How Astrocytic TDP-43 protein accumulation and dysregulation accelerate neurodegeneration
When most people think of neurodegenerative disease, they probably think of the loss of neurons and corresponding loss of memories or cognitive function. This expected relationship between neurons and neurodegenerative disease makes sense. After all, neurons are the cells that send information throughout the brain, so why wouldn’t their decline be the cause of neurodegenerative disease? However, recent research published in the journal Scientific Advances has drawn attention to the role of neuron support cells called astrocytes in the cognitive decline of neurodegenerative diseases, providing valuable insight into how such diseases can be treated [1].
Previous research has established a relationship between neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer’s Disease (AD), and frontotemporal dementia (FTD) and the aggregation of a protein called TDP-43 in neurons [2]. On its own, TDP-43 is normal within cells but becomes harmful when it is hyperphosphorylated, leading to its aggregation. However, a gap remains to be filled regarding the exact mechanism by which TDP-43 accumulation in the brain leads to cognitive decline [2]. Recently, there has been increasing interest in the study of how damage to non-neuronal brain cells such as glia, support cells for neurons, may modulate these neurodegenerative diseases. A study conducted by researchers at Weill Cornell Medicine investigated whether TDP-43 aggregation in astrocytes also contributes to neurodegeneration [1]. Astrocytes are a type of glia that provide nutrients to neurons and regulate the information that is exchanged across the junction between two neurons, known as a synapse. Researchers found that TDP-43 buildups in the astrocytes of patients afflicted with AD and FTD, supporting the idea that neurodegeneration may involve more than just damage to neurons [1].
Researchers developed transgenic mice to determine if this astrocytic TDP-43 accumulation in the hippocampus, a brain region essential to the formation of memories, increases neurodegenerative symptoms. In this study, this controlled expression of aggregate-prone astrocytic TDP-43 provided a method to observe how astrocytic TDP-43 affected the cognition and behavior of mice [1].
Researchers found that astrocytic aggregates of TDP-43 in the hippocampus led to a progressive memory decline, one of the hallmark symptoms of neurodegeneration, in mice during a water maze learning system [1]. Interestingly, other neurodegenerative symptoms such as motor impairment were not observed, implying astrocytic aggregation only contributes to memory loss. After confirming this connection, the researchers further explored the mechanism of TDP-43-induced neuron dysfunction by measuring the expression of various genes associated with neuroinflammation. Notably, they observed increased expression of chemokines, signaling proteins that play a major role in the immune response, in mice with the astrocytic TDP-43. Despite the activation of an immune response, these mice were less resistant to viral infections, suggesting that the overactive immune response and neuroinflammation contribute to astrocyte-mediated neuronal dysfunction [1].
Although the present study provides novel information about the potential role of astrocytic TDP-43 aggregation in neurodegenerative disease, many questions still remain. For example, is astrocytic TDP-43 a cause or a result of disease? Does the aggregation of other proteins in the astrocytes produce similar effects? How may astrocytes impair chemokine function? Future studies will further investigate these relationships to strengthen the understanding of how AD, FTD, and ALS develop, hopefully providing insight as to how to best combat their progression and improve the lives of those suffering from neurodegenerative disease.
References:
[1] Licht-Murava, A., Meadows, S. M., Palaguachi, F., Song, S. C., Jackvony, S., Bram, Y., Zhou, C., Schwartz, R. E., Froemke, R. C., Orr, A. L., & Orr, A. G. (2023). Astrocytic TDP-43 dysregulation impairs memory by modulating antiviral pathways and interferon-inducible chemokines. Science advances, 9(16). https://doi.org/10.1126/sciadv.ade1282
[2] Shenouda, M., Zhang, A. B., Weichert, A., & Robertson, J. (2018). Mechanisms Associated with TDP-43 Neurotoxicity in ALS/FTLD. Advances in neurobiology, 20, 239–263. https://doi.org/10.1007/978-3-319-89689-2_9