Biology subjects

Bilkei-Gorzo, A.

Publications and source records attributed to Bilkei-Gorzo, A..

4 recordsLinked to original sources

bioRxiv2024

FAAH Inhibition as a Path to Mitigate Alzheimer's Disease Progression in Mouse Models of Amyloidosis

The endocannabinoid N-arachidonoylethanolamine (AEA) is a pro-homeostatic bioactive lipid known for its anti-inflammatory, anti-oxidative, immunomodulatory, and neuroprotective properties, which may contrast/mitigate Alzheimers disease (AD) pathology. This study explores the therapeutic potential of targeting fatty acid amide hydrolase (FAAH), the major enzyme degrading AEA, in mouse models of amyloidosis APP/PS1 and Tg2576. Enhancing AEA signaling by genetic deletion of FAAH delayed cognitive deficits in APP/PS1 mice and improved cognitive symptoms in 12-month-old AD-like mice. Chronic pharmacological FAAH inhibition fully reverted neurocognitive decline, attenuated neuroinflammation, and promoted neuroprotective mechanisms in Tg2576 mice. Additionally, pharmacological FAAH inactivation robustly suppressed {beta}-amyloid production and accumulation, associated with decreased expression of {beta}-site amyloid precursor protein cleaving enzyme 1 (BACE1), possibly through a cannabinoid receptor 1-dependent epigenetic mechanism. These findings improve our understanding of AEA signaling in AD pathogenesis, and provide proof-of-concept that selective targeting of FAAH activity could be a promising therapeutic strategy against AD.

biochemistry↗

bioRxiv2021

Dysfunction of grey matter NG2 glial cells affects neuronal plasticity and behavior

NG2 glia represent a distinct type of macroglial cells in the CNS and are unique among glia because they receive synaptic input from neurons. They are abundantly present in white and grey matter. While the majority of white matter NG2 glia differentiates into oligodendrocytes, the physiological impact of grey matter NG2 glia and their synaptic input are ill defined yet. Here we asked whether dysfunctional NG2 glia affect neuronal signaling and behavior. We generated mice with inducible deletion of the K+ channel Kir4.1 in NG2 glia and performed comparative electrophysiological, immunohistochemical, molecular and behavioral analyses. Focussing on the hippocampus, we found that loss of the Kir4.1 potentiated synaptic depolarizations of NG2 glia and enhanced the expression of myelin basic protein. Notably, while mice with targeted deletion of the K+ channel in NG2 glia showed impaired long term potentiation at CA3-CA1 synapses, they demonstrated improved spatial memory as revealed by testing new object location recognition. Our data demonstrate that proper NG2 glia function is critical for normal brain function and behavior.

neuroscience↗

bioRxiv2021

Autocrine regulation of adult neurogenesis by the endocannabinoid 2-arachidonoylglycerol (2-AG)

The endocannabinoid system modulates adult hippocampal neurogenesis by promoting the proliferation and survival of neural stem and progenitor cells (NSPCs). Specifically, deleting cannabinoid receptors on NSPCs or the constitutive deletion of the endocannabinoid 2-arachidonoylglycerol (2-AG) producing enzyme diacylglycerol lipase alpha (DAGLa) disrupts adult neurogenesis. However, it is not known which cells are the producers of 2-AG relevant to neurogenesis. In this paper, we investigated the cellular source of endocannabinoids in the subgranular zone (SGZ) of the hippocampus, an important neurogenic niche. For this purpose, we used two complementary Cre-deleter mouse strains to delete DAGLa either in neurons or astroglia and NSPCs. Surprisingly, neurogenesis was not altered in mice with a deletion of Dagla in neurons (Syn-Dagla KO), although they are the main source for the endocannabinoids in the brain. In contrast, mice with a specific inducible deletion of Dagla in NPSCs and astrocytes (GLAST-CreERT2-Dagla KO) showed a strongly impaired neurogenesis with significantly reduced proliferation and survival of newborn cells. These results identify Dagla in NSPCs in the SGZ of dentate gyrus or in astrocytes, as the cellular source for 2-AG in adult hippocampal neurogenesis. In summary, 2-AG produced by progenitor cells or astrocytes in the SGZ regulates adult hippocampal neurogenesis. SummaryDAGLa in neuronal progenitor cells in the SGZ of dentate gyrus is identified as the cellular source for 2-AG in adult hippocampal neurogenesis.

neuroscience↗

bioRxiv2020

Immunohistochemical Characterization of Phosphorylated Ubiquitin in the Mouse Hippocampus

Mitochondrial autophagy (mitophagy) is an essential and evolutionarily conserved process that maintains mitochondrial integrity via the removal of damaged or superfluous mitochondria in eukaryotic cells. Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and Parkin promote mitophagy and function in a common signaling pathway. PINK1-mediated ubiquitin phosphorylation at Serine 65 (Ser65-pUb) is a key event in the efficient execution of PINK1/Parkin-dependent mitophagy. However, few studies have used immunohistochemistry to analyze Ser65-pUb in the mouse. Here, we examined the immunohistochemical characteristics of Ser65-pUb in the mouse hippocampus. Some hippocampal cells were Ser65-pUb positive, whereas the remaining cells expressed no or low levels of Ser65-pUb. PINK1 deficiency resulted in a decrease in the density of Ser65-pUb-positive cells, consistent with a previous hypothesis based on in vitro research. Interestingly, Ser65-pUb-positive cells were detected in hippocampi lacking PINK1 expression. The CA3 pyramidal cell layer and the dentate gyrus (DG) granule cell layer exhibited significant reductions in the density of Ser65-pUb-positive cells in PINK1-deficient mice. Moreover, Ser65-pUb immunoreactivity colocalized predominantly with neuronal markers. These findings suggest that Ser65-pUb may serve as a biomarker of in situ PINK1 signaling in the mouse hippocampus; however, the results should be interpreted with caution, as PINK1 deficiency downregulated Ser65-pUb only partially.

neuroscience↗