TDP-43 pathology is associated with increased tau burdens and seeding.
Mol Neurodegener
; 18(1): 71, 2023 09 30.
Article
en En
| MEDLINE
| ID: mdl-37777806
ABSTRACT
BACKGROUND:
Most Alzheimer's Disease (AD) cases also exhibit limbic predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), besides amyloid-ß plaques and neurofibrillary tangles (NFTs) containing hyperphosphorylated tau (p-tau). LATE-NC is characterized by cytoplasmic aggregates positive for pathological TDP-43 and is associated with more severe clinical outcomes in AD, compared to AD cases lacking TDP-43 pathology TDP-43 AD(LATE-NC-). Accumulating evidence suggests that TDP-43 and p-tau interact and exhibit pathological synergy during AD pathogenesis. However, it is not yet fully understood how the presence of TDP-43 affects p-tau aggregation in symptomatic AD.METHODS:
In this study, we investigated the impact of TDP-43 proteinopathy on p-tau pathology with different approaches histologically, in a human post-mortem cohort (n = 98), as well as functionally using a tau biosensor cell line and TDP-43A315T transgenic mice.RESULTS:
We found that AD cases with comorbid LATE-NC, AD(LATE-NC+), have increased burdens of pretangles and/or NFTs as well as increased brain levels of p-tau199, compared to AD(LATE-NC-) cases and controls. The burden of TDP-43 pathology was also correlated with the Braak NFT stages. A tau biosensor cell line treated with sarkosyl-insoluble, brain-derived homogenates from AD(LATE-NC+) cases displayed exacerbated p-tau seeding, compared to control and AD(LATE-NC-)-treated cells. Consistently, TDP-43A315T mice injected with AD(LATE-NC+)-derived extracts also exhibited a more severe hippocampal seeding, compared to the remaining experimental groups, albeit no TDP-43 aggregation was observed.CONCLUSIONS:
Our findings extend the current knowledge by supporting a functional synergy between TDP-43 and p-tau. We further demonstrate that TDP-43 pathology worsens p-tau aggregation in an indirect manner and increases its seeding potential, probably by increasing p-tau levels. This may ultimately contribute to tau-driven neurotoxicity and cell death. Because most AD cases present with comorbid LATE-NC, this study has an impact on the understanding of TDP-43 and tau pathogenesis in AD and LATE, which account for the majority of dementia cases worldwide. Moreover, it highlights the need for the development of a biomarker that detects TDP-43 during life, in order to properly stratify AD and LATE patients.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
6_ODS3_enfermedades_notrasmisibles
Problema de salud:
6_alzheimer_other_dementias
/
6_endocrine_disorders
/
6_mental_health_behavioral_disorders
Asunto principal:
Proteinopatías TDP-43
/
Enfermedad de Alzheimer
Tipo de estudio:
Risk_factors_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Mol Neurodegener
Año:
2023
Tipo del documento:
Article
País de afiliación:
Bélgica