Biology subjects

Landreth, G. E.

Publications and source records attributed to Landreth, G. E..

7 recordsLinked to original sources

bioRxiv2026

Therapeutic Targeting of Microglial Hexokinase-2 Recalibrates Inflammasome Activation and Improves Functional Recovery After Traumatic Brain Injury

Traumatic brain injury (TBI) initiates a secondary inflammatory cascade in which sustained microglial activation contributes to long-term neurological dysfunction. Microglial inflammatory states depend on glycolytic reprogramming, suggesting that targeted modulation of metabolic regulators may attenuate post-traumatic inflammation while preserving essential immune functions. Hexokinase-2 (HK2), a rate-limiting glycolytic enzyme, regulates inflammatory signaling and inflammasome activation in microglia in neurodegenerative contexts; however, its role in TBI remains undefined. We therefore examined whether partial suppression of microglial HK2 modulates inflammatory responses following severe TBI. HK2 was robustly induced in microglia during the sub-acute phase after injury. Pharmacological inhibition of HK2 improved motor coordination without impairing locomotion or cognitive performance and selectively reduced inflammasome-related gene expression and ASC accumulation, particularly within the hippocampal hilus. Importantly, HK2 antagonism slowed microglial proliferation while preserving efferocytic capacity. Partial genetic reduction of microglial HK2 phenocopied these molecular and behavioral effects, supporting an HK2-dependent mechanism. Together, these findings identify microglial HK2 as a therapeutically targetable regulator of inflammatory amplification after TBI. Partial modulation of this pathway attenuates secondary neuroinflammation while maintaining critical microglial functions, highlighting HK2 as a promising strategy to improve functional recovery after traumatic brain injury.

neuroscience↗

bioRxiv2024

Functional 3'-UTR Variants Identify Regulatory Mechanisms Impacting Alcohol Use Disorder and Related Traits

Although genome-wide association studies (GWAS) have identified loci associated with alcohol consumption and alcohol use disorder (AUD), they do not identify which variants are functional. To approach this, we evaluated the impact of variants in 3 untranslated regions (3-UTRs) of genes in loci associated with substance use and neurological disorders using a massively parallel reporter assay (MPRA) in neuroblastoma and microglia cells. Functionally impactful variants explained a higher proportion of heritability of alcohol traits than non-functional variants. We identified genes whose 3-UTR activities are associated with AUD and alcohol consumption by combining variant effects from MPRA with GWAS results. We examined their effects by evaluating gene expression after CRISPR inhibition of neuronal cells and stratifying brain tissue samples by MPRA-derived 3-UTR activity. A pathway analysis of differentially expressed genes identified inflammation response pathways. These analyses suggest that variation in response to inflammation contributes to the propensity to increase alcohol consumption.

genomics↗

bioRxiv2023

Therapeutic targeting of immunometabolism in Alzheimers disease reveals a critical reliance on Hexokinase 2 dosage on microglial activation and disease progression.

Microgliosis and neuroinflammation are prominent features of Alzheimers disease (AD). Disease-responsive microglia meet their increased energy demand by reprogramming metabolism, specifically, switching to favor glycolysis over oxidative phosphorylation. Thus, targeting of microglial immunometabolism might be of therapeutic benefit for treating AD, providing novel and often well understood immune pathways and their newly recognized actions in AD. We report that in the brains of 5xFAD mice and postmortem brains of AD patients, we found a significant increase in the levels of Hexokinase 2 (HK2), an enzyme that supports inflammatory responses by rapidly increasing glycolysis. Moreover, binding of HK2 to mitochondria has been reported to regulate inflammation by preventing mitochondrial dysfunction and NLRP3 inflammasome activation, suggesting that its inflammatory role extends beyond its glycolytic activity. Here we report, that HK2 antagonism selectively affects microglial phenotypes and disease progression in a gene-dose dependent manner. Paradoxically, complete loss of HK2 fails to improve AD progression by exacerbating inflammasome activity while its haploinsufficiency results in reduced pathology and improved cognition in the 5XFAD mice. We propose that the partial antagonism of HK2, is effective in slowed disease progression and inflammation through a non-metabolic mechanism associated with the modulation of NFK{beta} signaling, through its cytosolic target IKB. The complete loss of HK2 affects additional inflammatory mechanisms associated to mitochondrial dysfunction. HighlightsO_LIHexokinase 2, the first and rate-limiting enzyme of glycolysis, is specifically upregulated in plaque-associated microglia of AD mice models and in the postmortem cortex of human AD patients. C_LIO_LIMicroglia haploinsufficient in HK2 exhibit reduced amyloid burden and inflammation as well as improved cognition in a mouse model of AD. Paradoxically, the complete loss of HK2 results in opposite effects, by exacerbating inflammation. C_LIO_LILonidamine, an anticancer drug that inhibits HK2, mimics the salutary effects of HK2 haploinsufficiency in the 5xFAD mice, but only in males during the early stages of disease. C_LIO_LIHK2 deletion induced mitochondrial dysfunction associated to increased expression of inflammasome elements and IL-1{beta}. C_LIO_LIHK2 partial antagonism exerts beneficial effects independent of its energetic or mitochondrial role, likely through cytosolic stabilization of I{kappa}B and inhibition of the NF-{kappa}B pathway, leading to reduced proinflammatory gene expression. C_LI

neuroscience↗

bioRxiv2022

Genetic Variants of Phospholipase C-γ 2 Confer Altered Microglial Phenotypes and Differential Risk for Alzheimers Disease

Genetic association studies have demonstrated the critical involvement of the microglial immune response in Alzheimers disease (AD) pathogenesis. Phospholipase C-gamma-2 (PLCG2) is selectively expressed by microglia and acts in many immune receptor signaling pathways. In AD, PLCG2 is induced uniquely in plaque-associated microglia. A genetic variant of PLCG2, PLCG2P522R, is a mild hypermorph that attenuates AD risk. We report the identification of a PLCG2 variant, PLCG2M28L, associated with loss-of-function and confers increased AD risk. PLCG2P522R attenuates disease in an amyloidogenic murine AD model, whereas PLCG2M28L exacerbates the plaque burden associated with altered phagocytosis and A{beta} clearance. The variants bidirectionally modulate disease pathology by inducing distinct transcriptional programs that identify microglial subpopulations associated with protective or detrimental phenotypes. In summary, these findings identify PLCG2M28L as a new AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/519685v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@19f0aa6org.highwire.dtl.DTLVardef@74191eorg.highwire.dtl.DTLVardef@1d3a3forg.highwire.dtl.DTLVardef@db2a44_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIA genetic variant of PLCG2, M28L, is associated with an increased risk for Alzheimers disease (AD) C_LIO_LIIn an amyloidogenic AD mouse model, PLCG2M28L exacerbates disease pathogenesis C_LIO_LIConversely, PLCG2P522R, a protective PLCG2 variant, attenuates AD pathogenesis C_LIO_LIThe PLCG2 variants uniquely alter the microglial transcriptome and phenotypes C_LI

neuroscience↗

bioRxiv2020

INPP5D expression is associated with risk for Alzheimer's disease and induced by plaque-associated microglia

BackgroundAlzheimers disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, robust microgliosis, neuroinflammation, and neuronal loss. Genome-wide association studies recently highlighted a prominent role for microglia in late-onset AD (LOAD). Specifically, inositol polyphosphate-5-phosphatase (INPP5D), also known as SHIP1, is selectively expressed in brain microglia and has been reported to be associated with LOAD. Although INPP5D is likely a crucial player in AD pathophysiology, its role in disease onset and progression remains unclear. MethodsWe performed differential gene expression analysis to investigate INPP5D expression in LOAD and its association with plaque density and microglial markers using transcriptomic (RNA-Seq) data from the Accelerating Medicines Partnership for Alzheimers Disease (AMP-AD) cohort. We also performed quantitative real-time PCR, immunoblotting, and immunofluorescence assays to assess INPP5D expression in the 5xFAD amyloid mouse model. ResultsDifferential gene expression analysis found that INPP5D expression was upregulated in LOAD and positively correlated with amyloid plaque density. In addition, in 5xFAD mice, Inpp5d expression increased as the disease progressed, and selectively in plaque-associated microglia. Increased Inpp5d expression levels in 5xFAD mice were abolished entirely by depleting microglia with the colony-stimulating factor receptor-1 antagonist PLX5622. ConclusionsOur findings show that INPP5D expression increases as AD progresses, predominantly in plaque-associated microglia. Importantly, we provide the first evidence that increased INPP5D expression might be a risk factor in AD, highlighting INPP5D as a potential therapeutic target. Moreover, we have shown that the 5xFAD mouse model is appropriate for studying INPP5D in AD.

neuroscience↗

bioRxiv2020

PLCG2 as a Risk Factor for Alzheimer's Disease

Alzheimers disease (AD) is characterized by robust microgliosis and phenotypic changes that accompany disease pathogenesis. Indeed, genetic variants in microglial genes are linked to risk for AD. Phospholipase C{gamma} 2 (PLCG2) participates in the transduction of signals emanating from immune cell-surface receptors that regulate the inflammatory response and is selectively expressed by microglia in the brain. A rare variant in PLCG2 (P522R) was previously found to be protective against AD, indicating that PLCG2 may play a role in AD pathophysiology. Here, we report that a rare missense variant in PLCG2 confers increased AD risk (p=0.047; OR=1.164 [95% CI=1.002-1.351]). Additionally, we observed that PLCG2 expression levels are increased in several brain regions of AD patients, correlating with brain amyloid deposition. This provides further evidence that PLCG2 may play an important role in AD pathophysiology. Together, our findings indicate that PLCG2 is a potential new therapeutic target for AD.

neuroscience↗

bioRxiv2019

Three dimensional nanoscopy of whole cells and tissues with in situ point spread function retrieval

Single-molecule localization microscopy is a powerful tool in visualizing organelle structures, interactions, and protein functions in biological research. However, whole-cell and tissue specimens challenge the achievable resolution and depth of nanoscopy methods. As imaging depth increases, photons emitted by fluorescent probes, the sole source of molecular positions, were scattered and aberrated, resulting in image artifacts and rapidly deteriorating resolution. We propose a method to allow constructing the in situ 3D response of single emitters directly from single-molecule dataset and therefore allow pin-pointing single-molecule locations with limit-achieving precision and uncompromised fidelity through whole cells and tissues. This advancement expands the routine applicability of super-resolution imaging from selected cellular targets near coverslips to intra- and extra-cellular targets deep inside tissues. We demonstrate this across a range of cellular-tissue architectures from mitochondrial networks, microtubules, and nuclear pores in 2D and 3D cultures, amyloid-{beta} plaques in mouse brains to developing cartilage in mouse forelimbs.

biophysics↗