| First Author | Shih YH | Year | 2020 |
| Journal | Nat Commun | Volume | 11 |
| Issue | 1 | Pages | 5950 |
| PubMed ID | 33230138 | Mgi Jnum | J:299821 |
| Mgi Id | MGI:6490707 | Doi | 10.1038/s41467-020-19786-7 |
| Citation | Shih YH, et al. (2020) TDP-43 interacts with amyloid-beta, inhibits fibrillization, and worsens pathology in a model of Alzheimer's disease. Nat Commun 11(1):5950 |
| abstractText | 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 (Abeta) fibrillization. To elucidate the role of TDP-43 in AD, here, we examined the effect of TDP-43 in Abeta aggregation and the attributed toxicity in mouse models. We found TDP-43 inhibited Abeta fibrillization at initial and oligomeric stages. Abeta fibrillization was delayed specifically in the presence of N-terminal domain containing TDP-43 variants, while C-terminal TDP-43 was not essential for Abeta interaction. TDP-43 significantly enhanced Abeta'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 Abeta, and exacerbated AD-like pathology. TDP-43 oligomers mostly colocalized with intracellular Abeta in the brain of AD patients. We conclude that TDP-43 inhibits Abeta fibrillization through its interaction with Abeta and exacerbates AD pathology. |
