Open research questions in Neuroinflammation and Neurodegeneration Mechanisms
1,210 gap statements mined from Neuroinflammation and Neurodegeneration Mechanisms papers in our 7.9M-paper local library, which holds 4,524 papers on the topic — drawn mostly from each paper's own stated research gap, future-work, challenge and limitation notes, and its abstract. The ones listed below are a selection still marked open; each names the study that raised it, with a DOI link where the paper has one.
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What the literature leaves open
Current therapies are often constrained by limitations in timing and effectiveness. There is a need to characterize molecular events associated with ischemic injury and neuroprotection.
Exploring key genes associated with metabolic cell death in ischemic stroke: a comprehensive analysis of single-cell, bulk transcriptome, and experimental validation · 2026 · DOIThe need to develop effective treatment strategies for depression that take into account the etiological heterogeneity of the disorder. The challenge of translating the findings from animal models to humans.
Dynamic Remodeling of Dentate Gyrus Microglia Underlies Adult Depression-Like Outcomes Following Adolescent High-Fat Diet Exposure · 2026 · DOIThe effects of Tinosinenside A on AD-related neuroinflammation remain unclear. There is a need for further investigation of natural-product-derived therapeutic leads for AD.
Tinosinenside A ameliorates Alzheimer’s disease-related pathology in APP/PS1 mice, accompanied by reduced neuroinflammation and altered microglial phenotype-associated marker expression · 2026 · DOIThe adverse effects of inflammation on memory formation have been well documented, but its contribution to the process of forgetting has been less explored. The mechanisms underlying accelerated forgetting are not well understood, and the role of the integrated stress response (ISR) in this process is unknown.
Integrated stress response inhibition rescues inflammation-associated accelerated forgetting of recognition memory in mice · 2026 · DOIThe need for further research to fully understand the therapeutic potential of G. elata and its components. The challenge of translating preclinical findings to clinical applications.
Gastrodia elata in neurological disorders: a systematic review of anti-inflammatory mechanisms and cross-disease therapeutic potential · 2026 · DOINeed for improving pharmacokinetic properties and reducing systemic side effects of phytochemicals.
Dietary phytochemicals targeting neuroinflammation: mechanisms, bioavailability and translational challenges · 2026 · DOIThe mechanisms of ARBD progression to advanced stages with permanent disability are not well understood. There is a need to characterize the effects of chronic heavy ethanol feeding on white matter myelin protein expression, neuroinflammation, and mTOR signaling.
Progressive Alcohol-Related Brain Atrophy and White Matter Pathology Are Linked to Long-Term Inhibitory Effects on mTOR Signaling · 2025 · DOIThe lack of effective treatments for neurodegenerative diseases. The need for novel compounds with anti-inflammatory and ferroptosis-inhibiting effects. The limited understanding of the pharmacological mechanisms of compounds derived from deep-sea fungi.
Deep-Sea-Derived Isobisvertinol Targets TLR4 to Exhibit Neuroprotective Activity via Anti-Inflammatory and Ferroptosis-Inhibitory Effects · 2025 · DOILimited research has explored whether microglia in different regions of the central nervous system possess distinct traits. The integration of microglia into brain organoids has been accomplished effectively, but continuous challenges remain that hinder the progression and broader application in the field of neurology and immunology.
The need to improve the biocompatibility and targeting properties of nanoparticles. The challenge of traversing the blood-brain barrier to deliver drugs to the brain. The need to develop novel therapeutic approaches that can improve brain tissue's ischemic state and attenuate neurological damage and dysfunction.
Application and Development of Cell Membrane Functionalized Biomimetic Nanoparticles in the Treatment of Acute Ischemic Stroke · 2024 · DOIOne challenge is the limited accessibility of the human CNS for investigations. Another challenge is the complexity of the interplay between resident innate immune cells and other cell types involved in MS.
The need for further comprehensive investigation to fully comprehend the pathogenesis of neuropathic pain. The potential of ferroptosis as a target for treating neuropathic pain is not fully explored.
New Insight into Neuropathic Pain: The Relationship between α7nAChR, Ferroptosis, and Neuroinflammation · 2024 · DOIFurther studies are needed to characterize molecular events associated with ischemic injury and neuroprotection. The complex interactions between ischemic conditions and metabolic cell death pathways should be further explored. Therapeutic strategies targeting the identified genes and pathways should be developed.
Exploring key genes associated with metabolic cell death in ischemic stroke: a comprehensive analysis of single-cell, bulk transcriptome, and experimental validation · 2026 · DOIHowever, the mechanisms underlying selective crosstalk between microglial subtypes and distinct inhibitory neuronal subtypes remain unclear.
Single-cell Dissection of Microglial Heterogeneity Reveals Subtype-driven Immune-metabolic Crosstalk in Major Depressive Disorder · 2026 · DOIAlthough the precise role of neuroinflammation in the pathogenesis of AD remains incompletely elucidated, an increasing number of studies have revealed that pathological Aβ and Tau proteins are extensively involved in the neuroinflammatory process mediated by microglia activation in AD, exhibiting a complex interplay.
Involvement and Mechanisms of Aβ and Tau in the Neuroinflammatory Response of Alzheimer’s Disease · 2026 · DOIContradictory data and mechanistic evidence were assessed for every communication pathway; knowledge gaps were identified, and specific experiments were proposed to resolve these uncertainties.
Dysfunctional Crosstalk in Ischemic Stroke: Exploring Network Failure and Emerging Communication Pathways · 2026 · DOIAlthough rare and common variants in ABCA7 associated with AD alter the coding sequence and are predicted to impair protein function, the precise cell-type consequences of ABCA7 deficiency remain incompletely defined.
The Alzheimer's disease risk gene ABCA7 regulates microglial lysosomal and lipid homeostasis and promotes phagocytosis to maintain neuronal health · 2026 · DOISoluble epoxide hydrolase (sEH), which degrades anti-inflammatory epoxyeicosatrienoic acids (EETs), is elevated in the AD brain, yet how EETs restrain inflammation remains poorly understood.
Astrocytic sEH-EET signaling regulates microglial lysosomal function and suppresses the STING-Type I interferon pathway in Alzheimer's disease · 2026 · DOIInvestigate the effects of HFD exposure on other brain regions and cell types. Examine the effects of other types of dietary interventions on dentate gyrus microglia and behavior. Investigate the potential therapeutic use of minocycline in preventing HFD-induced behavioral changes in humans. Examine the effects of HFD exposure on mental health outcomes in females.
Dynamic Remodeling of Dentate Gyrus Microglia Underlies Adult Depression-Like Outcomes Following Adolescent High-Fat Diet Exposure · 2026 · DOIFurther investigation of Tis A as a natural-product-derived therapeutic lead for AD, - Evaluation of Tis A effects on other AD-related pathologies, - Investigation of the mechanisms underlying Tis A's effects on neuroinflammation and AD-related…
Tinosinenside A ameliorates Alzheimer’s disease-related pathology in APP/PS1 mice, accompanied by reduced neuroinflammation and altered microglial phenotype-associated marker expression · 2026 · DOIExtremely poor bioavailability, low water solubility, rapid hepatic metabolism, and rapid elimination of phytochemicals - Limited data from clinical trials for neurological disorders - Differences in dose, route of administration, disease models, metabolism, and pharmacokinetic profiles may limit direct extrapolation…
Dietary phytochemicals targeting neuroinflammation: mechanisms, bioavailability and translational challenges · 2026 · DOIElucidate the causal relations between the alteration of astrocytes and GFAP staining, and neural processes, - Determine the mechanisms involved in GFAP's influence on the elimination of free oxidative radicals, - Investigate the role of GFAP in transport functions and its association with enzymes, - Examine the relationship between GFAP and psychiatric diseases, such…
Investigation of repurposing drugs with anti-inflammatory properties for the treatment of epilepsy, - Study of the role of microglia-astrocyte crosstalk in neuroinflammation…
Neuroinflammation and Epilepsy: From Pathophysiology to Therapies Based on Repurposing Drugs · 2024 · DOIHuman brain organoids are constantly arising and getting closer to the human brain, but they are still scarcely recapitulating the whole complexity of the human CNS, - The 'brain-on-a-dish' approach lacks, in most cases, a proper immune system, a vasculature system, a lymphatic system…
Further comprehensive investigation to fully comprehend the pathogenesis of neuropathic pain, - The potential mechanisms that may be involved in ferroptosis, such as fluctuations in intracellular iron ion concentrations, the modulation of glutamate excitability, and lipid…
New Insight into Neuropathic Pain: The Relationship between α7nAChR, Ferroptosis, and Neuroinflammation · 2024 · DOI
Most-cited papers in Neuroinflammation and Neurodegeneration Mechanisms
- Neurotoxic reactive astrocytes are induced by activated microglia · Nature · 2017 · 7,318 citations
- Resting Microglial Cells Are Highly Dynamic Surveillants of Brain Parenchyma in Vivo · Science · 2005 · 4,944 citations
- Fate Mapping Analysis Reveals That Adult Microglia Derive from Primitive Macrophages · Science · 2010 · 4,491 citations
- Synaptic Pruning by Microglia Is Necessary for Normal Brain Development · Science · 2011 · 3,868 citations
- Complement and microglia mediate early synapse loss in Alzheimer mouse models · Science · 2016 · 3,107 citations
- Reactive astrocyte nomenclature, definitions, and future directions · Nature Neuroscience · 2021 · 2,308 citations
- Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain · Nature · 2003 · 2,267 citations
- Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain · Nature Neuroscience · 2020 · 1,400 citations
- Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease · Nature Medicine · 2020 · 1,148 citations
- Negative feedback control of neuronal activity by microglia · Nature · 2020 · 997 citations
Most recent work
- Nanoparticles hijack calvarial immune cells for CNS drug delivery and stroke therapy · Cell · 2026
- The rise of astrocytes: are they guardians or troublemakers of the brain disorder? · Experimental & Molecular Medicine · 2026
- The TREM2 agonistic antibody AL002 in early Alzheimer’s disease: a phase 2 randomized trial · Nature Medicine · 2026
- Peripheral cancer attenuates amyloid pathology in Alzheimer’s disease via cystatin-c activation of TREM2 · Cell · 2026
- Glial Cell Dynamics in Neuroinflammation: Mechanisms, Interactions, and Therapeutic Implications · Biomedicines · 2026
- Efficacy and safety of minocycline in patients with acute ischaemic stroke (EMPHASIS): a multicentre, double-blind, randomised controlled trial · The Lancet · 2026
- Decoding TREM2 Signaling Pathways · Neurology Neuroimmunology & Neuroinflammation · 2026
- Clonal CD8+ T cells populate the leptomeninges and coordinate with immune cells in human degenerative brain diseases · Nature Immunology · 2026
- cGAS-STING signaling in Alzheimer's disease: Microglial mechanisms and therapeutic opportunities · Molecular Aspects of Medicine · 2026
- The spatiotemporal dynamic evolution of post-stroke neuroinflammation: energy metabolism mechanisms of acute response and chronic progression · Frontiers in Pharmacology · 2026
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