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1. IL-1β Antibody Protects Brain from Neuropathology of Hypoperfusion

   https://doi.org/10.3390/cells10040855  

   Quintana, Dominic; Ren, Xuefang; Hu, Heng; Corbin, Deborah; Engler-Chiurazzi, Elizabeth; Alvi, Muhammad; Simpkins, James (April 2021, Cells)

   null (Ed.)

   Chronic brain hypoperfusion is the primary cause of vascular dementia and has been implicated in the development of white matter disease and lacunar infarcts. Cerebral hypoperfusion leads to a chronic state of brain inflammation with immune cell activation and production of pro-inflammatory cytokines, including IL-1β. In the present study, we induced chronic, progressive brain hypoperfusion in mice using ameroid constrictor, arterial stenosis (ACAS) surgery and tested the efficacy of an IL-1β antibody on the resulting brain damage. We observed that ACAS surgery causes a reduction in cerebral blood flow (CBF) of about 30% and grey and white matter damage in and around the hippocampus. The IL-1β antibody treatment did not significantly affect CBF but largely eliminated grey matter damage and reduced white matter damage caused by ACAS surgery. Over the course of hypoperfusion/injury, grip strength, coordination, and memory-related behavior were not significantly affected by ACAS surgery or antibody treatment. We conclude that antibody neutralization of IL-1β is protective from the brain damage caused by chronic, progressive brain hypoperfusion. 

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2. CD36‐Binding Amphiphilic Nanoparticles for Attenuation of α‐Synuclein‐Induced Microglial Activation

   https://doi.org/10.1002/anbr.202100120  

   Zhao, Nanxia; Francis, Nicola_L; Song, Shuang; Kholodovych, Vladyslav; Calvelli, Hannah_R; Hoop, Cody_L; Pang, Zhiping_P; Baum, Jean; Uhrich, Kathryn_E; Moghe, Prabhas_V (March 2022, Advanced NanoBiomed Research)

   Neuroinflammation is one of the hallmarks contributing to Parkinson's disease (PD) pathology, where microglial activation occurs as one of the earliest events, triggered by extracellular α‐synuclein (aSYN) binding to the cluster of differentation 36 (CD36) receptor. Herein, CD36‐binding nanoparticles (NPs) containing tartaric acid–based amphiphilic macromolecules (AMs) are rationally designed to inhibit this aSYN–CD36 binding. In silico docking reveals that four AMs with varying alkyl side chain lengths present differential levels of CD36 binding affinity and that an optimal alkyl chain length promotes the strongest inhibitory activity toward aSYN–CD36 interactions. In vitro competitive binding assays indicate that the inhibitory activity of AM‐based NPs plateaus at intermediate side chain lengths of 12 and 18 carbons, supporting the in silico docking predictions. These intermediate‐length AM NPs also has significantly stronger effects on reducing aSYN internalization and inhibiting proinflammatory molecules tumor necrosis factor α (TNF‐α) and nitric oxide from aSYN‐challenged microglia. All four NPs modulate the gene expression of aSYN‐challenged microglia, downregulating proinflammatory genes TNF, interleukin 6 (IL‐6), and IL‐1β, and upregulating anti‐inflammatory genes transforming growth factor β (TGF‐β) and Arg1 expression. Herein, overall, a novel polymeric nanotechnology platform is represented that can be used to modulate aSYN‐induced microglial activation. 

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3. Role of Metalloproteinases in Diabetes-associated Mild Cognitive Impairment

   https://doi.org/10.2174/1570159X22666240517090855  

   Pereira, Vitoria Mattos; Pradhanang, Suyasha; Prather, Jonathan F; Nair, Sreejayan (January 2025, Current Neuropharmacology)

   :Diabetes has been linked to an increased risk of mild cognitive impairment (MCI), a conditioncharacterized by a subtle cognitive decline that may precede the development of dementia. Theunderlying mechanisms connecting diabetes and MCI involve complex interactions between metabolicdysregulation, inflammation, and neurodegeneration. A critical mechanism implicated in diabetes andMCI is the activation of inflammatory pathways. Chronic low-grade inflammation, as observed in diabetes,can lead to the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha(TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and interferon-gamma (IFNγ), each of whichcan exacerbate neuroinflammation and contribute to cognitive decline. A crucial enzyme involved inregulating inflammation is ADAM17, a disintegrin, and metalloproteinase, which can cleave and releaseTNF-α from its membrane-bound precursor and cause it to become activated. These processes, inturn, activate additional inflammation-related pathways, such as AKT, NF-κB, NLP3, MAPK, andJAK-STAT pathways. Recent research has provided novel insights into the role of ADAM17 in diabetesand neurodegenerative diseases. ADAM17 is upregulated in both diabetes and Alzheimer's disease,suggesting a shared mechanism and implicating inflammation as a possible contributor to muchbroader forms of pathology and pointing to a possible link between inflammation and the emergenceof MCI. This review provides an overview of the different roles of ADAM17 in diabetes-associatedmild cognitive impairment diseases. It identifies mechanistic connections through which ADAM17and associated pathways may influence the emergence of mild cognitive impairment. 

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4. Brain rhythms control microglial response and cytokine expression via NF-κB signaling

   https://doi.org/10.1126/sciadv.adf5672  

   Prichard, Ashley; Garza, Kristie M; Shridhar, Avni; He, Christopher; Bitarafan, Sara; Pybus, Alyssa; Wang, Yunmiao; Snyder, Emma; Goodson, Matthew C; Franklin, Tina C; et al (August 2023, Science Advances)

   Microglia transform in response to changes in sensory or neural activity, such as sensory deprivation. However, little is known about how specific frequencies of neural activity, or brain rhythms, affect microglia and cytokine signaling. Using visual noninvasive flickering sensory stimulation (flicker) to induce electrical neural activity at 40 hertz, within the gamma band, and 20 hertz, within the beta band, we found that these brain rhythms differentially affect microglial morphology and cytokine expression in healthy animals. Flicker induced expression of certain cytokines independently of microglia, including interleukin-10 and macrophage colony-stimulating factor. We hypothesized that nuclear factor κB (NF-κB) plays a causal role in frequency-specific cytokine and microglial responses because this pathway is activated by synaptic activity and regulates cytokines. After flicker, phospho–NF-κB colabeled with neurons more than microglia. Inhibition of NF-κB signaling down-regulated flicker-induced cytokine expression and attenuated flicker-induced changes in microglial morphology. These results reveal a mechanism through which brain rhythms affect brain function by altering microglial morphology and cytokines via NF-κB. 

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5. The inflammatory response to birth requires MyD88 and is driven by both mother and offspring

   https://doi.org/10.1016/j.bbi.2023.11.011  

   Gray, Jennifer M.; Major, Kharli; Castillo-Ruiz, Alexandra; Shipley, Michael; Gangappa, Shivaprakash; Forger, Nancy G. (January 2024, Brain, Behavior, and Immunity)

   Birth is an inflammatory event for the newborn, characterized by elevations in interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α peripherally and/or centrally, as well as changes in brain microglia. However, the mechanism(s) underlying these responses is unknown. Toll-like receptors (TLRs) play crucial roles in innate immunity and initiate inflammatory cascades upon recognition of endogenous or exogenous antigens. Most TLR signaling depends on the adaptor molecule myeloid differentiation primary response 88 (MyD88). We independently varied MyD88 gene status in mouse dams and their offspring to determine whether the inflammatory response to birth depends on MyD88 signaling and, if so, whether that signaling occurs in the offspring, the mother, or both. We find that the perinatal surges in plasma IL-6 and brain expression of TNF-α depend solely on MyD88 gene status of the offspring, whereas postnatal increases in plasma IL-10 and TNF-α depend on MyD88 in both the pup and dam. Interestingly, MyD88 genotype of the dam primarily drives differences in offspring brain microglial density and has robust effects on developmental neuronal cell death. Milk cytokines were evaluated as a possible source of postnatal maternal influence; although we found high levels of CXCL1/GROα and several other cytokines in ingested post-partum milk, their presence did not require MyD88. Thus, the inflammatory response previously described in the late-term fetus and newborn depends on MyD88 (and, by extension, TLRs), with signaling in both the dam and offspring contributing. Unexpectedly, naturally-occuring neuronal cell death in the newborn is modulated primarily by maternal MyD88 gene status. 

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