Year: 2023
Type: article
Study design: Observational Study
Abstract: Background TDP‐43 is known to co‐accumulate in the brains of most Alzheimer’s Disease (AD) cases, in addition to amyloid‐β plaques and tau tangles, and it has been recently defined as limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC). TDP‐43 pathology is thought to worsen cognitive decline and neurodegeneration, but it is not yet understood whether TDP‐43 expression impacts AD pathogenesis, specifically tau pathology. Method We performed a histological evaluation of 85 human cases including controls, symptomatic AD cases with (ADNC+LATENC) and without (ADNC) LATE‐NC using paraffin‐embedded post‐mortem tissue. We quantitatively assessed pTau load and neuronal density. Additionally, we measured brain levels of p‐tauT181 and total TDP‐43 (1‐300aa.) through ELISA using fresh frozen tissue of controls, ADNC, ADNC+LATENC and FTLD‐TDP cases. Moreover, we tested the seeding potential of ADNC+LATENC and AD seeds in vivo, using a TDP‐43A315T transgenic mouse model as well as in vitro, using a tau biosensor cell line (HEK293T cells transfected with a tau PS301S mutation). Result We observed that ADNC+LATENC cases presented increased neuronal loss (p = 0.0231) and hippocampal tau pathology (p<0.0001) compared to ADNC and controls. Moreover, the ADNC+LATENC group showed increased levels of the p‐tauT181 in frontal (p = 0.0212) and entorhinal cortex (p = 0.0003) compared to the ADNC group. Total TDP‐43 levels were decreased in ADNC+LATENC and FTLD‐TDP cases compared to controls in entorhinal (p = 0.0151 and p = 0.0041, respectively) but not frontal cortex. Moreover, we observed that TDP‐43A315T mice injected with ADNC+LATENC seeds exhibited significantly increased p‐tau seeding compared to ADNC (p = 0.0163) and control‐injected animals (p = 0.0007). In line with these findings, ADNC+LATENC seeds also triggered increased p‐tau cell seeding in tau biosensor cells compared to ADNC seeds (p = 0.0048). Conclusion These results highlight the synergy between TDP‐43 and tau proteins in the context of AD pathogenesis. Specifically, our data suggest that the presence of comorbid LATE‐NC in AD aggravates tau pathology, increasing its aggregation and seeding. Moreover, a decrease in total TDP‐43 in ADNC+LATENC and FTLD‐TDP groups points to a loss of function of this protein. We highlight the importance of considering comorbid co‐pathologies in the context of clinical diagnosis and patient stratification.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.073996
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4390196225