The nervous system processes a vast amount of information, performing computations that underlie perception, cognition, and behavior. During development, neuronal guidance genes, which encode extracellular cues, their receptors, and downstream signal transducers, organize neural wiring to generate the complex architecture of the nervous system. It is now evident that many of these neuroguidance cues and their receptors are active during development and are also expressed in the adult nervous system. This suggests that neuronal guidance pathways are critical not only for neural wiring but also for ongoing function and maintenance of the mature nervous system. Supporting this view, these pathways continue to regulate synaptic connectivity, plasticity, and remodeling, and overall brain homeostasis throughout adulthood. Genetic and transcriptomic analyses have further revealed many neuronal guidance genes to be associated with a wide range of neurodegenerative and neuropsychiatric disorders. Although the precise mechanisms by which aberrant neuronal guidance signaling drives the pathogenesis of these diseases remain to be clarified, emerging evidence points to several common themes, including dysfunction in neurons, microglia, astrocytes, and endothelial cells, along with dysregulation of neuron-microglia-astrocyte, neuroimmune, and neurovascular interactions. In this review, we explore recent advances in understanding the molecular and cellular mechanisms by which aberrant neuronal guidance signaling contributes to disease pathogenesis through altered cell-cell interactions. For instance, recent studies have unveiled two distinct semaphorin-plexin signaling pathways that affect microglial activation and neuroinflammation. We discuss the challenges ahead, along with the therapeutic potentials of targeting neuronal guidance pathways for treating neurodegenerative diseases. Particular focus is placed on how neuronal guidance mechanisms control neuron-glia and neuroimmune interactions and modulate microglial function under physiological and pathological conditions. Specifically, we examine the crosstalk between neuronal guidance signaling and TREM2, a master regulator of microglial function, in the context of pathogenic protein aggregates. It is well-established that age is a major risk factor for neurodegeneration. Future research should address how aging and neuronal guidance signaling interact to influence an individual's susceptibility to various late-onset neurological diseases and how the progression of these diseases could be therapeutically blocked by targeting neuronal guidance pathways.

Neurodegenerative diseases currently represent one of the most serious health pitfalls for the world population. Considering their multifactorial nature, research has focused on the study of small molecules able to simultaneously tackle different targets involved in their onset and progression. In this paper, two sets of acylaminopyrazole-based compounds were designed to exploit the aminopyrazole core as a privileged structure properly decorated with an acyl moiety and a further amide function, connected with a proper spacer. Indeed, acylated aminopyrazoles could be able to establish the appropriate hydrogen bond pattern to both bind GSK-3β, responsible for tau hyperphosphorylation, prevent the formation of insoluble Aβ-protein aggregates and have the structural features to show chelating properties towards metals involved in neuroinflammation. The collection of compounds was tested in vitro for GSK-3β inhibition activity, antiaggregating and chelating properties. Selected compounds were able to inhibit GSK-3β in the low micromolar range with a reversible and competitive mechanism of action, as established by Microfluidic Mobility Shift Assay (MMSA) and showed metal chelating ability. Preliminary Structure Activity Relationships (SARs) to hit these distinct and interconnected targets for neuromodulation were established. Finally, selected compounds showed good apparent permeability values in parallel artificial membrane permeability assay (PAMPA) together with good cellular safety profile. The collected results validated acylaminopyrazole as promising scaffold for the development of multitarget-directed ligands. Compounds 1c and 4c emerged as promising prototypes, and deserve further optimization in the search for drug candidates for polypharmacological approach in neurodegenerative disease.

To address the multifactorial pathology of Alzheimer's disease (AD), eighteen butyrylcholinesterase (BChE) and histone deacetylase 6 (HDAC6) dual inhibitors were designed, synthesized, and biologically evaluated. Through structure-activity relationship studies, compound 17 emerged as the most potent candidate, with IC50 value of 0.3 nM for human BChE and 56.7 nM for HDAC6. This compound demonstrated favorable safety profiles, drug-like properties, and significant neuroprotective effects in vitro. In a mouse model of scopolamine-induced cognitive impairment, 17 (10 mg/kg) exhibited excellent safety and markedly improved cognitive deficits. These findings highlight compound 17 as a promising BChE/HDAC6 dual inhibitor, supporting its further development as a potential therapeutic agent for AD.

Regulated cell death (such as apoptosis, necroptosis, pyroptosis, autophagy, cuproptosis, ferroptosis, disulfidptosis) involves complex signaling pathways and molecular effectors, and has been proven to be an important regulatory mechanism for regulating neuronal aging and death. However, excessive activation of regulated cell death may lead to the progression of aging-related diseases. This review summarizes recent advances in the understanding of seven forms of regulated cell death in age-related diseases. Notably, the newly identified ferroptosis and cuproptosis have been implicated in the risk of cognitive impairment and neurodegenerative diseases. These forms of cell death exacerbate disease progression by promoting inflammation, oxidative stress, and pathological protein aggregation. The review also provides an overview of key signaling pathways and crosstalk mechanisms among these regulated cell death forms, with a focus on ferroptosis, cuproptosis, and disulfidptosis. For instance, FDX1 directly induces cuproptosis by regulating copper ion valency and dihydrolipoamide S-acetyltransferase aggregation, while copper mediates glutathione peroxidase 4 degradation, enhancing ferroptosis sensitivity. Additionally, inhibiting the Xc- transport system to prevent ferroptosis can increase disulfide formation and shift the NADP + /NADPH ratio, transitioning ferroptosis to disulfidptosis. These insights help to uncover the potential connections among these novel regulated cell death forms and differentiate them from traditional regulated cell death mechanisms. In conclusion, identifying key targets and their crosstalk points among various regulated cell death pathways may aid in developing specific biomarkers to reverse the aging clock and treat age-related neurodegenerative conditions.

The oral cavity is a complex physiological community encompassing a wide range of microorganisms. Dysbiosis of oral microbiota can lead to various oral infectious diseases, such as periodontitis and tooth decay, and even affect systemic health, including brain aging and neurodegenerative diseases. Recent studies have highlighted how oral microbes might be involved in brain aging and neurodegeneration, indicating potential avenues for intervention strategies. In this review, we summarize clinical evidence demonstrating a link between oral microbes/oral infectious diseases and brain aging/neurodegenerative diseases, and dissect potential mechanisms by which oral microbes contribute to brain aging and neurodegeneration. We also highlight advances in therapeutic development grounded in the realm of oral microbes, with the goal of advancing brain health and promoting healthy aging.

Neuroinflammation is implicated in nearly all pathological processes of central nervous system (CNS) diseases. However, no medications specifically targeting neuroinflammation are clinically available, and conventional anti-inflammatory drugs exhibit limited efficacy. Here, we identified cytochrome P450 2E1 (CYP2E1) as a novel therapeutic target in neuroinflammation. Elevated CYP2E1 levels were observed in hippocampal tissues of mouse and rat neuroinflammation models, as well as in LPS-stimulated primary microglia. Genetic ablation of Cyp2e1 improved spatial learning and memory in neuroinflammatory rats and reduced pro-inflammatory cytokine levels in Cyp2e1-deficient microglia. Furthermore, Q11 (1-(4-methyl-5-thiazolyl) ethanone), a novel CYP2E1 inhibitor developed and synthesized in our laboratory, effectively ameliorated Alzheimer's disease-related spatial learning and memory functions and depression-related anxiety-like behaviors in mice/rats. Mechanistically, Q11 attenuated microglial activation, neuronal damage, oxidative stress, and neuroinflammation by suppressing the PI3K/Akt, STAT1/3, and NF-κB signaling pathways. These findings establish CYP2E1 as a druggable target for neuroinflammation and propose Q11 as a promising candidate for treating neuroinflammation-related diseases.

Recent work leveraging artificial intelligence has offered promise to dissect disease heterogeneity by identifying complex intermediate brain phenotypes, called dimensional neuroimaging endophenotypes (DNEs). We advance the argument that these DNEs capture the degree of expression of respective neuroanatomical patterns measured, offering a dimensional neuroanatomical representation for studying disease heterogeneity and similarities of neurologic and neuropsychiatric diseases. We investigate the presence of nine DNEs derived from independent yet harmonized studies on Alzheimer's disease, autism spectrum disorder, late-life depression and schizophrenia in the UK Biobank study. Phenome-wide associations align with genome-wide associations, revealing 31 genomic loci (P < 5 × 10-8/9) associated with the nine DNEs. The nine DNEs, along with their polygenic risk scores, significantly enhanced the predictive accuracy for 14 systemic disease categories, particularly for conditions related to mental health and the central nervous system, as well as mortality outcomes. These findings underscore the potential of the nine DNEs to capture the expression of disease-related brain phenotypes in individuals of the general population and to relate such measures with genetics, lifestyle factors and chronic diseases.

With population aging, Alzheimer's disease (AD) is becoming increasingly prevalent, causing great health and economic burdens worldwide. Despite decades of research, there are still no effective disease-modifying treatments for AD, highlighting the urgent need for more in-depth understanding of the disease-causing mechanisms. The brain serotonin (5-HT) neurotransmission system undergoes structural and functional changes in aging and AD, which contributes to cognitive decline and comorbid mood disturbances. This review discusses the critical involvement of the brain 5-HT system in aging and AD. Existing findings on the changes in projection fiber innervation and receptor/transporter expression in AD are reviewed. Preclinical and clinical progress on the development of 5-HT-modulating drugs for AD and the obstacles faced by these development efforts are discussed. Epigenetic control of the brain 5-HT system and the potential of modulating 5-HT transmission via DNA methylation are also examined.

The nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, discovered 20 years ago, is crucial in controlling innate immune reactions in Alzheimer's disease (AD). By initiating the release of inflammatory molecules (including caspases, IL-1β, and IL-18), the excessively activated inflammasome complex in microglia leads to chronic inflammation and neuronal death, resulting in the progression of cognitive deficiencies. Even though the involvement of NLRP3 has been implicated in neuroinflammation and widely explored in several studies, there are plenty of controversies regarding its precise roles and activation mechanisms in AD. Another prominent feature of AD is impairment in microglial autophagy, which can be either the cause or the consequence of NLRP3 activation and contributes to the aggregation of misfolded proteins and aberrant chronic inflammatory state seen in the disease course. Studies also demonstrate that intracellular buildup of dysfunctional and damaged mitochondria due to defective mitophagy enhances inflammasome activation, further suggesting that restoration of impaired autophagy and mitophagy can effectively suppress it, thereby reducing inflammation and protecting microglia and neurons. This review is primarily focused on the role of NLRP3 inflammasome in the etiopathology of AD, its interactions with microglial autophagy/mitophagy, and the latest developments in NLRP3 inflammasome-targeted therapeutic interventions being implicated for AD treatment.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder globally, with no effective treatment available yet. A crucial pathological hallmark of AD is the accumulation of hyperphosphorylated tau protein, which is deteriorated by reactive oxygen species (ROS) and neuroinflammation in AD progression. Thus, alleviation of ROS and inflammation has become a potential therapeutic strategy in many studies. Herein, we reported ultrasmall coordination polymer nanoparticles formed by ferric ions and gallic acid (Fe-GA CPNs), which owned antioxidant and anti-inflammation properties for AD therapeutics. The facilely prepared Fe-GA CPNs exhibited remarkable superoxide dismutase-like, peroxidase-like enzyme activity, and ROS eliminating ability with great water solubility, compared with gallic acid. We demonstrated that Fe-GA CPNs effectively relieved oxidative stress, ameliorated inflammation by modulating microglial polarization towards anti-inflammation phenotype, and reduced hyperphosphorylated tau protein levels. Furthermore, Fe-GA CPNs treatment significantly improved cognitive function in tauopathy-induced AD rats, and achieved a neuroprotective effect against AD pathology. This study highlights the potential of coordination polymer nanoparticles as promising therapeutic candidates for AD and other tau-related neurodegenerative diseases.

Health span, that period between birth and onset of major disease(s), when adequate physical and cognitive function permit those daily living activities essential to life quality, is lower in the United States than other developed countries. Physical inactivity and excessive calorie intake occupy dominant roles both in the problem, and by redressing them, in the solution. Consequently, this review focuses on evidence that appropriate exercise engagement and calorie restriction (CR) can improve physical and mental health with a view to extending the health span. Humanity, writ large, has grasped these underlying concepts for Millennia but has been largely intransigent to them. Thus, the final section proposes a novel Monty Python-esque approach that encompasses humanity's inimical sense of humor to increase physical fitness and mental health, restore energy balance, sustain better cognitive function, and extend the health span.

Mitochondria, essential organelles responsible for cellular energy production, emerge as a key factor in the pathogenesis of neurodegenerative disorders. This review explores advancements in mitochondrial biology studies that highlight the pivotal connection between mitochondrial dysfunctions and neurological conditions such as Alzheimer's, Parkinson's, Huntington's, ischemic stroke, and vascular dementia. Mitochondrial DNA mutations, impaired dynamics, and disruptions in the ETC contribute to compromised energy production and heightened oxidative stress. These factors, in turn, lead to neuronal damage and cell death. Recent research has unveiled potential therapeutic strategies targeting mitochondrial dysfunction, including mitochondria targeted therapies and antioxidants. Furthermore, the identification of reliable biomarkers for assessing mitochondrial dysfunction opens new avenues for early diagnosis and monitoring of disease progression. By delving into these advancements, this review underscores the significance of understanding mitochondrial biology in unraveling the mechanisms underlying neurodegenerative disorders. It lays the groundwork for developing targeted treatments to combat these devastating neurological conditions.

Emerging evidence indicates the inhibition of neuroinflammation is an important and promising strategy for managing Alzheimer's disease. Anti-neuroinflammatory agents are potential drug leads. In this work, seventeen diterpenoids (1-17) including ten previously undescribed ones, named excoaglolides A-J (1-10) were isolated from the stems and twigs of the mangrove plant, Excoecaria agallocha L. The undescribed diterpenoids could be categorized into four subclasses, viz., ent-isopimaranes (1-4), ent-beyeranes (5-7), ent-atisanes (8-9), and ent-labdane (10). Their structures including absolute configurations were unambiguously characterized by spectroscopic methods, single crystal X-ray diffraction analyses, ECD calculations, and modified Mosher's method. Notably, compound 1 was a rare 3,4-seco-3,11-lactone-ent-isopimarane, whereas compound 2 was the first 2,3-seco-2,11-lactone-ent-isopimarane; compound 5 represents the first example of 2,3-seco-2-nor-1,3-lactone-ent-beyerane, compound 8 was the first member of 18(4 → 3)-abeo-ent-atisane forming through a Wagner-Meerwein rearrangement, compound 9 was an unusual rearranged 3,4-seco-ent-atisane possessing a cyclobutane ring, and compound 10 featuring a rare chlorine substitution at C-15. In addition, the stereochemistry of the known diterpenoid excoagallochaol D (11) with a unique 6/7/4-fused ring system was firstly determined by single crystal X-ray diffraction analyses in this study. Compounds 1, 12, 15, and 16 showed significant nitric oxide production inhibition in lipopolysaccharide-induced BV-2 microglial cells with IC50 values ranging from 2.0 to 13.5 μM. Further mechanistic investigations revealed that compound 1 inhibited macrophage polarization and decreased the expression levels of representative inflammation-related genes, including IL-1β, IL-6, TNF-α, COX-2, and iNOS. These were associated with suppressions of proteins related to inflammasome, including caspase 1 and NLRP3, and secretion of IL-1β. The present study revealed that the mangrove diterpenoid excoaglolide A (1) would be promising structure base for developing neuroinflammation-related neurodegeneration diseases.

Perioperative neurocognitive disorders (PND), common complications that occur after anesthetized surgery in elderly patients, are major challenges to our rapidly growing aging population. The transcription factor known as nuclear factor erythroid-2-related factor 2 (Nrf2) is an essential component of the cellular antioxidant response, purportedly contributing to the preservation of cognitive functions such as learning and memory. Nevertheless, the function and intracellular processes involving Nrf2 in PND remain largely unknown. Therefore, we evaluate the influence and fundamental mechanism of Nrf2 on PND in aged mice. To establish the postoperative neurocognitive dysfunction (PND) model, aged mice were subjected to anesthesia via inhalation of 3% sevoflurane for a duration of 2 h. The role of Nrf2 in PND was investigated by administering microinjections of either the adeno-associated virus (AAV)-Nrf2 vector or a null virus vector into the hippocampal CA1 region of aged mice 28 days before exposure to sevoflurane. Various assays including enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining, and western blotting were employed to assess levels of pro-inflammatory cytokines, microglial activation, and the oxidative stress response. Furthermore, synaptic plasticity was evaluated through long-term potentiation (LTP) recording and Golgi staining techniques. Elevated expression of Nrf2 within the hippocampal CA1 region ameliorated sevoflurane-induced cognitive deficits, synaptic plasticity anomalies, and the oxidative stress reaction in aged mice. Furthermore, the activation of microglia and the release of pro-inflammatory cytokines (including IL-6, TNF-α, and IL-1β) within the hippocampus post-sevoflurane exposure were modulated in an Nrf2-dependent fashion. Based on the findings from present research, we conclude that Nrf2 ameliorates sevoflurane-induced cognitive dysfunction by inhibiting hippocampal neuroinflammation, thereby proposing a potential therapeutic target for PND.

Genetic studies can offer powerful insights for the development of disease-modifying therapies for Alzheimer's disease. Protective genetic variants that delay the onset of cognitive impairment have been found in people with sporadic Alzheimer's disease and in carriers of mutations that usually cause autosomal-dominant Alzheimer's disease in mid-life. The study of families who carry autosomal dominant mutations provides a unique opportunity to uncover genetic modifiers of disease progression, including rare variants in genes such as APOE and RELN. Understanding how these variants confer protection can help identify the biological pathways that contribute to cognitive resilience, such as the heparan-sulphate proteoglycan-APOE receptor pathway, the TREM-2-driven signalling pathways in the microglia, and phagocytosis. Therapies able to replicate the beneficial effects of these natural defences could provide novel strategies for slowing or preventing the progression of Alzheimer's disease.

The detailed mycochemical exploration of the EtOAc extract of a famous edible mushroom Thelephora ganbajun, resulted in the isolation of six new p-terphenyl derivatives, named theleganbanins A - F (1-6), together with five known ones, namely atromentin (7), fendleryl B (8), 2-O-methylatromentin (9), vialinin B (10), and ganbajunin B (11). Their structures were precisely determined through comprehensive spectroscopic analyses, especially 1D and 2D NMR data and HRMS measurement. Single crystal X-ray diffraction and comparison of calculated and experimental ECD spectra were conducted to further confirm the absolute configurations of compounds 1-6. Theleganbanins A (1) and B (2) featuring a rare α, β-unsaturated-γ-butyrolactone core were proposed to be biosynthesized through aldol condensation for the first time in naturally occurring p-terphenyl derivatives. Theleganbanin C (3) was identified as a pair of p-terphenyl enantiomers with a novel 1', 6'-dyhydro-2', 5'-pyridinedione ring. Theleganbanin D (4) was the first example of p-terphenyl derivatives with a hemiacetal furanone moiety. The anti-neuroinflammatory activities of compounds 1-2 and 4-10 were screened. As a result, these compounds showed inhibitory activity on the production of pro-inflammatory cytokines TNF-α, IL-6 and IL-1β in lipopolysaccharide (LPS)-induced BV-2 microglial cells. Further investigation showed that compound 2 could inhibit the phosphorylation of JAK2/STAT3 signaling pathway. These finding indicated that p-terphenyl derivatives from edible mushroom Thelephora ganbajun Zang would be promising drug candidates in treatment of neuroinflammatory related diseases.

The histone acetyl transferases (HATs) and histone deacetylases (HDACs), which are mostly recognized for their involvement in regulating chromatin remodeling via histone acetylation/deacetylation, have been shown to also change several non-histone proteins to regulate other cellular processes. Acetylation affects the activity or function of cytokine receptors, nuclear hormone receptors, intracellular signaling molecules, and transcription factors in connection to inflammation. Some small-molecule HDAC inhibitors are utilized as anticancer medications in clinical settings due to their capability to regulate cellular growth arrest, differentiation, and death. Here, we summarize our present knowledge of the innate and adaptive immunological pathways that classical HDAC enzymes control. The aim is to justify the targeted (or non-targeted) use of inhibitors against certain HDAC enzymes in inflammatory diseases such as arthritis, inflammatory bowel diseases (IBD), airways inflammation and neurological diseases.

Alzheimer's disease (AD) represents a leading cause of dementia, characterized by progressive cognitive and functional decline. Although extensive research has unraveled critical aspects of AD pathology, its etiology remains incompletely understood, urging further exploration into potential risk factors. Growing evidence underscores a significant link between cardiovascular disease (CVD) risk factors and AD, with modifiable lifestyle elements - such as physical inactivity, high low-density lipoprotein (LDL) levels, obesity, hypertension, atherosclerosis, and diabetes - emerging as contributors to cerebrovascular damage and neurodegeneration. ADAM10, a disintegrin and metalloproteinase involved in the non-amyloidogenic processing of amyloid precursor protein (APP), has garnered interest for its dual role in cardiovascular and neurodegenerative processes. ADAM10's regulation of neuroinflammation, endothelial function, and proteolytic cleavage of APP potentially moderates amyloid-β (Aβ) peptide formation, thus influencing both cardiovascular and brain health. Given these interconnected roles, this narrative review investigates whether ADAM10-driven vascular dysfunction accelerates neurodegeneration, how lipid metabolism influences ADAM10 activity in CVD and AD, and whether targeting ADAM10 could offer a dual-benefit therapeutic strategy to mitigate disease burden. By exploring epidemiological data, clinical studies, and molecular pathways, we aim to clarify ADAM10's bridging function between AD and cardiovascular risk, offering a new perspective into therapeutic opportunities to alleviate the dual burden of these interrelated conditions.

Health damage caused by environmental arsenic pollution has attracted widespread attention, with Alzheimer's disease (AD) thought to be one of the adverse effects of long-term arsenic exposure. In this study, we sought to investigate the relationship between arsenic exposure and AD-like neurodegeneration and to determine the role of microglia in the process of AD-like neurodegeneration induced by arsenic exposure. The relationship between arsenic exposure and AD-like neurodegeneration was investigated using cognitive assessments and biological experiments. Arsenic exposure induced memory impairment in C57BL/6 mice and resulted in a significant increase in the number of Aβ+ and pTau+ cells in the entorhinal cortex and hippocampus with neuronal granular vacuolar degeneration and necroptosis, accompanied by upregulated expression of related proteins, which showed dose- and time-response relationships. Arsenic exposure intensified memory decline in FAD4T mice with accelerated AD-like neurodegeneration. Correlation analysis showed a negative correlation between memory impairment and neurodegeneration in the entorhinal cortex and hippocampus in mice. Arsenic exposure also activated microglia in the entorhinal cortex and hippocampus, with enlargement of the cytosol, shortened and thickened cell protrusions, hypertrophic changes, and abnormal proliferation, as well as upregulated expression of the pro-inflammatory cytokines TNF-α and IL-1β. Arsenic exposure induced overactivation of microglia in the entorhinal cortex and hippocampus of FAD4T mice, resulting in de-branching or bulbous protrusions and fragmented cytoplasm. Our findings suggest that arsenic exposure promotes the occurrence and development of AD-like neurodegeneration via the activation of microglia, which induces neuroinflammation in mice.

Chronic neuroinflammation, driven by central nervous system (CNS)-resident astrocytes and microglia, as well as infiltration of the peripheral immune system, is an important pathologic mechanism across a range of neurologic diseases. For decades, research focused almost exclusively on how neuroinflammation impacted neuronal function; however, there is accumulating evidence that injury to the oligodendrocyte lineage is an important component for both pathologic and clinical outcomes. While oligodendrocytes are able to undergo an endogenous repair process known as remyelination, this process becomes inefficient and usually fails in the presence of sustained inflammation. The present review focuses on our current knowledge regarding activation of the innate and adaptive immune systems in the chronic demyelinating disease, multiple sclerosis, and provides evidence that sustained neuroinflammation in other neurologic conditions, such as perinatal white matter injury, traumatic brain injury, and viral infections, converges on oligodendrocyte injury. Lastly, the therapeutic potential of targeting the impact of inflammation on the oligodendrocyte lineage in these diseases is discussed.

Medicinal plants and their phytochemicals have been extensively employed worldwide for centuries to address a diverse range of ailments, boasting a history that spans several decades. These plants are considered the source of numerous medicinal compounds. For instance, silymarin is a polyphenolic flavonoid extract obtained from the milk thistle plant or Silybum marianum which has been shown to have significant neuroprotective effects and great therapeutic benefits. Neurodegenerative diseases (NDs) are a class of neurological diseases that have become more prevalent in recent years, and although treatment is available, there is no complete cure developed yet. Silymarin utilizes a range of molecular mechanisms, including modulation of MAPK, AMPK, NF-κB, mTOR, and PI3K/Akt pathways, along with various receptors, enzymes, and growth factors. These mechanisms collectively contribute to its protective effects against NDs such as Alzheimer's disease, Parkinson's disease, and depression. Despite its safety and efficacy, silymarin faces challenges related to bioavailability and aqueous solubility, hindering its development as a clinical drug. This review highlights the molecular mechanisms underlying silymarin's neuroprotective effects, suggesting its potential as a promising therapeutic strategy for NDs.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β plaques, tau hyperphosphorylation, and neuroinflammation. The choroid plexus (ChP), serving as the blood-cerebrospinal fluid-brain barrier, plays essential roles in immune response to stress and brain homeostasis. However, the cellular and molecular contributions of the ChP to AD progression remain inadequately understood.

To elucidate the molecular abnormalities during the early stages of AD, we acquired single-cell transcription profiling of ChP from APP/PS1 mice with early-stage of Aβ pathology and litter-mate controls. The transcriptional alterations that occurred in each cell type were identified by differentially expressed genes, cell-cell communications and pseudotemporal trajectory analysis. The findings were subsequently validated by a series of in situ and in vitro assays.

We constructed a comprehensive atlas of ChP at single-cell resolution and identified six major cell types and immune subclusters in male mice. The majority of dysregulated genes were found in the epithelial cells of APP/PS1 mice in comparison to wild-type (WT) mice, and most of these genes belonged to down-regulated module involved in mitochondrial respirasome assembly, cilium organization, and barrier integrity. The disruption of the epithelial barrier resulted in the downregulation of macrophage migration inhibitory factor (MIF) secretion in APP/PS1 mice, leading to macrophage activation and increased phagocytosis of Aβ. Concurrently, ligands (e.g., APOE) secreted by macrophages and other ChP cells facilitated the entry of lipids into ependymal cells, leading to lipid accumulation and the activation of microglia in the brain parenchyma in APP/PS1 mice compared to WT controls.

Taken together, these data profiled early transcriptional and cellular abnormalities of ChP within an AD mouse model, providing novel insights of cerebral vasculature into the pathobiology of AD.

Alzheimer's disease (AD) is an incurable and irreversible type of dementia. Existing drugs cannot meet clinical needs; thus, developing new treatments is necessary. Traditional Chinese medicine (TCM) has been used in the prevention and treatment of AD. TCM holds the theory that "the kidney support brain function" and believes that dementia can be addressed from a kidney-based perspective. Kidney-tonifying herbs are a class of medicines that have the effect of tonifying the kidney and benefiting the brain. Some of these herbs have been shown to have anti-AD effects. Iridoid glycosides (IGs), which are important components of kidney-tonifying herbs, may have the potential to prevent and treat AD. However, their effects on AD have not yet been reviewed.

This literature review provides a comprehensive summary of the potential of IGs in the prevention and treatment of AD. It also sets the foundation for future studies that will make the use of such drugs in clinical practice possible.

Kidney-tonifying Chinese herbs were selected with reference to the Chinese Pharmacopoeia (2020 edition) and the textbook of Chinese Materia Medica (5th edition). Literature survey was conducted using PubMed, Web of Science, Google Scholar, and CNKI, with "Alzheimer's disease," "kidney-tonifying Chinese medicinal herbs," and "Iridoid Glycosides" as the primary keywords.

Kidney-tonifying herbal IGs include loganin, morroniside, verbenalin, cornuside, catalpol, rehmannioside A, geniposidic acid, and aucubin. These IGs have shown multiple pharmacological effects, including anti-AD effects. The effective mechanisms of IGs for AD treatment include anti-oxidative stress, inhibiting neuronal apoptosis, antagonizing amyloid neurotoxicity and tau protein hyperphosphorylation, regulating immune function, anti-inflammation, normalizing the function of the cholinergic nervous system, recuperating neurobiochemical, and regulating AD-related genes. Consequently, IGs can combat AD by modulating multiple targets and pathways.

Kidney-tonifying herbal IGs have great potential to combat AD.

The triggering receptor expressed on myeloid cells 2 (TREM2) has become a promising target for biologics in both monitoring and treating neuroinflammation in Alzheimer's disease (AD). This study aimed to develop and compare bispecific anti-TREM2 antibodies featuring different transferrin receptor (TfR) binders to enhance brain delivery, identifying the most suitable format for in vivo PET imaging of TREM2 in transgenic AD mice.

Three bispecific TREM2-antibody formats were produced and evaluated for their ability to cross the blood-brain barrier (BBB) via TfR-mediated transcytosis and bind TREM2. Blood concentration profiles up to 72 h post-injection (p.i.), and ex vivo brain uptake of iodine-125-labeled antibody constructs were quantified in AppNL-G-F and age-matched wild type (WT) mice using a γ-counter. The best-performing bispecific TREM2-antibody was radiolabeled with iodine-124 and used for in vivo PET imaging of brain TREM2 levels in AppNL-G-F mice at 72 h p.i. Brain TREM2 concentrations were subsequently quantified using ELISA.

The antibody format carrying two scFv8D3 TfR-binders (IgG-scFv2), demonstrated the highest brain concentrations of all tested bispecific constructs. This antibody also exhibited significantly higher brain concentrations in AppNL-G-F mice compared to WT mice at both 48 and 72 h p.i. This difference was further visualized and quantified through in vivo PET imaging. Moreover, brain concentrations of the antibody ligand correlated with elevated TREM2 levels in brain homogenates.

These findings highlight IgG-scFv2 as a promising radioligand for in vivo PET imaging of TREM2, advancing non-invasive neuroinflammation studies and supporting drug development for AD and other neurodegenerative diseases.

Insulin receptors are present on cells throughout the body, including the brain. Dysregulation of insulin signaling in neurons and astrocytes has been implicated in altered mood, cognition, and the pathogenesis of Alzheimer's disease (AD). To define the role of insulin signaling in microglia, the primary phagocytes in the brain critical for maintenance and damage repair, we created mice with an inducible microglia-specific insulin receptor knockout (MG-IRKO). RiboTag profiling of microglial mRNAs revealed that loss of insulin signaling results in alterations of gene expression in pathways related to innate immunity and cellular metabolism. In vitro, loss of insulin signaling in microglia results in metabolic reprogramming with an increase in glycolysis and impaired uptake of Aβ. In vivo, MG-IRKO mice exhibit alterations in mood and social behavior, and when crossed with the 5xFAD mouse model of AD, the resultant mice exhibit increased levels of Aβ plaque and elevated neuroinflammation. Thus, insulin signaling in microglia plays a key role in microglial cellular metabolism and the ability of the cells to take up Aβ, such that reduced insulin signaling in microglia alters mood and social behavior and accelerates AD pathogenesis. Together, these data indicate key roles of insulin action in microglia and the potential of targeting insulin signaling in microglia in treatment of AD.

Necroptosis is a novel mode of cell death that differs from traditional apoptosis, characterized by distinct molecular mechanisms and physiopathological features. Recent research has increasingly underscored the pivotal role of necroptosis in various neurological diseases, including stroke, Alzheimer's disease and multiple sclerosis. A defining hallmark of these conditions is neuroinflammation, a complex inflammatory response that critically influences neuronal survival. This review provides a comprehensive analysis of the mechanistic underpinnings of necroptosis and its intricate interplay with neuroinflammation, exploring the interrelationship between the two processes and their impact on neurological disorders. In addition, we discuss potential therapeutic strategies that target the intervention of necroptosis and neuroinflammation, offering novel avenues for intervention. By deepening our understanding of these interconnected processes, the development of more effective treatments approaches holds significant promise for improving patient outcomes in neurological disorders.

Alzheimer's disease (AD) is the most common form of dementia for which the role of neuroinflammation is becoming more realized. Recent studies have shown that immune cells infiltrate the hippocampus and the cortex of AD patients as well as mouse models of the disease. In this study, we employed T2-weighted magnetic resonance imaging (MRI) to view changes in ventricular volume in addition to spectral flow cytometric assessment of the hippocampus infiltrating immune profile in the aged APP/PS1 mice. Aged APP/PS1 mice present with increased size of lateral, dorsal, and ventral ventricles plus increased numbers of hippocampus infiltrating effector immune cell subsets, including CD8 T cells expressing IFNγ, granzyme B, and perforin along with other cell types such as γδ T cells, neutrophils, and NK cells. The concurrent increase in effector cell types with ventricular enlargement expands the putative mechanism of brain atrophy in the APP/PS1 mouse model to include cytolytic functions of these aforementioned immune cell subsets.

Neuroinflammation plays a complex and context-dependent role in many neurodegenerative diseases. We identified a key pathogenic function of macrophages in a mouse model of a rare human congenital neuropathy in which SARM1, the central executioner of axon degeneration, is activated by hypomorphic mutations in the axon survival factor NMNAT2. Macrophage depletion blocked and reversed neuropathic phenotypes in this sarmopathy model, revealing SARM1-dependent neuroimmune mechanisms as key drivers of disease pathogenesis. In this study, we investigated the impact of chronic subacute SARM1 activation on the peripheral nerve milieu using single cell/nucleus RNA-sequencing (sc/snRNA-seq). Our analyses reveal an expansion of immune cells (macrophages and T lymphocytes) and repair Schwann cells, as well as significant transcriptional alterations to a wide range of nerve-resident cell types. Notably, endoneurial fibroblasts show increased expression of chemokines (Ccl9, Cxcl5) and complement components (C3, C4b, C6) in response to chronic SARM1 activation, indicating enhanced immune cell recruitment and immune response regulation by non-immune nerve-resident cells. Analysis of CD45+ immune cells in sciatic nerves revealed an expansion of an Il1b+ macrophage subpopulation with increased expression of markers associated with phagocytosis and T cell activation/proliferation. We also found a significant increase in T cells in sarmopathic nerves. Remarkably, T cell depletion rescued motor phenotypes in the sarmopathy model. These findings delineate the significant changes chronic SARM1 activation induces in peripheral nerves and highlights the potential of immunomodulatory therapies for SARM1-dependent peripheral neurodegenerative disease.

In recent years, the gut microbiota has been increasingly recognized for its influence on various central nervous system diseases mediated by microglia, yet the underlying mechanisms remain unclear. As key metabolites of the gut microbiota, short-chain fatty acids (SCFAs) have emerged as a focal point in understanding microglia-related interactions. In this review, we further refine the connection between the gut microbiota and microglia by introducing the concept of the "SCFAs-microglia" pathway. We summarize current knowledge on this pathway, recent discoveries regarding its role in neurological diseases, and potential pharmacological strategies targeting it. Finally, we outlined the current challenges and limitations in this field of research. We hope this review provides new insights into the role of the gut microbiota in neuroimmune regulation.

Alzheimer's disease (AD) is a common neurodegenerative disorder that leads to cognitive decline. CaMKII is a calcium-regulated kinase that is crucial for synaptic plasticity and memory. Phytochemicals with diverse origins, safety, and biological activity have attracted considerable attention in AD research. This systematic analysis of phytochemicals targeting CaMKII reveals their neuroprotective mechanisms against AD pathogenesis, highlighting CaMKII as a promising therapeutic target that warrants further preclinical investigation and drug development. We conducted a comprehensive review of the literature of phytochemicals that target CaMKII as a protective mechanism against AD. The search was conducted across multiple databases, including PubMed, Web of Science, China National Knowledge Internet, and Google Scholar, and covered the period from January 2000 to October 2024. A total of 301 articles were retrieved, of which 22 articles were included. The results showed that flavonoid, glycoside, terpene, and polyphenol analogs positively regulated CaMKII expression, whereas alkaloid analogs negatively regulated CaMKII expression. Different components of traditional Chinese medicine played different roles in CaMKII expression. Flavonoid compounds upregulated the expression of SYN, PSD-95, MAP2, and GluR1 to exert neuroprotective effects. Alkaloid and glycoside analogs inhibited Aβ deposition and tau hyperphosphorylation. Terpene analogs upregulated the SYN, PSD-95, NMDAR, BDNF, and PI3K/Akt signaling pathways to exert neuroprotection. Polyphenol analogs upregulated PSD-95, Munc18-1, SNAP25, SYN, and BDNF to exert neuroprotective effects. Emerging evidence demonstrates that select phytochemicals and traditional Chinese medicine compounds exert neuroprotective effects in AD by modulating CaMKII activity, thereby reducing Aβ accumulation, attenuating tau hyperphosphorylation, and enhancing synaptic plasticity, suggesting promising therapeutic potential.

Memory loss, and behavioral impairments. Hallmark pathological features include amyloid-beta (Aβ) plaques, tau neurofibrillary tangles, chronic inflammation, and impaired neuronal signaling. Physical exercise is increasingly recognized as a non-pharmacological intervention to attenuate Alzheimer's disease (AD) risk and progression by enhancing neuroplasticity, improving mitochondrial function, and modulating immune responses. The let-7 family of microRNAs is critically involved in AD pathology. Elevated levels of let-7b and let-7e have been reported in the cerebrospinal fluid of AD patients, with let-7b levels correlating positively with total tau and phosphorylated tau concentrations. Overexpression of let-7a enhances Aβ-induced neurotoxicity, increases neuronal apoptosis by up to 45%, and alters autophagy-related signaling via the PI3K/Akt/mTOR pathway, as shown by 1.8-fold increases in LC3-II/I ratios and 2.2-fold upregulation of Beclin-1 expression. Exercise modulates let-7 expression in a tissue-specific and context-dependent manner. Aerobic training reduces skeletal muscle expression of let-7b-5p by 30-35%, while increasing its suppressor Lin28a by 40%, thereby improving mitochondrial respiration. Overall, modulation of let-7 by exercise influences neuronal survival, autophagy, and inflammation, offering a potential mechanism through which physical activity exerts neuroprotective effects in AD. Quantitative characterization of let-7 expression patterns may support its use as a diagnostic and therapeutic biomarker, though further research is needed to establish optimal modulation strategies.

Microglial activation has emerged as a hallmark of neuroinflammation in Alzheimer's disease (AD). Central to this process is the formation and accumulation of amyloid beta (Aβ) peptide and neurofibrillary tangles, both of which contribute to synaptic dysfunction and neuronal cell death. Aβ oligomers trigger microglial activation, leading to the release of pro-inflammatory cytokines, which further exacerbates neuroinflammation and neuronal damage. Importantly, the presence of activated microglia surrounding amyloid plaques is correlated with heightened production of cytokines such as interleukin (IL)-1β and tumor necrosis factor-alpha (TNF-α), creating a vicious cycle of inflammation. While microglia play a protective role by clearing Aβ plaques during the early stages of AD, their chronic activation can lead to detrimental outcomes, including enhanced tau pathology and neuronal apoptosis. Recent studies have highlighted the dualistic nature of microglial activation, showcasing both inflammatory (M1) and anti-inflammatory (M2) phenotypes that fluctuate based on the surrounding microenvironment. Disruption in microglial function and regulation can lead to neurovascular dysfunction, further contributing to the cognitive decline seen in AD. Moreover, emerging biomarkers and imaging techniques are unveiling the complexity of microglial responses in AD, providing avenues for targeted therapeutics aimed at modulating these cells. Understanding the intricate interplay between microglia, Aβ, and tau pathology is vital for developing potential interventions to mitigate neuroinflammation and its impact on cognitive decline in AD. This review synthesizes current findings regarding microglial activation and its implications for AD pathogenesis, offering insights into future therapeutic strategies.

Monomeric C-reactive protein (mCRP) is a pro-inflammatory molecule generated by the dissociation of native CRP. Clinical and experimental studies suggest that mCRP deposition in the brain induces Alzheimer's disease (AD) pathology and cognitive loss. Pathological neuroinflammation is increasingly suggested as relevant in AD. Innovative therapies against neuroinflammation are desperately needed, and inhibitors of the enzyme soluble epoxide hydrolase (sEH) are a promising new generation of anti-inflammatory drugs. Mouse primary microglia and BV2 cell line cultures were exposed to mCRP to analyze its pro-inflammatory mechanisms. sEH inhibitors, both newly synthesized UB-SCG-55 and UB-SCG-65, and the reference agent TPPU, were tested for their anti-inflammatory action against mCRP. Phenotypic changes were analyzed through cell imaging techniques, as well as molecular analysis of inflammatory mediators and gene activation pathways. Results show that mCRP triggers a pro-inflammatory response through three main inflammatory pathways: iNOS, NLRP3, and COX-2, followed by increased cytokine generation. Polarization of microglia toward a M1-like phenotype was confirmed by morphological analysis. Also, mCRP can bind to and cross the cell membrane, providing further insight into its mechanisms of action. sEH inhibitors were effective against mCRP induction of a reactive microglial phenotype. The first-line compound UB-SCG-55 emerged as the most potent anti-inflammatory against mCRP injury. Therefore, the direct activation of microglia by mCRP provides evidence of its role in triggering and exacerbating neurodegenerative diseases with a neuroinflammatory component, such as AD. Furthermore, the protection given by inhibitors of sEH confirms its potential as innovative drugs against deleterious effects of neuroinflammation.

Parkinson's disease (PD) is a neurodegenerative disease, and inflammation is a key factor in the progression of PD. S100A9 mediates pyroptosis and implicates in various diseases including PD. Pyroptosis, an emerging form of programmed cell death, usually causes cell rupture and death via an inflammatory response. α-Lipoic acid (α-ALA), a cellular coenzyme, participates in anti-inflammatory and antioxidant processes. Although its role in PD has been confirmed, but the exact mechanism of its anti-inflammatory effect remains unclear. In our research, we examined the potential mechanisms of pyroptosis mediated by S100A9 in PD and the neuroprotective effects of α-ALA. We used 6-hydroxydopamine (6-OHDA) to induce SH-SY5Y cells in vitro and in C57BL/6 mice in vivo. The cell viability of SH-SY5Y cells confirmed the neuroprotective effect of α-ALA. Proteomics analysis indicated that S100A9 was involved in 6-OHDA-mediated neuronal injury, while α-ALA could inhibit. We found that α-ALA ameliorated PD symptoms induced by 6-OHDA and decreased the levels of NLRP3 inflammasome, Gasdermin D, and IL-1β, which are major hallmarks of pyroptosis. Furthermore, our research demonstrated that α-ALA mitigated cell injury by suppressing NLRP3-dependent pyroptosis mediated by S100A9. In brief, pyroptosis is pivotal in PD, while α-ALA protects dopaminergic neurons by suppressing pyroptosis mediated through the NLRP3 inflammasome, directly reducing S100A9, and subsequently inhibiting the NLRP3/Gasdermin D signaling pathways. Our results collectively suggest that suppressing S100A9-mediated pyroptosis and administering α-ALA may represent a novel approach in treating of PD.

Diabetic encephalopathy (DE) is a neurological complication characterized by neuroinflammation, cognitive impairment, and memory decline, with its pathogenesis closely linked to the activation of the NLRP3 inflammasome. As a central regulator of the innate immune system, the NLRP3 inflammasome plays a pivotal role in DE progression by mediating neuroinflammation, pyroptosis, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum (ER) stress, and microglial polarization. This review systematically explores the molecular mechanisms by which the NLRP3 inflammasome contributes to DE, focusing on its role in neuroinflammatory cascades and neuronal damage, as well as the diabetes-associated physiological changes that exacerbate DE pathogenesis. Furthermore, we summarize emerging therapeutic strategies targeting the NLRP3 inflammasome, including small-molecule inhibitors and bioactive compounds derived from traditional herbal medicine, highlighting their potential for DE treatment. These findings not only advance our understanding of DE but also provide a foundation for developing NLRP3-targeted pharmacological interventions.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by amyloid beta (Aβ) deposition, phosphorylated Tau protein aggregation, inflammation, and neuronal damage. Neuronal autophagy plays an important role in ameliorating central nervous system diseases such as AD. As an emerging form of iron-dependent cell death, ferroptosis has attracted great attention in the field of neurodegenerative diseases. Berberine (BBR), a natural alkaloid, has demonstrated excellent in inflammation reduction, inhibition of Aβ production, and neuroprotection, making it a potential candidate for AD treatment. However, the mechanisms of autophagy and ferroptosis in BBR treatment of AD have not been elucidated.

This study aimed to investigate the potential of BBR in alleviating AD and evaluate its molecular mechanism through a combination of network pharmacology and biological experiments.

We assessed alterations in Aβ plaques, neurons, neuroinflammation, and autophagy-related markers in the mice brain using immunofluorescence staining. Network pharmacology and molecular docking were used to analyze the potential targets and signaling pathways of BBR in the treatment of AD. Morris Water Maze (MWM) and new object recognition (NOR) experiments were used to test the spatial memory ability of mice. In addition, we validated the relationship between JNK-P38MAPK, autophagy, ferroptosis, and BBR treatment in 5xFAD mice and A β-induced SH-SY5Y cell models.

The results of immunofluorescence staining showed that BBR effectively mitigated Aβ plaque deposition, ameliorated neuronal damage and neuroinflammation. The autophagy-related markers Beclin1 and LC3B were upregulated and P62 was downregulated after BBR treatment. The expression levels of ROS and lipid peroxide MDA decreased significantly after BBR treatment. qPCR results showed that the expression levels of ferroptosis-related genes TFR1, ASCL4, DMT1, and IREB2 were decreased, while the expression levels of FTH1 and SLC7A11 increased after BBR treatment. Behavioral experiments showed that BBR treatment enhanced spatial memory impairment in 5xFAD mice. Network pharmacological and in vitro analyses demonstrated that BBR activated autophagy and inhibited ferroptosis by inhibiting the JNK-P38MAPK signaling pathway. Following treatment with an autophagy inhibitor on SH-SY5Y cells, autophagy was markedly suppressed, and ferroptosis was induced.

In summary, we found that BBR alleviates AD by inhibiting the JNK-P38MAPK pathway to enhance autophagy and inhibit ferroptosis, further reducing Aβ plaque deposition, inhibiting inflammatory response, and improving neuronal damage.

Alzheimer's disease (AD) is the primary cause of dementia in the elderly. However, effective therapies that modify the disease process in AD remain elusive. Far-infrared radiation (FIR) is commonly utilized as a complementary treatment a range of disease, for example insomnia and rheumatoid arthritis. In this research, we explored how FIR light impacts the cognitive functions of TgCRND8 AD mice and elucidated its underlying molecular mechanism. The cognitive capabilities of TgCRND8 mice assessed by employing the Morris water maze. The concentrations of IL-1β, TNF-α, IL-4, Aβ40, and Aβ42 protein were assessed by enzyme-linked immunosorbent assay. Immunostaining was conducted to assess the Aβ deposits and microglial presence in the brains of TgCRND8 mice. Western blot was applied to detect the protein expressions of tau phosphorylation, amyloid-β (Aβ) production, Jak-2/Stat3, and Nrf-2/HO-1 pathways. The results indicated that FIR light notably ameliorated the cognitive impairments of the AD mice, reduced both Aβ deposition and tau protein hyperphosphorylation at sites of Thr205, Ser369, Ser404, and Thr181, suppressed the release of TNF-α and IL-1β, attenuated the ratios of p-Jak-2/Jak-2 and p-Stat3/Stat3, while increased the protein levels of IL-4, Nrf-2, and HO-1 in the brains of TgCRND8 mice. These findings amply demonstrated that FIR light ameliorated cognitive deficits of TgCRND8 mice via reducing both Aβ burden and tau protein hyperphosphorylation, suppressing the neuroinflammation, and restoring the levels of the oxidative-related proteins through modulating Jak-2/Stat3 and Nrf-2/HO-1 pathways. These experimental findings indicate that FIR light treatment is a promising treatment approach for AD.

Mild cognitive impairment (MCI) is primarily characterized by a gradual decline in cognitive function, where early detection and intervention are crucial to preventing Alzheimer's disease progression. This study integrates upper limb multimodal tasks (ULMTs) with functional near-infrared spectroscopy (fNIRS) to assess cognitive and motor functions in MCI patients. Thirty-seven elderly participants were categorized into healthy control (HC) and MCI groups. The experiment consisted of resting state, numerical cognitive task (NCT), motor task (MT), and ULMT phases. fNIRS measured hemodynamic responses in the prefrontal and motor cortices, while an upper limb trainer recorded motor data. Results showed weaker cortical responses in the MCI group during rest and reduced motor cortex activation during NCT. Both groups displayed increased cortical activity during ULMT compared to NCT but reduced motor performance compared to MT. These findings demonstrate the potential of ULMTs combined with fNIRS for early MCI assessment and intervention.