About this Research Topic
Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease, and Huntington’s disease, are a group of multifactorial disorders driven by a variety of pathological mechanisms, eventually culminating in neuronal death. Some cases are instigated by genetics, while others occur sporadically.
Protein aggregation, synapse loss, oxidative injury, mitochondrial dysfunction and disruption of trafficking are some of the pathological hallmarks of these disorders.
Because of the heterogenous nature of the disease processes, it is becoming clear that druggable targets to fight neurodegeneration must have the ability to impact a variety of cellular and molecular pathways.
Despite their differences, neurodegenerative diseases commonly feature chronic neuroinflammation and dysfunction of the microtubule cytoskeleton. Both of these pathological hallmarks could negatively affect a multitude of downstream neuronal pathways.
Neuroinflammation is both a consequence and driver of neurodegeneration. Microglia, the primary immune cells of the central nervous system, are a major player in brain inflammation. These cells have highly mobile ramified branches that dynamically and continuously survey brain parenchyma to detect and eliminate debris through phagocytosis. Their dysfunction is linked to synapse loss, impaired phagocytosis, reduced blood brain barrier integrity and reactive oxygen species generation.
Microglia actively maintain their protective role during normal aging, but this ability is considerably decreased in a proinflammatory context. In animal models of AD, the phagocytic activity and clearance capacity of microglia is inversely correlated with Aβ plaque deposition and aging.
Microglia are highly plastic cells that can undergo profound functional reprogramming. A simplified view recognizes two extremes of functional reprogramming in response to cytokines, chemokines and other soluble factors produced by damaged neurons: the classical pro-inflammatory M1 phenotype (M1 cells classified as reactive cells that release pro-inflammatory cytokines) and the anti-inflammatory M2 phenotype (M2 cells classified as non-reactive cells that secrete anti-inflammatory cytokines and have beneficial, neuroprotective properties). Between these extreme functional states, a plethora of intermediate states is possible.
In neurodegeneration, cytoskeletal disruption and alterations in microtubule dynamics begin a cascade of events, including synapse loss, improper trafficking, mitochondrial dysfunction, and oxidative stress, leading to neuronal damage and death. The full role of the neuronal cytoskeleton in neurodegenerative disease remains an understudied area, and more research is needed to provide insight into how alterations of the cytoskeleton can act as markers and drivers of neurodegeneration, as well as to identify where interventions can be targeted.
The cytoskeleton is inherently tied to neuronal function. In particular, the microtubule cytoskeleton plays of a number of critical roles in the neuron. Microtubules support the complex, branching structures of the dendritic tree and axonal arbor. Besides providing long-term structural stability, microtubules also act as an intracellular highway, creating a road for protein motors to deliver organelles and cargoes to various regions of the cell. Loss of efficient transport is a hallmark of neurodegenerative disease and is linked to mitochondrial and lysosomal dysfunction. Dynamic microtubules support synapse maintenance and synaptic transmission. From a post-synaptic perspective, microtubules transiently grow into dendritic spines in an activity-dependent manner and enter long enough for kinesin Kif1A to drop off cargo. Microtubule nucleation at presynaptic boutons is induced by neuronal activity and is essential for the trafficking of synaptic vesicles.
Understanding the heterogeneity of microglia and their crosstalk with other cells in the central nervous system, as well as the numerous functions of the microtubule cytoskeleton in neurons, is vital for characterizing neurodegenerative processes and fundamental for devising suitable therapeutic strategies.
Investigators are invited to contribute to this Research Topic with original research articles and review articles that can improve the understanding of the role of microglia or the neuronal microtubule cytoskeleton in neurodegenerative disease.
Protein aggregation, synapse loss, oxidative injury, mitochondrial dysfunction and disruption of trafficking are some of the pathological hallmarks of these disorders.
Because of the heterogenous nature of the disease processes, it is becoming clear that druggable targets to fight neurodegeneration must have the ability to impact a variety of cellular and molecular pathways.
Despite their differences, neurodegenerative diseases commonly feature chronic neuroinflammation and dysfunction of the microtubule cytoskeleton. Both of these pathological hallmarks could negatively affect a multitude of downstream neuronal pathways.
Neuroinflammation is both a consequence and driver of neurodegeneration. Microglia, the primary immune cells of the central nervous system, are a major player in brain inflammation. These cells have highly mobile ramified branches that dynamically and continuously survey brain parenchyma to detect and eliminate debris through phagocytosis. Their dysfunction is linked to synapse loss, impaired phagocytosis, reduced blood brain barrier integrity and reactive oxygen species generation.
Microglia actively maintain their protective role during normal aging, but this ability is considerably decreased in a proinflammatory context. In animal models of AD, the phagocytic activity and clearance capacity of microglia is inversely correlated with Aβ plaque deposition and aging.
Microglia are highly plastic cells that can undergo profound functional reprogramming. A simplified view recognizes two extremes of functional reprogramming in response to cytokines, chemokines and other soluble factors produced by damaged neurons: the classical pro-inflammatory M1 phenotype (M1 cells classified as reactive cells that release pro-inflammatory cytokines) and the anti-inflammatory M2 phenotype (M2 cells classified as non-reactive cells that secrete anti-inflammatory cytokines and have beneficial, neuroprotective properties). Between these extreme functional states, a plethora of intermediate states is possible.
In neurodegeneration, cytoskeletal disruption and alterations in microtubule dynamics begin a cascade of events, including synapse loss, improper trafficking, mitochondrial dysfunction, and oxidative stress, leading to neuronal damage and death. The full role of the neuronal cytoskeleton in neurodegenerative disease remains an understudied area, and more research is needed to provide insight into how alterations of the cytoskeleton can act as markers and drivers of neurodegeneration, as well as to identify where interventions can be targeted.
The cytoskeleton is inherently tied to neuronal function. In particular, the microtubule cytoskeleton plays of a number of critical roles in the neuron. Microtubules support the complex, branching structures of the dendritic tree and axonal arbor. Besides providing long-term structural stability, microtubules also act as an intracellular highway, creating a road for protein motors to deliver organelles and cargoes to various regions of the cell. Loss of efficient transport is a hallmark of neurodegenerative disease and is linked to mitochondrial and lysosomal dysfunction. Dynamic microtubules support synapse maintenance and synaptic transmission. From a post-synaptic perspective, microtubules transiently grow into dendritic spines in an activity-dependent manner and enter long enough for kinesin Kif1A to drop off cargo. Microtubule nucleation at presynaptic boutons is induced by neuronal activity and is essential for the trafficking of synaptic vesicles.
Understanding the heterogeneity of microglia and their crosstalk with other cells in the central nervous system, as well as the numerous functions of the microtubule cytoskeleton in neurons, is vital for characterizing neurodegenerative processes and fundamental for devising suitable therapeutic strategies.
Investigators are invited to contribute to this Research Topic with original research articles and review articles that can improve the understanding of the role of microglia or the neuronal microtubule cytoskeleton in neurodegenerative disease.
Keywords: Neurodegeneration, Neuroinflammation, Phagocytosis, Cytokines, Chemokines, Cytoskeleton, Microglia, Microtubules
Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.
