Transactive Response DNA-binding Protein 43 Pathology Research Articles

The Lysosomal Trafficking Transmembrane Protein 106B Is Linked to Cell Death

A common genetic variation in the transmembrane protein 106B (TMEM106B) gene has been suggested to be a risk factor for frontotemporal lobar degeneration (FTLD) with inclusions of transactive response DNA-binding protein-43 (TDP-43) (FTLD-TDP), the most common pathological subtype in FTLD. Furthermore, previous studies have shown that TMEM106B levels are up-regulated in the brains of FTLD-TDP patients, although the significance of this finding remains unknown. In this study, we show that the overexpression of TMEM106B and its N-terminal fragments induces cell death, enhances oxidative stress-induced cytotoxicity, and causes the cleavage of TDP-43, which represents TDP-43 pathology, using cell-based models. TMEM106B-induced death is mediated by the caspase-dependent mitochondrial cell death pathways and possibly by the lysosomal cell death pathway. These findings suggest that the up-regulation of TMEM106B may increase the risk of FTLD by directly causing neurotoxicity and a pathological phenotype linked to FTLD-TDP.

Temporal course of neurodegenerative effects on cognition in old age.

To test the hypothesis that different forms of neurodegeneration are differentially related to longitudinal cognitive trajectories in old age. Participants are 420 older persons from 2 clinical-pathologic studies without cognitive impairment at study onset. They completed a battery of 17 cognitive tests annually for a minimum of 5 years, died, and underwent a neuropathologic examination to quantify neuronal neurofibrillary tangles and transactive response DNA-binding protein 43 (TDP-43) pathology and to identify Lewy bodies and hippocampal sclerosis. The authors used sigmoid mixed models based on the 4-parameter logistic distribution to decompose nonlinear global cognitive trajectories into components and assess the relation of each neuropathologic marker to each trajectory component. Cognitive function was assessed for a mean of 10.5 years before death. In the absence of pathology, global cognition was relatively stable before declining moderately in the last 3 to 4 years of life. Tangles were related to all trajectory components except initial level. TDP-43 pathology was the only marker related to initial level of function. It was also associated with an earlier midpoint of decline but not to slope of decline. Hippocampal sclerosis was related to an earlier midpoint of decline and more rapid slope of decline. Lewy bodies were associated with faster slope of decline and lower level of function proximate to death. Neurodegenerative processes are differentially related to cognitive trajectories, with TDP-43 pathology most potently impacting incipient cognitive decline, AD pathology and hippocampal sclerosis affecting the progression of cognitive decline, and Lewy bodies impacting terminal decline. (PsycINFO Database Record

Temporal course and pathologic basis of unawareness of memory loss in dementia.

To characterize the natural history and neuropathologic basis of unawareness of memory loss in late-life dementia. Analyses are based on 2,092 older persons from 3 longitudinal clinical-pathologic cohort studies who had no memory or cognitive impairment at baseline. Annual evaluations included clinical classification of dementia plus self-rating and performance testing of memory. At death, there was a uniform neuropathologic examination to quantify 7 dementia-related pathologies. In the full group, memory ratings were modestly correlated with memory performance (intercepts r = 0.26, p < 0.001; slopes r = 0.23, p < 001) and so we regressed each person's memory performance on their memory ratings, and the residuals provided longitudinal indicators of memory awareness. In a subset of 239 persons who developed dementia, episodic memory awareness was stable until a mean of 2.6 years before dementia onset (95% credible interval -2.7, -1.6); thereafter, memory awareness declined rapidly (mean annual change -0.32, 95% credible interval -0.37, -0.28). Older age at baseline was associated with later onset of memory unawareness. In a subset of 385 persons who died and underwent neuropathologic examination, transactive response DNA-binding protein 43 (TDP-43) pathology, tau tangles, and gross cerebral infarcts were related to decline in memory awareness. In the absence of these pathologies, no decline in memory awareness was evident. Results were similar in subgroups with and without dementia. Awareness of memory impairment typically begins to decline about 2-3 years before dementia onset and is associated with postmortem evidence of TDP-43 pathology, tangles, and gross cerebral infarcts.

Frontotemporal dementia: a bridge between dementia and neuromuscular disease.

The concept that frontotemporal dementia (FTD) is a purely cortical dementia has largely been refuted by the recognition of its close association with motor neuron disease, and the identification of transactive response DNA-binding protein 43 (TDP-43) as a major pathological substrate underlying both diseases. Genetic findings have transformed this field and revealed connections between disorders that were previous thought clinically unrelated. The discovery that the C9ORF72 locus is responsible for the majority of hereditary FTD, amyotrophic lateral sclerosis (ALS), and FTD-ALS cases and the understanding that repeat-containing RNA plays a crucial role in pathogenesis of both disorders has paved the way for the development of potential biomarkers and therapeutic targets for these devastating diseases. In this review, we summarize the historical aspects leading up to our current understanding of the genetic, clinical, and neuropathological overlap between FTD and ALS, and include brief discussions on chronic traumatic encephalopathy (CTE), given its association with TDP-43 pathology, its associated increased dementia risk, and reports of ALS in CTE patients. In addition, we describe other genetic associations between dementia and neuromuscular disease, such as inclusion body myositis with Paget's disease and FTD.

TDP-43 pathology, cognitive decline, and dementia in old age.

Cognitive decline is a leading cause of disability and death in old age but its neurobiological bases are not well understood. To test the hypothesis that transactive response DNA-binding protein 43 (TDP-43) is related to late-life cognitive decline. Longitudinal clinical-pathologic cohort study involving more than 40 Catholic groups across the United States. A total of 130 older Catholic nuns, priests, and monks underwent annual clinical evaluations, including detailed cognitive testing, for a mean of 10.1 years prior to death. On neuropathologic examination, we collected semiquantitative measures of TDP-43 pathology, density of neuronal neurofibrillary tangles, area occupied by amyloid-beta plaques, and the presence of alpha-synuclein Lewy bodies from multiple brain regions. Gross and microscopic cerebral infarcts and hippocampal sclerosis were also identified. Annual rate of change in a previously established composite measure of global cognition during a mean of 10.1 years of annual observation before death. Transactive response DNA-binding protein 43 pathology, ranging from sparse to severe, was identified in 46% of participants and was associated with amyloid plaques, tangles, and hippocampal sclerosis but not neocortical Lewy bodies or cerebral infarcts. After controlling for amyloid plaques, tangles, and hippocampal sclerosis, TDP-43 pathology was associated with more rapid cognitive decline and accounted for nearly as much of the variability in rates of global cognitive decline as did tangles. Transactive response DNA-binding protein 43 pathology had a distinct cognitive profile that differed from other neuropathologic processes (related to decline in episodic and working memory but not in other cognitive domains), and it was elevated in those who developed dementia but not in those with mild cognitive impairment. The results suggest that TDP-43 is an important brain pathology underlying cognitive decline and dementia in old age.

Expansive Gene Transfer in the Rat CNS Rapidly Produces Amyotrophic Lateral Sclerosis Relevant Sequelae When TDP-43 is Overexpressed

Improved spread of transduction in the central nervous system (CNS) was achieved from intravenous administration of adeno-associated virus serotype-9 (AAV9) to neonatal rats. Spinal lower motor neuron transduction efficiency was estimated to be 78% using the highest vector dose tested at a 12-week interval. The widespread expression could aid studying diseases that affect both the spinal cord and brain, such as amyotrophic lateral sclerosis (ALS). The protein most relevant to neuropathology in ALS is transactive response DNA-binding protein 43 (TDP-43). When expressed in rats, human wild-type TDP-43 rapidly produced symptoms germane to ALS including paralysis of the hindlimbs and muscle wasting, and mortality over 4 weeks that did not occur in controls. The hindlimb atrophy and weakness was evidenced by assessments of rotarod, rearing, overall locomotion, muscle mass, and histology. The muscle wasting suggested denervation, but there was only 14% loss of motor neurons in the TDP-43 rats. Tissues were negative for ubiquitinated, cytoplasmic TDP-43 pathology, suggesting that altering TDP-43's nuclear function was sufficient to cause the disease state. Other relevant pathology in the rats included microgliosis and degenerating neuronal perikarya positive for phospho-neurofilament. The expression pattern encompassed the distribution of neuropathology of ALS, and could provide a rapid, relevant screening assay for TDP-43 variants and other disease-related proteins.

Transactive Response DNA-Binding Protein 43 Burden in Familial Alzheimer Disease and Down Syndrome

To assess the transactive response DNA-binding protein 43 (TDP-43) burden in familial forms of Alzheimer disease (FAD) and Down syndrome (DS) to determine whether TDP-43 inclusions are also present. Using standard immunohistochemical techniques, we examined brain tissue samples from 42 subjects with FAD and 14 with DS. We found pathological TDP-43 aggregates in 14.0% of participants (6 of 42 and 2 of 14 participants with FAD and DS, respectively). In both FAD and DS, TDP-43 immunoreactivity did not colocalize with neurofibrillary tangles. Occasionally participants with FAD or DS had TDP-43-positive neuropil threads or dots. Overall, the amygdala was most commonly affected, followed by the hippocampus, with no TDP-43 pathology in neocortical regions. A similar distribution of TDP-43 inclusions is seen in sporadic Alzheimer disease, but it differs from that seen in amyotrophic lateral sclerosis and frontotemporal dementia. Transactive response DNA-binding protein 43 pathology occurs in FAD and DS, similar to that observed in sporadic Alzheimer disease. Thus, pathological TDP-43 may contribute the cognitive impairments in familial and sporadic forms of Alzheimer disease.