Dataset Information

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

ABSTRACT: 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-? (A?) fibrillization. To elucidate the role of TDP-43 in AD, here, we examined the effect of TDP-43 in A? aggregation and the attributed toxicity in mouse models. We found TDP-43 inhibited A? fibrillization at initial and oligomeric stages. A? 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? interaction. TDP-43 significantly enhanced A?'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?, and exacerbated AD-like pathology. TDP-43 oligomers mostly colocalized with intracellular A? in the brain of AD patients. We conclude that TDP-43 inhibits A? fibrillization through its interaction with A? and exacerbates AD pathology.

SUBMITTER: Shih YH

PROVIDER: S-EPMC7683652 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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

Shih Yao-Hsiang YH Tu Ling-Hsien LH Chang Ting-Yu TY Ganesan Kiruthika K Chang Wei-Wei WW Chang Pao-Sheng PS Fang Yu-Sheng YS Lin Yeh-Tung YT Jin Lee-Way LW Chen Yun-Ru YR

Nature communications 20201123 1

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-β (Aβ) fibrillization. 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. We found TDP-43 inhibited Aβ fibrillization at initial and oligomeric stages. Aβ fibrillization was delayed speci ...[more]

PMID: 33230138

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Project description:The co-existence of multiple pathologies and proteins is a common feature in the brains of cognitively impaired elderly individuals. Transactive response DNA-binding protein (TDP-43) has been discovered to accumulate in limbic brain regions of a portion of late-onset Alzheimer's disease (AD) patients, in addition to amyloid-? and ? protein. However, it is not yet known whether the TDP-43 species in the AD brain differ in their composition, when compared among different AD cases and to frontotemporal lobar degeneration cases with TDP-43 inclusions (FTLD-TDP). Furthermore, it is not known whether TDP-43 pathology in AD is related to symptoms of the frontotemporal dementia (FTD) spectrum. In this study, we investigated the molecular pattern of TDP-43 lesions with five different antibodies against different phosphorylated (pTDP-43) and non-phosphorylated TDP-43 epitopes. We analyzed a cohort of 97 autopsy cases, including brains from 20 non-demented individuals, 16 cognitively normal pathologically-defined preclinical AD (p-preAD), 51 neuropathologically-confirmed AD cases and 10 FTLD-TDP cases as positive controls. We observed distinct neuropathological patterns of TDP-43 among AD cases. In 11 neuropathologically-confirmed AD cases we found dystrophic neurites (DNs), neuronal cytoplasmic inclusions (NCIs) and/or neurofibrillary tangle (NFT)-like lesions not only positive for pTDP-43409/410, but also for pTDP-43 phosphorylated at serines 403/404 (pTDP-43403/404) and non-phosphorylated, full-length TDP-43, as seen with antibodies against C-terminal TDP-43 and N-terminal TDP-43. These cases were referred to as ADTDP?+?FL because full-length TDP-43 was presumably present in the aggregates. FTLD-TDP cases showed a similar molecular TDP-43 pattern. A second pattern, which was not seen in FTLD-TDP, was observed in most of p-preAD, as well as 30 neuropathologically-confirmed AD cases, which mainly exhibited NFTs and NCIs stained with antibodies against TDP-43 phosphorylated at serines 409/410 (pTDP-43409, pTDP-43409/410). Because only phosphorylated C-terminal species of TDP-43 could be detected in the lesions we designated these AD cases as ADTDP?+?CTF. Ten AD cases did not contain any TDP-43 pathology and were referred to as ADTDP-. The different TDP-43 patterns were associated with clinically typical AD symptoms in 80% of ADTDP?+?CTF cases, 63,6% of ADTDP?+?FL and 100% of the ADTDP- cases. On the other hand, clinical symptoms characteristic for FTD were observed in 36,4% of ADTDP?+?FL, in 16,6% of the ADTDP?+?CTF, and in none of the ADTDP- cases. Our findings provide evidence that TDP-43 aggregates occurring in AD cases vary in their composition, suggesting the distinction of different molecular patterns of TDP-43 pathology ranging from ADTDP- to ADTDP?+?CTF and ADTDP?+?FL with possible impact on their clinical picture, i.e. a higher chance for FTD-like symptoms in ADTDP?+?FL cases.

Dataset Information

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

Publications

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

Similar Datasets

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