Research – Mendiola Lab

Transcriptional mechanisms of neurotoxic microglia in multiple sclerosis

How are neurotoxic microglia transcriptionally regulated in MS?

Oxidative stress is coupled to neurodegeneration, myelin damage and disease progression in multiple sclerosis. We recently developed Tox-seq and generated the first molecular map of the oxidative stress transcriptome of central nervous system innate immune cells in neuroinflammation. Using Tox-seq, we discovered that oxidative stress-producing microglia and macrophages share a core gene signature coupled to coagulation, antigen presentation and glutathione pathways. We now investigate the oxidative stress epigenome to understand how neurotoxic microglia are transcriptional regulated in mouse models of multiple sclerosis and demyelination.

Understanding the epigenetic regulators such as enhancers, promoters and transcription factors driving neurotoxic microglia may illuminate new cell-specific druggable targets to halt neurodegeneration in multiple sclerosis. This work has the potential to open therapeutic avenues for MS to prevent neurodegeneration that are not currently addressed by other treatments.

Transcriptional mechanisms of neurotoxic microglia in Alzheimer’s disease

How are neurotoxic microglia transcriptionally regulated in AD?

Oxidative stress is inversely coupled to brain function and neuropathology in AD. However, the mechanisms of microglia and other cells in the brain that mediate oxidative stress are largely unknown. Using Tox-seq, we recently generated the first molecular map of the oxidative stress transcriptome of microglia in neurodegeneration. We discovered that oxidative stress-producing microglia are transcriptionally distinct from cells that do not produce oxidative stress in the 5XFAD mouse model of AD. While we know ROS+ microglia converge to a core oxidative stress gene signature, it remains unknown the mechanisms that regulate oxidative stress genes and their functions in AD. We now investigate the oxidative stress epigenome to understand how neurotoxic microglia are transcriptional regulated in mouse models of AD.

By targeting cis-regulatory regions of oxidative stress-producing microglia, we open a novel therapeutic strategy for AD in which the early and progressive tissue damage caused oxidative stress are prevented. This work has the potential to open therapeutic avenues for AD and related dementias to prevent neurodegeneration that are not currently addressed by other treatments.

Neurovascular mechanisms of oxidative stress and mitochondrial dysfunction

How does blood protein leakage through a disrupted blood-brain barrier (BBB) regulate innate immune activation and mitochondrial dysfunction?

We recently defined blood-induced microglia functions in neurodegeneration through multiomic profiling. Our work suggests 1) BBB disruption is a driver of pathologic polarization of innate immune cells, and 2) blood proteins, and in particular, the blood coagulation protein fibrinogen is a unique blood protein necessary and sufficient for the activation of neurodegenerative microglia. We now investigate how fibrin reprograms the mitochondrial and metabolic fitness of microglia in chronic neurological disease such as AD and MS.

BBB disruption is an early pathological feature proceeding demyelination and neurodegeneration in AD and MS. By decoding how BBB disruption and the ensuing leakage of blood proteins drives innate immune-mediated neuroinflammation and neurodegeneration may shed light on new therapeutic strategies

Oxidative stress and chromatin architecture in innate immunity

How does oxidative stress affect the DNA and change chromatin structure in innate immune cells?

We have discovered prooxidant programming of neurotoxic microglia occurs along common molecular pathways across neurodegeneration and CNS autoimmunity. We are now studying how intracellular redox controls chromatin structure and gene expression in pro-oxidant innate immune cells.

Given the broad range of disease with increased oxidative stress, our findings on how oxidative stress alters the DNA of innate immune cells may inform new principles of neuroimmunology and redox biology that could have therapeutic implications.