The TDP-43 protein (transactive response DNA binding protein), encoded by the TARDBP gene, plays an important role in regulating transcriptional repression, RNA metabolism and gene splicing under normal conditions 1. Typically, TDP-43 is continually shuttled between the nucleus and cytoplasm to perform its functions 2. However, pathological consequences result when TDP-43 aggregates in the cytoplasm in a phosphorylated state and forms inclusion bodies in neurons and glia leading to neuronal loss in the central nervous system and resulting neurodegenerative disease 1. TDP-43 inclusions have been found to be the primary protein aggregates associated with Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) 2,6. In addition, mutations in multiple genes affecting the functioning of the TDP-43 protein (e.g., GRN, MAPT) have been implicated as disease-causing in patients diagnosed with ALS and FTD 2,3. Until recently, there has been little focus on the relationship between the TDP-43 protein and the pathology associated with Alzheimer’s disease (AD).
Historically, AD pathology was thought to primarily involve two proteins, i.e., beta amyloid deposited as extracelluar, senile plaques and hyperphosphorylated Tau deposited in intraneuronal, neurofibrillary tangles 2. However, brains of elderly individuals who remained asymptomatic up until their death have also been shown to contain abundant senile plaques and/or neurofibrillary tangles 4,5. Recently, the presence of a third protein aggregate, TDP-43 inclusions, were identified during neuropathological study in the brains of individuals diagnosed with Alzheimer’s disease.
Based on results of a longitudinal, autopsy-based study presented at the Alzheimer’s Association International Conference, Keith Josephs, MD and colleagues, posed the following question: does TDP-43 have an independent effect on clinical and neuroimaging findings associated with Alzheimer’s disease? 342 subjects pathologically-diagnosed with AD were screened for TDP-43 protein deposition using amygdala sections. AD cases showing TDP-43 immunoreactivity were considered positive, while those without considered negative. Other brain regions were subsequently screened for those subjects considered TDP-43 positive. The majority of subjects also had an antemortem volumetric MRI performed. All individuals were recruited prospectively and had undergone a clinical exam, neuropsychological testing and were categorized as either cognitively normal or impaired before death. Results indicated that TDP-43 deposition was associated with major features of AD, most strongly memory loss and medial temporal atrophy. Conversely, the absence of TDP-43 pathology was associated with normal cognition. This effect was still present when the impact of confounding variables (i.e., tau, alpha beta amyloid, lewy bodies, infarctions) was removed. Of note, the distribution of pathology suggested a pattern of spread starting in the amygdala and then progressing to the hippocampus, frontal cortex and temporal cortex. These findings strongly implicated TDP-43 as a unique factor associated with AD symptomology. What was previously referred to as “cognitive resilience,” to explain the presence of Tau and Beta amyloid in the setting of normal cognition, may actually be related to the absence of TDP-43 accumulation with the most impressive impact being on memory functions. TDP-43 may be the third protein whose presence has an additive or synergistic effect with other AD pathology 4.
Results from the current study and other recent work suggest the following: 1) TDP-43 accumulation presents as a distinct factor in AD pathology, 2) similarities in pathology in ALS, FTD and AD (i.e., misfolded protein aggregates that appear before clinical symptoms) indicate that these multiple disease pathways likely interact and overlap. For example, it has been proposed that TDP-43 plays a role in modifying an enzyme involved in the AD amyloid cascade 2 , and 3) TDP-43 pathology should be considered a potential therapeutic target for AD treatment. In the future, further study and confirmation is needed to determine whether TDP-43 accumulation is a central and necessary factor for developing AD, whether its presence is a cause of pathology or a symptom resulting from other disease factors, and how knowledge of TDP-43 involvement in neurodegeneration can contribute to therapeutic intervention for AD. Although many questions remain unanswered, this current study provides strong support that TDP-43 is an important player in AD and reinforces the recognition that AD is a multifactorial disorder, certainly more complex than previously imagined.
Medical Director Comments
TDP-43 is one of the misfolded proteins in neurodegenerative diseases that includes b-amyloid, tau, and a-synuclein. Hyperphosphorylated TDP-43 is cytotoxic and follows a stereotypical pattern of deposition in Alzheimer’s disease which begins in the amygdala (stage I), followed by hippocampus, limbic, temporal, and finally frontostriatum (stage V). More research is needed to determine the risk factors for the deposition of TDP-43, elucidate the pathogenic mechanisms of TDP-43 transformation, develop biomarkers that can detect TDP-43 antemortem, and the design therapies that target pathologic TDP-43.
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2. Youmans, K and Wolozin, B. TDP-43: A new player on the AD field? Experimental Neurology. 2012; 237(1): 90-95.
3. Wilson, R, Yu, Lei, Trojanowski, J, and et al. TDP-43 Pathology, Cognitive Decline, and Dementia in old age. JAMA Neurol. 2013; 70(11):1-14.
4. Josephs, K, Whitwell, J, Weigand, S, et al. TDP-43 is a key player in the clinical features associated with Alzheimer’s disease. Acta Neuropathol. 2014; 127 (6): 811-24.
5. Davis, D , Schmitt, F, Wekstein, D, Markesbery, W. Alzheimer Neuropathologic Alterations in Aged Cognitively Normal Subjects. Journal of Neuropathology & Experimental Neurology. 1999; 58 (4): 376-88.
6. Neumann, M, Sampathu, D, Kwong, L, et al. Ubiquitinated TDP-43 in frontotemporal lobe degeneration and amyotrophic lateral sclerosis. Science 2006; 314: 130-133.