TDP-43 Pathology in Alzheimer’s Disease

Abstract

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.

Loss of Stathmin-2, a hallmark of TDP-43-associated ALS, causes motor neuropathy

“…Finally, TDP-43 pathology occurs in multiple neurodegenerative diseases. For example, TDP-43 inclusions have been seen in over half of individuals with Alzheimer Disease and presence of inclusions corresponds with greater cognitive impairment (Nag et al ., 2018; Meneses et al ., 2021). TDP-43 inclusions are also found in ∼50% of patients with frontotemporal dementia (Cairns et al ., 2007).…”

TDP-43 Pathology and Prionic Behavior in Human Cellular Models of Alzheimer’s Disease Patients

“…TDP-43 pathological changes observed in AD lymphoblasts are similar to those found in lymphoblastoid cell lines derived from FTLD-TDP and ALS patients [ 39 , 40 ], despite the fact that distribution of TDP-43 pathology in AD seem to be distinct from other TDP-43 proteinopathies [ 26 ]. In AD, pathological TDP-43 is limited to the limbic system of the brain, being the amygdala the most vulnerable area [ 49 ].…”

“…Nowadays, there is an expanding field of research trying to elucidate how TDP-43 pathology may be mechanistically related with AD, especially with the limbic-predominant subtype, in which TDP-43 deposition is more frequent [ 50 ]. It is now recognized that TDP-43 deposition increases the risk for developing AD and influences the clinical features of dementia including cognitive deficits [ 26 ]. In addition, the fact that TDP-43 deposits are more abundant in the limbic system suggest a possible role of TDP-43 in the action control and emotion processing impaired in AD due to atrophy of prefrontal cortex and limbic system [ 6 ].…”

“…TDP-43 proteinopathy is the hallmark for the FTD/ALS spectrum. In addition, it is now recognized that TDP-43 pathology is present in other neurological diseases including AD and even in non-demented individuals [ 26 , 27 ].…”

Microglia phenotypes are associated with subregional patterns of concomitant tau, amyloid-β and α-synuclein pathologies in the hippocampus of patients with Alzheimer’s disease and dementia with Lewy bodies

“…Abnormal accumulations of TDP-43 in neurons were originally associated with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. TDP-43 inclusions are now frequently reported in AD [ 62 ] and DLB + AD cases [ 65 ] and could play a substantial role in the hippocampal atrophy rate [ 41 ]. Finally, we have analyzed the medium part of the hippocampus, i.e., the body, between the uncus and Corpus geniculatum laterale , a region which is usually poorly described, contrary to the head at the uncus level or the tail close to the Corpus geniculatum laterale , both more regularly used for neuropathology diagnostic and research.…”