Biology subjects

Elahi, M.

Publications and source records attributed to Elahi, M..

4 recordsLinked to original sources

bioRxiv2026

Ferroptosis of selective progenitor cell types during embryogenesis ensures proper organ morphogenesis

Ferroptosis, a form of non-apoptotic cell death, is induced by lipid peroxidation resulting from an intracellular accumulation of labile iron (1). While apoptosis is involved in embryonic development (2), the role of ferroptosis in embryogenesis is unknown. Here, we report that the ferroptosis process occurs in the embryonic lung and kidney at mid- and late-gestation. In these tissues, pro-ferroptotic cells include subpopulations of the Sox9+ distal lung epithelial cells and the Flk1+ vascular progenitors in the kidney glomeruli. Lipidomic analysis reveals mixed lipid peroxidation as the driver for ferroptosis. The role of ferroptosis in the morphogenesis of these organs was confirmed by triple positivity of TfR1, 4-HNE and TUNEL, mitochondrial defects, cell membrane breakage, dead cell remnants, single-cell RNA-sequencing of a ferroptosis gene signature. Genetic manipulation of Gpx4, an endogenous inhibitor of ferroptosis. Further, genetic knockout or transgenic overexpression of Gpx4 affects lung and kidney development and results in cystic lungs and kidneys. Notably, conditional deletion Gpx4 results in hypoplasia of the lung epithelia and of the renal glomeruli, while transgenic overexpression of Gpx4 resulted in atelectasis with collapsed lung alveoli and hypertrophic glomeruli. Together, these findings show that ferroptosis regulates lung and kidney morphogenesis by acting in key progenitor cell populations during gestation. Supplementation of iron or polyunsaturated fatty acid during pregnancy has implications for organogenesis.

developmental biology↗

bioRxiv2026

Early Insulin Signaling Defects and Oxidative Stress Kinase Activation Precede Tau Pathology in PS19 Tau Transgenic Mice

Pathological tau accumulation is a hallmark of Alzheimers disease (AD), yet its relationship with impaired insulin signaling remains unclear. Previously, we reported altered IRS1 phosphorylation reduced p IR beta, and GLUT3 expression in young AD transgenic mice prior to overt pathology. Here, we investigated insulin signaling and oxidative stress pathways in the Tau P301S (PS19) mouse model. We found that alterations in phospho IRS1, phospho IR beta, and the glucose transporters GLUT3 and GLUT4 occur before pathogenic tau deposition. In stable tau expressing human neuronal cell lines, tau expression was similarly associated with impaired insulin signaling. Concurrent dysregulation of insulin signaling and activation of oxidative stress responsive kinases, accompanied by increased microglial abundance, were evident in 2 month old PS19 mice and persisted into adulthood. Together, these findings demonstrate that insulin signaling abnormalities and oxidative stress kinase activation are early and sustained features of PS19 tauopathy, preceding the onset of overt neuropathology.

neuroscience↗

bioRxiv2022

SARS-CoV-2 invades cognitive centers of the brain and induces Alzheimer's-like neuropathology

Major cell entry factors of SARS-CoV-2 are present in neurons; however, the neurotropism of SARS-CoV-2 and the phenotypes of infected neurons are still unclear. Acute neurological disorders occur in many patients, and one-third of COVID-19 survivors suffer from "brain diseases". Here, we show that SARS-CoV-2 invades the brains of five patients with COVID-19 and Alzheimers, autism, frontotemporal dementia or no underlying condition by infecting neurons and other cells in the cortex. SARS-CoV-2 induces or enhances Alzheimers-like neuropathology with manifestations of {beta}-amyloid aggregation and plaque formation, tauopathy, neuroinflammation and cell death. SARS-CoV-2 infects mature but not immature neurons derived from inducible pluripotent stem cells from healthy and Alzheimers individuals through its receptor ACE2 and facilitator neuropilin-1. SARS-CoV-2 triggers Alzheimers-like gene programs in healthy neurons and exacerbates Alzheimers neuropathology. A gene signature defined as an Alzheimers infectious etiology is identified through SARS-CoV-2 infection, and silencing the top three downregulated genes in human primary neurons recapitulates the neurodegenerative phenotypes of SARS-CoV-2. Thus, SARS-CoV-2 invades the brain and activates an Alzheimers-like program.

neuroscience↗

bioRxiv2020

High-fat diet-induced activation of SGK1 contributes to Alzheimer's disease pathogenesis by promoting tau pathology

Type2 diabetes mellitus (T2DM) has long been considered a risk factor for Alzheimers disease (AD). However, the molecular links between T2DM and AD remain obscure. Here, we reported that serum/glucocorticoid-regulated kinase1 (SGK1) is activated by administering a chronic high-fat diet (HFD), which increases the risk of T2DM, and thus promotes Tau pathology via the phosphorylation of tau at Ser214 and the activation of a key tau kinase, namely, GSK-3{beta}, forming SGK1-GSK-3{beta}-tau complex. SGK1 was activated under conditions of elevated glucocorticoid and hyperglycemia associated with HFD, but not of fatty acid-mediated insulin resistance. Elevated expression of SGK1 in the mouse hippocampus led to neurodegeneration and impairments in learning and memory. Upregulation and activation of SGK1, SGK1-GSK-3{beta}-tau complex were also observed in the hippocampi of AD cases. Our results suggest that SGK1 is a key modifier of tau pathology in AD, linking AD to corticosteroid effects and T2DM.

physiology↗