Biology subjects

Hortobagyi, T.

Publications and source records attributed to Hortobagyi, T..

5 recordsLinked to original sources

bioRxiv2026

Stratifying cellular injury in Alzheimer's disease by chaperonin containing TCP1 subunits 2 and 3

Chaperonins complex into double-ringed octamers to aid peptide folding. Recent evidence implicates dysfunctional chaperonin subunits in cancer and neurodegenerative diseases because their deregulation exacerbates cellular injury. Nevertheless, a gap of knowledge exists regarding the expression and localization of chaperonin subunits in relation to amyloidogenic processes in Alzheimers disease (AD). Here, we show that reduced levels of chaperonin-containing TCP-1 subunits 2 (CCT2) and 3 (CCT3) stratify AD, with the subcellular distribution of their residua being mutually exclusive with both {beta}-amyloid and hyperphosphorylated tau in neurons. We find CCT3 localized to a subset of glial fibrillary acidic protein-positive astrocytes in AD. Increased oxidative stress in vitro upregulated CCT3 expression in astrocyte-like U251 cells. Conversely, CCT3, but not CCT2, loss-of-function in neuron-like SH-SY5Y cells increased intracellular {beta}-amyloid load. These data suggest that CCT2/CCT3 are faithful disease-state indicators and implicate CCT3 in oxidative stress-dependent cellular damage pathways.

neuroscience↗

bioRxiv2023

Infection-induced vascular inflammation in COVID-19 links focal microglial dysfunction with neuropathologies through IL-1/IL-6-related systemic inflammatory states

COVID-19 is associated with diverse neurological abnormalities, which predict poor outcome in patients. However, the mechanisms whereby infection-induced inflammation could affect complex neuropathologies in COVID-19 are unclear. We hypothesized that microglia, the resident immune cells of brain, are centrally involved in this process. To study this, we developed an autopsy platform allowing the integration of molecular anatomy-, protein- and mRNA data sets in post-mortem mirror blocks of brain and peripheral organ samples from COVID-19 cases. Nanoscale microscopy, single-cell RNA sequencing and analysis of inflammatory and metabolic signatures revealed distinct mechanisms of microglial dysfunction associated with cerebral SARS-CoV-2 infection. We observed focal loss of microglial P2Y12R at sites of virus-associated vascular inflammation together with dysregulated microglia-vascular-astrocyte interactions, Cx3Cr1-fractalkine axis deficits and mitochondrial failure in severely affected medullary autonomic nuclei and other brain areas. Microglial dysfunction occurs at sites of excessive synapse- and myelin phagocytosis and loss of glutamatergic terminals. While central and systemic viral load is strongly linked in individual patients, the regionally heterogenous microglial reactivity in the brain correlated with the extent of central and systemic inflammation related to IL-1 / IL-6 via virus-sensing pattern recognition receptors (PRRs) and inflammasome activation pathways. Thus, SARS-CoV-2-induced central and systemic inflammation might lead to a primarily glio-vascular failure in the brain, which could be a common contributor to diverse COVID-19-related neuropathologies.

immunology↗

bioRxiv2023

Pathway-specific progression of Tau pathology in the human thalamus

The Papez circuit comprises several interconnected brain areas important for spatial navigation and orientation. An early symptom of dementia is disorientation, suggesting that brain regions responsible for providing a sense of direction are adversely affected. We examined post-mortem human tissue from cases with no cognitive impairment, mild cognitive impairment, and Alzheimers disease. A key part of the Papez circuit, the anterodorsal thalamic nucleus (ADn), contained a high density of misfolded pathological Tau (pTau) at all disease stages, including in control cases. Moreover, pTau preferentially accumulated in calretinin-expressing neurons. At the subcellular level, we detected pTau filaments in ADn cell bodies, dendrites, and in specialized presynaptic terminals. Large vesicular-glutamate-transporter-2-containing terminals from the lateral mammillary nucleus, rather than corticothalamic terminals, preferentially contained pTau, suggesting that Tau crosses specific synapses within the Papez circuit. As the ADn contains a high density of head direction cells, pTau may degrade the processing of orientation signals, explaining why people become disorientated years-to-decades before memory deficits emerge.

neuroscience↗

bioRxiv2021

Central inhibition of P2Y12R differentially regulates survival and neuronal loss in MPTP-induced Parkinsonism in mice

Parkinsons disease (PD) is a chronic, progressive neurodegenerative condition; characterized with the degeneration of the nigrostriatal dopaminergic pathway and neuroinflammation. During PD progression, microglia, the resident immune cells in the central nervous system (CNS) display altered activity, but their role in maintaining PD development has remained unclear to date. The purinergic P2Y12 receptor (P2Y12R), which is exclusively expressed on the microglia in the CNS has been shown to regulate microglial activity and responses; however, the function of the P2Y12R in PD is unknown. Here we show that while pharmacological or genetic targeting of P2Y12R previous to disease onset augments acute mortality, these interventions protect against neurodegenerative cell loss and the development of neuroinflammation in vivo. Pharmacological inhibition of receptors during disease development reverses the symptoms of PD and halts disease progression. We found that P2Y12R regulate ROCK and p38 MAPK activity and control cytokine production. Understanding protective and detrimental P2Y12 receptor-mediated actions in the CNS may reveal novel approaches to control neuroinflammation and modify disease progression in PD.

neuroscience↗

bioRxiv2019

Microglia monitor and protect neuronal function via specialized somatic purinergic junctions

Microglia are the main immune cells in the brain with emerging roles in brain homeostasis and neurological diseases, while mechanisms underlying microglia-neuron communication remain elusive. Here, we identify a novel site of interaction between neuronal cell bodies and microglial processes in mouse and human brain. Somatic microglia-neuron junctions possess specialized nanoarchitecture optimized for purinergic signaling. Activity of neuronal mitochondria is linked with microglial junction formation, which is rapidly induced in response to neuronal activation and blocked by inhibition of P2Y12-receptors (P2Y12R). Brain injury-induced changes at somatic junctions trigger P2Y12R-dependent microglial neuroprotection, regulating neuronal calcium load and functional connectivity. Collectively, our results suggest that microglial processes at these junctions are in ideal position to monitor and protect neuronal functions in both the healthy and injured brain.\n\nOne-sentence summaryNeuronal cell bodies possess specialized, pre-formed sites, through which microglia monitor their status and exert neuroprotection.

neuroscience↗