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

Shih, Ying-Hsia; Tu, Ling Hsien; Chang, Tsin‐Yuan; Ganesan, Kiruthika; Chang, Wei Wei; Chang, Pao Sheng; Fang, Yuting; Lin, Yeh Tung; Jin, Lee Way; Chen, Yun‐Ru

doi:10.1038/s41467-020-19786-7

Cited by 51 publications

(90 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The frequent detection of TDP-43 positive inclusion bodies in AD could be due in part to this potential cross-seeding capacity of Aβ with TDP-43 [ 132 ]. Interestingly, full length TDP-43, as well as truncated N-terminal and C-terminal variants, were found to reduce Aβ fibrillization in a dose-dependent manner at oligomeric and other pre-fibril stages [ 92 , 125 ]. Analogous to the most significant deficits seen in humans with AD and TDP-43 pathologies, mice with recombinant TDP-43 oligomers injected into the hippocampus had exacerbation of neuroinflammation and memory deficits [ 125 ].…”

Section: Introductionmentioning

confidence: 99%

TDP-43 Pathology in Alzheimer’s Disease

Meneses

Koga

O’Leary

et al. 2021

Mol Neurodegeneration

128

View full text Add to dashboard Cite

Transactive response DNA binding protein of 43 kDa (TDP-43) is an intranuclear protein encoded by the TARDBP gene that is involved in RNA splicing, trafficking, stabilization, and thus, the regulation of gene expression. Cytoplasmic inclusion bodies containing phosphorylated and truncated forms of TDP-43 are hallmarks of amyotrophic lateral sclerosis (ALS) and a subset of frontotemporal lobar degeneration (FTLD). Additionally, TDP-43 inclusions have been found in up to 57% of Alzheimer’s disease (AD) cases, most often in a limbic distribution, with or without hippocampal sclerosis. In some cases, TDP-43 deposits are also found in neurons with neurofibrillary tangles. AD patients with TDP-43 pathology have increased severity of cognitive impairment compared to those without TDP-43 pathology. Furthermore, the most common genetic risk factor for AD, apolipoprotein E4 (APOE4), is associated with increased frequency of TDP-43 pathology. These findings provide strong evidence that TDP-43 pathology is an integral part of multiple neurodegenerative conditions, including AD. Here, we review the biology and pathobiology of TDP-43 with a focus on its role in AD. We emphasize the need for studies on the mechanisms that lead to TDP-43 pathology, especially in the setting of age-related disorders such as AD.

show abstract

Section: Introductionmentioning

confidence: 99%

TDP-43 Pathology in Alzheimer’s Disease

Meneses

Koga

O’Leary

et al. 2021

Mol Neurodegeneration

128

View full text Add to dashboard Cite

show abstract

“…There is some limited evidence supporting this hypothesis. In vitro, TDP-43 does not regulate expression or processing of amyloid precursor protein but accelerates Aβ aggregation, and in mouse models, it modulates Aβ fibrillization and worsens cognitive outcomes [41][42][43]. However, in an autopsy cohort of AD patients who underwent antemortem amyloid sensitive PET imaging, there were no correlates between TDP-43 pathology and global amyloid PET signal [44].…”

mentioning

confidence: 99%

Tau and TDP-43 synergy: a novel therapeutic target for sporadic late-onset Alzheimer’s disease

Latimer

Liachko

2021

GeroScience

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is traditionally defined by the presence of two types of protein aggregates in the brain: amyloid plaques comprised of the protein amyloid-β (Aβ) and neurofibrillary tangles containing the protein tau. However, a large proportion (up to 57%) of AD patients also have TDP-43 aggregates present as an additional comorbid pathology. The presence of TDP-43 aggregates in AD correlates with hippocampal sclerosis, worse brain atrophy, more severe cognitive impairment, and more rapid cognitive decline. In patients with mixed Aβ, tau, and TDP-43 pathology, TDP-43 may interact with neurodegenerative processes in AD, worsening outcomes. While considerable progress has been made to characterize TDP-43 pathology in AD and late-onset dementia, there remains a critical need for mechanistic studies to understand underlying disease biology and develop therapeutic interventions. This perspectives article reviews the current understanding of these processes from autopsy cohort studies and model organism-based research, and proposes targeting neurotoxic synergies between tau and TDP-43 as a new therapeutic strategy for AD with comorbid TDP-43 pathology.

show abstract

“…Instead, there was an accumulation of prefibril Aβ that correlated with the loss of synaptophysin at 8 months of age in APP swe /PS1ΔE9 without TDP-43. In the APP/PS1 murine AD model, TDP-43 oligomers were shown to inhibit the fibril formation of Aβ 1-40 in vitro, though TDP-43 did not inhibit the seeding of fibrils (Shih et al, 2020). In the same APP/PS1 mouse model, however, the injection of TDP-43 oligomers into brain increased Aβ plaques and worsened memory performance, indicating that in vivo conditions for Aβ and TDP-43 interaction may differ from the fibril formation in vitro (Shih et al, 2020).…”

Section: Tdp-43 Interaction With Aβmentioning

confidence: 95%

“…In the APP/PS1 murine AD model, TDP-43 oligomers were shown to inhibit the fibril formation of Aβ 1-40 in vitro, though TDP-43 did not inhibit the seeding of fibrils (Shih et al, 2020). In the same APP/PS1 mouse model, however, the injection of TDP-43 oligomers into brain increased Aβ plaques and worsened memory performance, indicating that in vivo conditions for Aβ and TDP-43 interaction may differ from the fibril formation in vitro (Shih et al, 2020). Additional data from studies employing lentiviral delivery of TDP-43 into rat cortex indicated that TDP-43 co-localized with BACE1 (a key Aβ cleaving enzyme), increased BACE1 expression, and led to increases in APP-c terminal fragment processing, a key mechanism for Aβ accumulation (Herman et al, 2012).…”

Section: Tdp-43 Interaction With Aβmentioning

confidence: 95%

“…It was repeatedly demonstrated that the presence of TDP-43 pathology induces microglia activation, or other neuroinflammation, beyond that seen in standard AD models. The injection of TDP-43 oligomers into the cortex of APP/PS1 mice caused an increase in Iba-1 expression, often thought to correlate with increased microgliosis (Shih et al, 2020). The increased accumulation of Aβ fibrils in the presence of TDP-43 in vivo compared to in vitro was attributed to the contributions of neuroinflammation, as suggested by the enhanced microglial Iba-1 immunoreactivity (Shih et al, 2020).…”

Section: Glial Tdp-43 In Admentioning

confidence: 99%

See 1 more Smart Citation

Glial TDP‐43 and TDP‐43 induced glial pathology, focus on neurodegenerative proteinopathy syndromes

Prater

Latimer

Jayadev

2021

Glia

View full text Add to dashboard Cite

Since its discovery in 2006, TAR DNA binding protein 43 (TDP-43) has driven rapidly evolving research in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and limbic predominant agerelated TDP-43 encephalopathy (LATE). TDP-43 mislocalization or aggregation is the hallmark of TDP-43 proteinopathy and is associated with cognitive impairment that can be mapped to its regional deposition. Studies in human tissue and model systems demonstrate that TDP-43 may potentiate other proteinopathies such as the amyloid or tau pathology seen in Alzheimer's Disease (AD) in the combination of AD+LATE.Despite this growing body of literature, there remain gaps in our understanding of whether there is heterogeneity in TDP-43 driven mechanisms across cell types.The growing observations of correlation between TDP-43 proteinopathy and glial pathology suggest a relationship between the two, including pathogenic glial cell-autonomous dysfunction and dysregulated glial immune responses to neuronal TDP-43. In this review, we discuss the available data on TDP-43 in glia within the context of the neurodegenerative diseases ALS and FTLD and highlight the current lack of information about glial TDP-43 interaction in AD+LATE. TDP-43 has proven to be a significant modulator of cognitive and neuropathological outcomes. A deeper understanding of its role in diverse cell types may provide relevant insights into neurodegenerative syndromes.

show abstract

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

Cited by 51 publications

References 63 publications

TDP-43 Pathology in Alzheimer’s Disease

TDP-43 Pathology in Alzheimer’s Disease

Tau and TDP-43 synergy: a novel therapeutic target for sporadic late-onset Alzheimer’s disease

Glial TDP‐43 and TDP‐43 induced glial pathology, focus on neurodegenerative proteinopathy syndromes

Contact Info

Product

Resources

About