Inflammation in common neurological diseases

The research program aims to understand the role of complex inflammatory processes in common neurodegenerative diseases such as stroke, Alzheimer's disease, epilepsy, neurodevelopmental disorders and vascular dementia. One of our key focus is to study changes of microglia, the main immune cells of the central nervous system, which undergo major phenotypic changes during neurodegenerative diseases and whose altered function has been shown to influence the outcome of neurodegenerative diseases. We will investigate how systemic and central inflammatory processes accompanying various infections, metabolic alterations and diseases play a role in altering the state of neurons and blood vessels and how microglia cells and their interactions are altered, their mediators and function in animal models of neurodegenerative diseases (developmental neuropathies, stroke, brain trauma, chronic brain inflammation, neurodegeneration, neuronal hyperactivity, epilepsy, etc.) and how central changes occur during systemic inflammatory conditions. Selective microglial manipulation methods (chemogenetic, optogenetic, manipulation, transgenic models, etc.), molecular anatomical techniques (confocal, superresolution and electron microscopy), complex imaging methods (laser speckle contrast imaging, in vivo two-photon microscopy, functional ultrasound, etc.), ex vivo methods (glial and neuronal cultures, acute or organotypic slices, biosensors, ex vivo time lapse imaging, flow cytometry, etc.), and transcriptomic, proteomic, lipidomic methods will be used to explore how compartment-specific mechanisms by which microglia regulate neuronal and vascular processes are altered in different disease states and how changes in these relationships are involved in the development of neurodegenerative diseases. Building on our recently published research that has demonstrated complex effects of inflammation- and microglia-mediated processes in the pathophysiology of neurodegenerative diseases (Szalay et al., Nature Communications 2016, Cserép et al. Science 2020, Császár et al., J Exp Med 2022, Tóth et al., PLOS Biology 2022, Fekete et al., Acta Neuropathologica 2018, Helyes et al. PNAS 2019, etc), a new complex molecular anatomical and biochemical methodology for high-resolution analysis of human brain tissue has been developed. In doing so, we are investigating inflammatory and microglial changes in the human brain during stroke, vascular dementia, Alzheimer's disease, epilepsy, ageing and COVID-19 and their correlation with inflammatory changes in the circulation and peripheral organs in order to identify new biomarkers, diagnostic methods and therapeutic targets for more effective therapy of common neurological diseases.

Our selected papers on this topic:

Császár, E., Lénárt, N., Cserép, C., Környei, Z., Fekete, R., Pósfai, B., Balázsfi, D., Hangya, B., Schwarcz, A.D., Szabadits, E., et al. (2022). Microglia modulate blood flow, neurovascular coupling, and hypoperfusion via purinergic actions. J. Exp. Med. 219.

Cserép, C., Pósfai, B., Lénárt, N., Fekete, R., László, Z.I., Lele, Z., Orsolits, B., Molnár, G., Heindl, S., Schwarcz, A.D., et al. (2020). Microglia monitor and protect neuronal function through specialized somatic purinergic junctions. Science (80-. ). 367.

Fekete, R., Cserép, C., Lénárt, N., Tóth, K., Orsolits, B., Martinecz, B., Méhes, E., Szabó, B., Németh, V., Gönci, B., et al. (2018). Microglia control the spread of neurotropic virus infection via P2Y12 signalling and recruit monocytes through P2Y12-independent mechanisms. Acta Neuropathol. 136, 461–482.

Helyes, Z., Tékus, V., Szentes, N., Pohóczky, K., Botz, B., Kiss, T., Kemény, Á., Környei, Z., Tóth, K., Lénárt, N., et al. (2019). Transfer of complex regional pain syndrome to mice via human autoantibodies is mediated by interleukin-1–induced mechanisms. Proc. Natl. Acad. Sci. 116, 13067–13076.

Szalay, G., Martinecz, B., Lénárt, N., Környei, Z., Orsolits, B., Judák, L., Császár, E., Fekete, R., West, B.L., Katona, G., et al. (2016). Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke. Nat. Commun. 7, 11499.

Tóth, K., Lénárt, N., Berki, P., Fekete, R., Szabadits, E., Pósfai, B., Cserép, C., Alatshan, A., Benkő, S., Kiss, D., et al. (2022). The NKCC1 ion transporter modulates microglial phenotype and inflammatory response to brain injury in a cell-autonomous manner. PLOS Biol. 20, e3001526.