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[Display omitted] • Platelet derived growth factor (PDGF) was isolated from human blood. • Intervertebral disc (IVD) degenerative model induced by Nicotine in BALB/C mice. • oxidative stress markers were accessed through Lipid peroxidation (LPO), Myeloperoxidase (MPO) and Nitric oxide (NO) estimation. • Endochondral bone formation confirmed by histology, Alizarin and Alcian blue staining, Immunohistochemistry (IHC) and qPCR. Intervertebral disc (IVD) degeneration is an age-related disease affecting the elderly population worldwide. The disease is contributed by degeneration of the cartilage tissue in the vertebral column. The current study explores the possibility of exploiting platelet derived growth factor (PDGF), a growth factor secreted by platelets, as a therapeutic agent against the IVD degeneration. BALB/c mice were exposed to nicotine at higher concentrations to induce IVD degeneration. Three different concentrations of PDGF (1 ng/mL, 2 ng/mL, 3 ng/mL) were used in the study. Oxidative stress parameters were assessed through Lipid peroxidation (LPO), Myeloperoxidase (MPO) and Nitric oxide (NO). Histopathology was done for assessing the extent of degeneration, collagen II, mucin, and calcium deposition by Haematoxylin and Eosin staining, immunohistochemistry, Alcian blue and Alizarin red staining respectively. Gene expression studies were carried out by quantitative real-time Polymerase chain reaction (RT-PCR) for Aggrecan, alkaline phosphatase, RUNX2, Collagen I alpha and osteocalcin. IVD degeneration was prominent and PDGF treatment restored the tissue as evidenced by H&E staining. Oxidative stress was induced by the nicotine treatment and all the biomarkers of oxidative stress were restored back to normal by PDGF in a dose dependent manner. Biomarkers of endochondral bone formation (aggrecan, alkaline phosphatase, RUNX2, Collagen I alpha and osteocalcin) was observed to be normalized by exposing to PDGF in mRNA level though RT-PCR. Mucin, calcium contents were also brought back to normal by PDGF treatment. In conclusion, current work strongly supports that PDGF could be used as a therapeutic agent for the treatment of IVD degeneration. [ABSTRACT FROM AUTHOR]

Background: Regulatory interactions between the gut and the brain are essential for energy homeostasis across systems. Current evidence indicates high‐fat, high‐carbohydrate diets (HFHC) impact Alzheimer's disease (AD) pathophysiology, however, the mechanisms underlying this association are poorly understood. We hypothesize that (1) Tumor Necrosis Factor (TNF) mediates metabolic inflammation in an obesogenic environment with impacts across the gut‐brain axis and (2) that HFHC interacts with an AD‐relevant genetic background to promote metabolic and immune dysregulation that accelerates pathological and behavioral dysfunction in an animal model of AD. Method: To investigate the effects of chronic systemic inflammation on AD‐associated pathology, 2‐month old female 5xFAD mice were fed HFHC or a control diets (CD) for 8 weeks. One month following dietary intervention, the brain‐permeant soluble TNF inhibitor XPro1595 or a brain‐impermeant pan (sol and membrane‐bound) TNF inhibitor Etanercept (Enbrel, Amgen‐Wyeth) or vehicle (saline) were dosed twice weekly for 4 weeks. Behavioral test were performed to assess cognitive parameters. Plasma, brain and gut were collected for evaluation of insulin impairment, metabolic and immune parameters. Cortical tissues were subjected to RNAseq analysis to determine gene pathways modified by interactions between diet, genotype, and TNF inhibition. Result: HFHC promoted metabolic syndrome features associated with increases in adiposity, body weight, and plasma glucose, cholesterol, leptin, and insulin. TNF inhibition did not rescue diet‐induced insulin increases, however XPro specifically reduced plasma glucose, while Enbrel increased HOMA‐IR in HFHC‐fed mice. HFHC diet increased circulating IL‐6, CXCL1, CXCL2 and CCL2 and TNF neutralization with either drug decreased IL‐6 in HFHC‐fed groups. In the colon, HFHC diet decreased CCL3 and TNF blockade increased colonic IL‐15 in HFHC‐fed mice. Ongoing behavioral assessment, cortical transcriptional analysis, and hippocampal protein profiles of insulin signaling and inflammatory markers will determine additional effects of TNF and HFHC in the 5XFAD animal model of AD. Conclusion: Collectively, these results suggest that TNF modulates systemic metabolic and inflammatory pathways induced by HFHC consumption and associated with neurodegeneration and neuroinflammation. Blocking soluble TNF decreases hyperglycemia triggered during diet‐induce obesity. Future studies focusing on the impact of TNF on energy homeostasis and inflammation will provide targets for new therapeutics against neurological disease. [ABSTRACT FROM AUTHOR]

Background: Mutations in the progranulin gene (GRN) reduce levels of progranulin (PGRN) and granulins (GRNs) causing frontotemporal dementia (FTD), the most common form of early‐onset dementia. PGRN loss in neurons is associated with lysosome dysfunction resulting in diminished cathepsin protease activity. PGRN is also highly expressed in brain‐resident microglia and peripheral immune cells. Therefore, we asked if PGRN loss impacts immune cell profiles and communication in the gut‐brain axis during chronic systemic inflammation. Methods: We measured lysosomal‐associated proteases in microglia and peripheral immune cells using probes for cathepsin D and pan‐cysteine cathepsins; performed multiplexed RNA & digital spatial protein profiling analyses, immunohistochemistry, and deep‐immunophenotyping by flow cytometry on brain, spleen, and peripheral blood of Grn KO and Grn‐suffficient mice aged 3‐30 months. Furthermore, we exposed mice to experimental colitis to interrogate alterations in the gut‐brain axis. Results: Highest cathepsin D activity was found amongst Ly6C+, CD11b+ blood monocytes while pan‐cathepsin activity was highest in neutrophils and monocytes. In the spleen of aged Grn KO mice, T cell counts were reduced while Ly6C‐, CD68+ macrophages were increased compared to age‐matched Grn‐sufficient mice. In blood, aberrant T cell and monocyte activation markers in Grn KO mice were evident with minimal increases in inflammatory cytokines in plasma. Aged Grn KO mice exhibited decreased microglia (CD45int, CD11bhi) in the brain relative to Grn‐sufficient mice, with altered MHCII and CD68 expression. Additionally, CD4+ and CD8+ T cells were impacted in the brain of Grn KO mice compared to age‐matched Grn‐sufficient mice. PGRN loss was also associated with increased brain infiltration of activated peripheral monocytes and, interestingly, increased vulnerability to experimental colitis that was mitigated by loss of CCR2 function. Conclusions: These novel findings suggest that PGRN plays key regulatory functions in innate and adaptive immune cell populations, in central‐peripheral immune cell crosstalk and traffic to the CNS, and in regulating susceptibility to immune challenges that disrupt the gut‐brain signaling axis. Analysis of peripheral immune cells and colonic tissue from patients with Grn mutations or SNPs is ongoing and may shed light on the mechanisms by which GRN haploinsufficiency causes FTD. [ABSTRACT FROM AUTHOR]

Background: Sporadic Alzheimer's disease (AD) is a product of complex gene‐environment (GxE) interactions. Central‐peripheral immune cell crosstalk and traffic across the blood‐brain barrier (BBB) have been implicated in AD pathophysiology by recent studies that demonstrate a T‐cell signature in AD brain, gut dysbiosis in AD patients, and a significant epidemiological association between metabolic syndrome, obesity, and type‐2 diabetes with increased incidence of AD. Soluble tumor necrosis factor (sTNF), a known regulator of BBB and gut‐epithelial barrier permeability in chronic systemic inflammatory diseases that is increased in AD patient blood, was investigated as a regulator of immune cell traffic and AD‐like pathology in a mouse model of amyloid pathology subjected to an obesogenic diet. Method: To investigate the effects of chronic peripheral inflammation on neuroinflammation and AD‐associated pathology, 2‐month old female 5xFAD (Tg) or non‐Tg mice were fed a high‐fat high‐carbohydrate diet (HFHC) or a balanced control diet (CD) for 8 weeks. After 4 weeks of diet, BBB‐permeant XPro®1595 was given subcutaneously every third day to selectively inhibit sTNF signaling. Neuroimmunological, histological, biochemical, genomic, and transcriptomic analyses were used to analyze effects on blood and brain immune populations, BBB permeability, inflammatory gene and protein expression, and gut microbiome. Result: HFHC‐fed Tg mice showed decreased T cell numbers in the blood and increased Ly6C+ T cells in the brain as compared to Tg mice fed CD or non‐Tg HFHC‐fed mice. Tg mice fed HFHC diet displayed increased hippocampal TNF and ZO‐1 mRNA, modestly increased Aβ burden, and marked increases of Iba1+ cells. Analysis of gut microbiota revealed significant beta diversity genotype‐ and diet‐dependent differences between Tg and non‐Tg mice, synergy in GxE interactions, and the ability of XPro®1595 to reverse many of these features. Conclusion: Together, these data suggest that an obesogenic diet enhances BBB permeability, disrupts innate and adaptive immune cell populations in the blood, promotes gut dysbiosis, and enhanced traffic of immune cells to the CNS through sTNF‐dependent mechanisms. Clinical trials in patients with MCI/early AD are underway to investigate the ability of a weekly dose of XPro1595 to reduce underlying inflammation without immunosuppression via selective targeting of sTNF. [ABSTRACT FROM AUTHOR]

Background: Insulin resistance (IR) and systemic inflammation are risk factors for Alzheimer's disease (AD); however, the molecular and signaling mechanisms underlying this relationship are not well understood. Elevated plasma cytokine levels are associated with increased risk for both AD and IR. The cytokine tumor necrosis factor (TNF) is a major driver of inflammation and is implicated in IR and neurodegeneration. Here, we hypothesize that soluble TNF (solTNF) drives metabolic and immune alterations in the CNS and periphery that promote IR, thereby increasing the risk for AD pathologies. Method: To investigate this hypothesis, 2‐month old female 5xFAD mice were fed a high‐fat high‐carbohydrate diet (HFHC) or a control diet (CD) for 8 weeks. After 1 month, the brain‐permeant solTNF inhibitor XPro1595 or a brain‐impermeant pan (sol and membrane‐bound) TNF inhibitor Etanercept or saline were dosed twice weekly for 4 weeks. Plasma, adipose tissue, and gut were collected for evaluation of IR, metabolic and immune parameters. Molecular markers of insulin signaling, oxidative stress, mitochondrial impairment and inflammation were assessed in relevant brain regions (hippocampus, hypothalamus and cortex). Result: Our preliminary data demonstrate that HFHC‐fed 5XFAD mice exhibit increased body weight gain compared to CD groups. Ectopic lipid deposition, as measured by gonadal fat pad and liver volumes, was significantly increased, concurrent to anatomical indicators of intestinal inflammation, including shortened small intestine and colon. HFHC diet promoted systemic inflammation, as measured by increases in the classical pro‐inflammatory cytokines IL‐6 and TNF. Further, plasma LCN2, a downstream TNF inflammatory molecule associated with insulin insensitivity, hippocampal alterations, and previously observed to be increased in AD patients, was also significantly increased. Ongoing assessments of mRNA and protein expression of insulin signaling and inflammation in the hippocampus and cortex will determine additional effects of TNF in central insulin impairment and AD pathogenesis and will be presented and integrated into the overall findings. Conclusion: Together, these data suggest HFHC diet disrupts peripheral immune and metabolic parameters in the 5XFAD animal model of AD‐like pathology, thereby triggering neuroinflammation and insulin insensitivity, conditions which have been implicated in significantly increasing the risk for development of AD in humans. [ABSTRACT FROM AUTHOR]