TDP-43 Pathology in Alzheimer's Disease.

Meneses A, Koga S, O'Leary J, Dickson DW, Bu G, Zhao N

Mol Neurodegener 2021

1. Mol Neurodegener. 2021 Dec 20;16(1):84. doi: 10.1186/s13024-021-00503-x. TDP-43 Pathology in Alzheimer's Disease. Meneses A(1), Koga S(1), O'Leary J(1), Dickson DW(1), Bu G(1), Zhao N(2). Author information: (1)Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. (2)Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Zhao.Na@mayo.edu. 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. © 2021. The Author(s). DOI: 10.1186/s13024-021-00503-x PMCID: PMC8691026 PMID: 34930382 [Indexed for MEDLINE] Conflict of interest statement: All the authors declare no competing interests.

4 Figures Extracted

Fig. 1 PMC

Protein structure of transactive response DNA binding protein of 43 kDa (TDP-43). TDP-43 is a 414 amino acid protein with a nuclear localization seque...

Fig. 2 PMC

Representative images of TDP-43 pathology subtypes in FTLD-TDP brains. (A) Immunohistochemistry with an anti-phosphorylated-TDP-43 antibody (pSer409/p...

Fig. 3 PMC

Illustration of the involvement of TDP-43 in the progression of Alzheimer’s disease. In the brain of Alzheimer’s disease (AD), the amyloid-β (Aβ) pept...

Fig. 4 PMC

Distribution pattern of TDP-43 pathology in AD. (Upper panel) Illustration of TDP-43 stage in AD. An anterior coronal section depicts TDP-43 pathology...