Heterogeneity analysis of astrocytes following spinal cord injury at single‐cell resolution

The FASEB Journal, Год журнала: 2022, Номер 36(8)

Опубликована: Июль 11, 2022

Astrocytes play many important functions in response to spinal cord injury (SCI) an activated manner, including clearance of necrotic tissue, formation protective barrier, maintenance microenvironment balance, interaction with immune cells, and the glial scar. More more studies have shown that astrocytes are heterogeneous, such as inflammatory astrocyte 1 (A1) neuroprotective 2 (A2) types. However, subtypes resulting from SCI not been clearly defined. In this study, using single-cell RNA sequencing, we constructed transcriptomic profile uninjured tissue injured nearby lesion epicenter at 0.5, 1, 3, 7, 14, 60, 90 days after mouse hemisection surgery. Our analysis uncovered six transcriptionally distinct states, Atp1b2+, S100a4+, Gpr84+, C3+/G0s2+, GFAP+/Tm4sf1+, Gss+/Cryab+ astrocytes. We used these new signatures combined canonical markers determine distribution morphologically physiologically population sites by immunofluorescence staining. Then identified dynamic evolution process each subtype following SCI. Finally, also revealed highly expressed genes different phases Together, provided resolution These data only contribute understand heterogeneity during but help find a target for repair.

Язык: Английский

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Inflammation as common link to progressive neurological diseases

Archives of Toxicology, Год журнала: 2023, Номер 98(1), С. 95 - 119

Опубликована: Ноя. 15, 2023

Abstract Life expectancy has increased immensely over the past decades, bringing new challenges to health systems as advanced age increases predisposition for many diseases. One of those is burden neurologic disorders. While hypotheses have been placed explain aging mechanisms, it widely accepted that increasing pro-inflammatory status with or “inflammaging” a main determinant biological aging. Furthermore, inflammaging at cornerstone age-related diseases and its involvement in disorders an exciting hypothesis. Indeed, development elderly seem share some basic pathways fundamentally converge on inflammation. Peripheral inflammation significantly influences brain function contributes neurological disorders, including Alzheimer’s disease, Parkinson’s multiple sclerosis. Understanding role pathogenesis progressive crucial importance developing effective treatments interventions can slow down prevent disease progression, therefore, decreasing social economic burden.

Язык: Английский

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Methylation differences in Alzheimer’s disease neuropathologic change in the aged human brain

Acta Neuropathologica Communications, Год журнала: 2022, Номер 10(1)

Опубликована: Ноя. 29, 2022

Abstract Alzheimer’s disease (AD) is the most common cause of dementia with advancing age as its strongest risk factor. AD neuropathologic change (ADNC) known to be associated numerous DNA methylation changes in human brain, but oldest old (> 90 years) have so far been underrepresented epigenetic studies ADNC. Our study participants were individuals aged over years (n = 47) from The + Study . We analyzed bulk samples eight precisely dissected regions brain: middle frontal gyrus, cingulate entorhinal cortex, dentate CA1, substantia nigra, locus coeruleus and cerebellar cortex. deconvolved our data into cell-type-specific (CTS) signals using computational methods. CTS differences across different levels highest amount ADNC related was found a region that has large scale multi-omic studies. In neurons significantly differed increased burden amyloid beta (Aβ) plaques at 5897 promoter protein-coding genes. Amongst these, higher Aβ plaque hypomethylation Presenilin enhancer 2 ( PEN-2 ) gene, one rate limiting genes formation gamma-secretase, multicomponent complex responsible part for endoproteolytic cleavage precursor protein peptides. addition novel changes, we present detailed array-based survey brain date. open-sourced dataset can serve reference panel future help advance research aging neurodegenerative diseases.

Язык: Английский

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Neuron‐specific deletion of presenilin enhancer2 causes progressive astrogliosis and age‐related neurodegeneration in the cortex independent of the Notch signaling

CNS Neuroscience & Therapeutics, Год журнала: 2020, Номер 27(2), С. 174 - 185

Опубликована: Сен. 22, 2020

Abstract Introduction Presenilin enhancer2 (Pen‐2) is an essential subunit of γ‐secretase, which a key protease responsible for the cleavage amyloid precursor protein (APP) and Notch. Mutations on Pen‐2 cause familial Alzheimer disease (AD). However, it remains unknown whether regulates neuronal survival neuroinflammation in adult brain. Methods Forebrain neuron‐specific conditional knockout ( cKO) mice were generated this study. cKO expressing Notch1 intracellular domain (NICD) conditionally cortical neurons also generated. Results Loss causes astrogliosis followed by age‐dependent atrophy loss. results microgliosis enhanced inflammatory responses cortex. Expression NICD cortices ameliorates neither neurodegeneration nor neuroinflammation. Conclusions required cerebral The Notch signaling may not be involved caused loss Pen‐2.

Язык: Английский

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Pen-2 Negatively Regulates the Differentiation of Oligodendrocyte Precursor Cells into Astrocytes in the Central Nervous System

Journal of Neuroscience, Год журнала: 2021, Номер 41(23), С. 4976 - 4990

Опубликована: Май 10, 2021

Mutations on γ-secretase subunits are associated with neurologic diseases. Whereas the role of in neurogenesis has been intensively studied, little is known about its astrogliogenesis. Recent evidence demonstrated that astrocytes can be generated from oligodendrocyte precursor cells (OPCs). However, it not well understood what mechanism may control OPCs to differentiate into astrocytes. To address above questions, we two independent lines lineage-specific presenilin enhancer 2 (Pen-2) conditional KO mice. Both male and female mice were used. Here demonstrate inactivation Pen-2 mediated by Olig1-Cre or NG2-CreERT2 causes enhanced generation Lineage-tracing experiments indicate abnormally derived Cre-expressing CNS Pen-2 Mechanistic analysis reveals deletion inhibits Notch signaling upregulate signal transducer activator transcription 3, which triggers activation GFAP promote astrocyte differentiation. Together, these novel findings regulates specification through 3 signaling. SIGNIFICANCE STATEMENT Astrocytes (OLs) play critical roles brain. OL remains poorly governs differentiation In this study, took advantage lineage specific (Pen-2) We show leads dramatically CNS. Hes1 activates trigger promotes Overall, study identifies a function astrogliogenesis OPCs.

Язык: Английский

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Alzheimer’s disease linked Aβ42 exerts product feedback inhibition on γ-secretase impairing downstream cell signaling

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Авг. 2, 2023

ABSTRACT Amyloid β (Aβ) peptides accumulating in the brain are proposed to trigger Alzheimer’s disease (AD). However, molecular cascades underlying their toxicity poorly defined. Here, we explored a novel hypothesis for Aβ42 that arises from its proven affinity γ-secretases. We hypothesized reported increases Aβ42, particularly endolysosomal compartment, promote establishment of product feedback inhibitory mechanism on γ-secretases, and thereby impair downstream signaling events. show human peptides, but neither murine nor Aβ17-42 (p3), inhibit γ-secretases accumulation unprocessed substrates neurons, including C-terminal fragments (CTFs) APP, p75 pan-cadherin. Moreover, treatment dysregulated cellular homeostasis, as shown by induction p75-dependent neuronal death two distinct systems. Our findings raise possibility pathological elevations contribute via γ-secretase inhibition, provide conceptual framework address Aβ context γ-secretase-dependent homeostatic signaling.

Язык: Английский

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Recording γ-secretase activity in living mouse brains

eLife, Год журнала: 2024, Номер 13

Опубликована: Апрель 26, 2024

γ-Secretase plays a pivotal role in the central nervous system. Our recent development of genetically encoded Förster resonance energy transfer (FRET)-based biosensors has enabled spatiotemporal recording γ-secretase activity on cell-by-cell basis live neurons culture . Nevertheless, how is regulated vivo remains unclear. Here, we employ near-infrared (NIR) C99 720–670 biosensor and NIR confocal microscopy to quantitatively record individual living mouse brains. Intriguingly, uncovered that may influence neighboring neurons, suggesting potential ‘cell non-autonomous’ regulation Given critical roles important biological events various diseases, our new assay would become platform enables dissecting essential normal health diseases.

Язык: Английский

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ERK inhibition reduces neuronal death and ameliorates inflammatory responses in forebrain‐specific Ppp2cα knockout mice

The FASEB Journal, Год журнала: 2022, Номер 36(9)

Опубликована: Авг. 23, 2022

It has been shown that PP2A is critical for apoptosis in neural progenitor cells. However, it remains unknown whether required neuronal survival. To address this question, we generated forebrain-specific Ppp2cα knockout (KO) mice. We show KO mice display robust and inflammatory responses the postnatal cortex. Previous evidence revealed PD98059 a potent ERK inhibitor may protect brain against cell death after cardiac arrest. study have any effects on mice, latter was treated with inhibitor. demonstrated total number of cleaved caspase3 positive (+) cells cortex significantly reduced compared those without treatment. observed IBA1+ decreased PD98059. Mechanistic analysis reveals deletion PP2Aca causes DNA damage, which be attenuated by Together, suggests inhibition an effective strategy to reduce diseases abnormal apoptosis.

Язык: Английский

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Novel hippocampal genes involved in enhanced susceptibility to chronic pain-induced behavioral emotionality

European Journal of Pharmacology, Год журнала: 2023, Номер 964, С. 176273 - 176273

Опубликована: Дек. 20, 2023

Язык: Английский

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Presenilin enhancer 2 is crucial for the transition of apical progenitors into neurons but into not basal progenitors in the developing hippocampus

Development, Год журнала: 2022, Номер 149(10)

Опубликована: Май 15, 2022

ABSTRACT Recent evidence has shown that presenilin enhancer 2 (Pen2; Psenen) plays an essential role in corticogenesis by regulating the switch of apical progenitors (APs) to basal (BPs). The hippocampus is a brain structure required for advanced functions, including spatial navigation, learning and memory. However, it remains unknown whether Pen2 important hippocampal morphogenesis. To address this question, we generated conditional knockout (cKO) mice, which inactivated neural progenitor cells (NPCs) primordium. We showed cKO mice exhibited malformation decreased population NPCs neuroepithelium hippocampus. found deletion neither affected proliferative capability APs nor BPs hippocampus, caused enhanced transition neurons. demonstrated expression Notch1 intracellular domain (N1ICD) significantly increased Collectively, study uncovers crucial maintenance during development.

Язык: Английский

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