Aβ in the brain of AD patients. In addition, we also investigated the interacting of TDP-43 and Aβ and found the interacting interface for TDP-43/Aβ. Potential interrupting agents were developed.
Conclusions
We conclude that TDP-43 inhibits Aβ fibrillization through its interaction with Aβ and exacerbates AD pathology.
