Biology subjects

Satpati, A.

Publications and source records attributed to Satpati, A..

4 recordsLinked to original sources

bioRxiv2025

Tau-Associated Neuronal Loss in the Intermediate Nucleus of the Human Hypothalamus (VLPO Analog): Unveiling the Basis of NREM Sleep Dysfunction in PSP and Alzheimer's Disease

Sleep disturbances are prevalent in Alzheimers disease (AD) and Progressive Supranuclear Palsy (PSP), often exacerbating disease progression. Understanding the neuropathological basis of these disturbances is essential for identifying potential therapeutic targets. This study investigates the intermediate nucleus (IntN) of the human hypothalamus--a key sleep-regulating region analogous to the rodent ventrolateral preoptic area (VLPO)--to assess neuronal loss and tau pathology in AD and PSP. Using postmortem brain tissue, we applied unbiased stereology to quantify galanin-expressing neurons and phosphorylated tau (p-tau) accumulation. Among 26 cases analyzed, both AD and PSP exhibited significant neuronal loss in the IntN, with PSP showing the most pronounced reduction (84.9% fewer neurons than healthy controls [HC]). In AD, neuronal loss correlated with Braak staging, with late-stage AD cases (Braak 5-6) demonstrating a 76.9% reduction in galanin-expressing neurons compared to HC, while non-galanin neurons exhibited a more moderate decline (45.7%). In PSP, extensive neuronal loss precluded a clear assessment of p-tau burden. These findings suggest a differential neuronal vulnerability to tau pathology across diseases, aligning with distinct sleep disturbances observed in each condition. PSP, characterized by severe insomnia despite preserved wake-promoting neurons, may be explained by the near-total loss of NREM sleep-regulating neurons. In contrast, AD exhibits a progressive decline in both wake- and sleep-promoting neurons, contributing to excessive daytime sleepiness and sleep fragmentation. This study provides critical insights into the selective neuronal vulnerabilities underlying sleep dysfunction in tauopathies, emphasizing the need for targeted interventions to mitigate sleep disturbances in these disorders.

neuroscience↗

bioRxiv2024

The wake and sleep-modulating neurons of the lateral hypothalamic area demonstrate a differential pattern of degeneration in Alzheimers disease

BackgroundSleep-wake dysfunction is an early and common event in Alzheimers disease (AD). The lateral hypothalamic area (LHA) regulates the sleep and wake cycle through wake-promoting orexinergic neurons (OrxN) and sleep-promoting melanin-concentrating hormone or MCHergic neurons (MCHN). These neurons share close anatomical proximity with functional reciprocity. This study investigated LHA OrxN and MCHN loss patterns in AD individuals. Understanding the degeneration pattern of these neurons will be instrumental in designing potential therapeutics to slow down the disease progression and remediate the sleep-wake dysfunction in AD. MethodsPostmortem human brain tissue from donors with AD (across progressive stages) and controls were examined using unbiased stereology. Formalin-fixed, celloidin-embedded hypothalamic sections were stained with Orx-A/MCH, p-tau (CP13), and counterstained with gallocyanin. Orx or MCH-positive neurons with or without CP13 inclusions and gallocyanin-stained neurons were considered for stereology counting. Additionally, we extracted RNA from the LHA using conventional techniques. We used customized Neuropathology and Glia nCounter(R) (Nanostring) panels to study gene expression. Wald statistical test was used to compare the groups, and the genes were considered differentially expressed when the p-value was <.05. ResultsWe observed a progressive decline in OrxN alongside a relative preservation of MCHN. OrxN decreased by 58% (p=.03) by Braak stages (BB) 1-2 and further declined to 81% (p=.03) by BB 5-6. Conversely, MCHN demonstrated a non-statistical significant decline (27%, p=.1088) by BB 6. We observed a progressive increase in differentially expressed genes (DEGs), starting with glial profile changes in BB2. While OrxN loss was observed, Orx-related genes showed upregulation in BB 3-4 compared to BB 0-1. GO and KEGG terms related to neuroinflammatory pathways were mainly enriched. ConclusionsTo date, OrxN loss in the LHA represents the first neuronal population to die preceding the loss of LC neurons. Conversely, MCHN shows resilience to AD p-tau accumulation across Braak stages. The initial loss of OrxN correlates with specific neuroinflammation, glial profile changes, and overexpression of HCRT, possibly due to hyperexcitation following compensation mechanisms. Interventions preventing OrxN loss and inhibiting p-tau accumulation in the LHA could prevent neuronal loss in AD and, perhaps, the progression of the disease.

neuroscience↗

bioRxiv2022

HLA-II-dependent neuroimmune changes in Group A Streptococcal Necrotizing Fasciitis

IntroductionStreptococcus pyogenes (Group A Streptococcus, GAS) bacteria cause a spectrum of human diseases ranging from self-limiting pharyngitis and mild uncomplicated skin infections (impetigo, erysipelas, cellulitis) to highly morbid and rapidly invasive life-threatening infections such as streptococcal toxic shock syndrome and necrotizing fasciitis (NF). HLA-Class II allelic polymorphisms are linked with differential outcomes and severity of GAS infections. The dysregulated immune response and peripheral cytokine storm elicited due to invasive GAS infections increase the risk for toxic shock and multiple organ failure in genetically susceptible individuals. We hypothesized that while the host immune mediators regulate the immune responses against peripheral GAS infections, these interactions may simultaneously trigger neuropathology and, in some cases, induce persistent alterations in the glial phenotypes. Here we studied the consequences of peripheral GAS skin infection on the brain in an HLA-II transgenic mouse model of GAS NF with and without treatment with an antibiotic, clindamycin (CLN). MethodsMice expressing the human HLA-II DR3 (DR3) or the HLA-II DR4 (DR4) allele were divided into three groups: i) uninfected controls, ii) subcutaneously infected with a clinical GAS strain isolated from a patient with GAS NF, and iii) GAS infected with CLN treatment (10mg/kg/5 days, intraperitoneal). The groups were monitored for 15 days post-infection. Skin GAS burden and lesion area, splenic and hippocampal mRNA levels of inflammatory markers, and immunohistochemical changes in hippocampal GFAP and Iba-1 immunoreactivity were assessed. ResultsSkin GAS burden and hippocampal mRNA levels of inflammatory markers S100A8/A9, IL-1{beta}, IL-33, inflammasome-related caspase-1 (Casp1), and NLRP6 were elevated in infected DR3 but not DR4 mice. The levels of these markers were significantly reduced following CLN treatment in DR3 mice. Although GAS was not detectable in the brain, astrocyte and microglia activation were evident from increased GFAP and Iba-1 mRNA levels respectively, in DR3 and DR4 mice. However, CLN treatment significantly reduced GFAP immunoreactivity in DR3 mice and not DR4 mice. ConclusionOur data suggest a skin-brain axis during GAS NF demonstrating that peripherally induced pathological conditions regulate neuroimmune and gliotic events, and CLN may attenuate peripheral infection and subsequent neuroimmune changes in an HLA-II-dependent manner.

neuroscience↗

bioRxiv2021

Metallothionein 3-zinc axis suppresses caspase-11 inflammasome activation and impairs antibacterial immunity

Non-canonical inflammasome activation by mouse caspase-11 (or human CASPASE- 4/5) is crucial for the clearance of certain gram-negative bacterial infections, but can lead to severe inflammatory damage. Factors that promote non-canonical inflammasome activation are well recognized, but less is known about the mechanisms underlying its negative regulation. Herein, we identify that the caspase-11 inflammasome in mouse and human macrophages (M{phi}) is negatively controlled by the zinc (Zn2+) regulating protein, metallothionein 3 (MT3). Upon challenge with intracellular lipopolysaccharide (iLPS), M{phi} increased MT3 expression that curtailed the activation of caspase-11 and its downstream targets caspase-1 and interleukin (IL)-1{beta}. Mechanistically, MT3 increased intramacrophage Zn2+ to downmodulate the TRIF-IRF3-STAT1 axis that is prerequisite for caspase-11 effector function. MT3 suppressed activation of the caspase-11 inflammasome, while caspase-11 and MT3 synergized in impairing antibacterial immunity. The present study identifies an important yin-yang relationship between the non-canonical inflammasome and MT3 in controlling inflammation and immunity to gram- negative bacteria. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=149 HEIGHT=200 SRC="FIGDIR/small/454033v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@15070f1org.highwire.dtl.DTLVardef@27174forg.highwire.dtl.DTLVardef@6b48beorg.highwire.dtl.DTLVardef@174b850_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗