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.

Emerging clinical and experimental evidence highlight the involvement of gut microbiota in the onset and progression of neurodegenerative diseases such as Alzheimer's disease (AD) via neuroinflammatory processes along the gut-brain axis. Despite this, the precise mechanisms governing gut microbial involvement in AD remain elusive. In this study, we observed that AppNL-G-F AD mice raised under germ-free (GF) conditions, display a reduced amyloid-β (Aβ) pathology, accompanied by a shift in microglial cells toward a less inflammatory state and increased phagocytotic efficiency. In addition, we demonstrate that gut microbiota depletion can protect against synaptic deficits in AD mice. Notably, administering bacterial extracellular vesicles (bEVs), i.e. nano-sized particles packed with bacterial components, derived from fecal slurry from specific pathogen-free housed AppNL-G-F AD mice, reversed the effects of GF conditions on both microglial activation and Aβ plaque accumulation. These findings reveal for the first time that commensal gut microbiota-derived bEVs have a major impact on AD pathology progression.

Given emerging evidence of immune involvement in Alzheimer's disease (AD), we aimed to clarify whether peripheral lymphocyte counts are associated with regional cerebral blood flow (rCBF) as measured by brain single-photon emission computed tomography (SPECT). Identifying such a relationship may help to establish early, accessible biomarkers of disease progression.

Participants were 111 patients diagnosed with AD at the Yokohama City University Hospital Medical Center for Dementia Diseases between January 2021 and December 2023 and who underwent blood tests and brain SPECT. Sex, age, cognitive function tests, peripheral blood values, and rCBF on brain SPECT were investigated retrospectively. Neutrophil and lymphocyte counts were extracted from blood values. In addition, the rCBF in each region (frontal, parietal, temporal, occipital, and limbic system) was calculated from brain SPECT, and correlation analysis between lymphocytes and rCBF was performed.

Significant positive correlations between lymphocyte counts in peripheral blood and rCBF were found in all regions except the left frontal lobe. In particular, the correlation coefficient between rCBF and lymphocyte count was highest in the right temporal lobe (ρ = 0.311, P = 0.001).

Peripheral blood lymphocyte counts are positively related to rCBF on brain SPECT, and lymphocytes can be an early biomarker that can be tested inexpensively and easily. Limitations include the retrospective cross-sectional design and single-center setting, which preclude analysis of causality and changes over time.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, mitochondrial dysfunction, and neuroinflammation. This study evaluates the therapeutic potential of DDQ, a small molecule in the humanized Abeta knockin (hAbKI) mice that represents late-onset AD. Our findings demonstrate that DDQ treatment significantly improves cognitive performance as assessed through behavioral tests, including the rotarod, open field, Y-maze, and Morris water maze, compared to untreated hAbKI mice. At the molecular level, DDQ promoted mitochondrial biogenesis, as evidenced by enhanced expression of key proteins like PGC1α, NRF1, and TFAM. Additionally, DDQ treatment facilitated mitophagy, as indicated by elevated levels of PINK1 and Parkin, and reduced neuroinflammation, reflected by decreased Iba1 and GFAP levels. Transmission electron microscopy analysis revealed a marked improvement in mitochondrial morphology, with increased mitochondrial length and reduced mitochondrial numbers in DDQ-treated mice. Furthermore, DDQ treatment led to an increase in mitophagic vacuoles, suggesting that it effectively removes dysfunctional mitochondria. Taken together, for the first time, our study results support the potential of DDQ as a promising neuroprotective agent for late-onset AD, addressing mitochondrial dysfunction, neuroinflammation, and cognitive decline. Our study focused on developing small molecules that modulate mitophagy, mitochondrial dynamics and neuroinflammatory pathways for aging, AD and other neurodegenerative disorders.

Microglia are the resident immune cells of the central nervous system (CNS), where lipid metabolism is critical for maintaining homeostasis. In response to various external stimuli, they demonstrate a range of phenotypic expressions and lipid metabolic reprogramming. Lipid droplets (LDs) are dynamic organelles that function beyond energy storage, actively participating in neuropathological progress. Recent investigations have identified a subset of microglia characterized by the accumulation of LDs, referred to as "lipid-droplet-accumulating microglia" (LDAM). This review aims to investigate the processes involved in LD formation and degradation, the factors that modulate them, focusing particularly on the function of LDAM and their implications for CNS disorders. By synthesizing current evidence, we clarify the biological significance of LDs in these cells and their therapeutic targeting potential, providing new directions for future research.

Microglial phagocytosis genes have been linked to increased risk for Alzheimer's disease (AD), but the mechanisms translating genetic association to cellular dysfunction remain unknown. Here, we showed that microglia formed lipid droplets (LDs) upon amyloid-β (Aβ) exposure and that LD loads increased with proximity to amyloid plaques in brains from individuals with AD and the 5xFAD mouse model. LD-laden microglia exhibited defects in Aβ phagocytosis, and unbiased lipidomic analyses identified a parallel decrease in free fatty acids (FFAs) and increase in triacylglycerols (TGs) as the key metabolic transition underlying LD formation. Diacylglycerol O-acyltransferase 2 (DGAT2)-a key enzyme that converts FFAs to TGs-promoted microglial LD formation and was increased in mouse 5xFAD and human AD brains. Pharmacologically targeting DGAT2 improved microglial uptake of Aβ and reduced plaque load and neuronal damage in 5xFAD mice. These findings identify a lipid-mediated mechanism underlying microglial dysfunction that could become a therapeutic target for AD.

Sirtuin 2 (SIRT2), a NAD+-dependent deacetylase, has been implicated in aging and neurodegenerative diseases such as Alzheimer's disease (AD). While global SIRT2 inhibition has shown promise in reducing amyloid-beta pathology and cognitive deficits in different mouse models of AD, peripheral SIRT2 inhibition has been associated with adverse effects, such as increased inflammation. This suggests that targeted inhibition of specific cellular populations within the brain may represent a more precise and effective approach for the treatment of AD. To explore this hypothesis, we generated a conditional microglial SIRT2 knockout mouse model in the context of AD. Our results reveal that microglial SIRT2 reduction does not confer protective effects in the APP/PS1 model; rather, it aggravates cognitive decline, accelerates amyloid plaque deposition, and increases levels of pro-inflammatory cytokines at early stages of AD pathology. Transcriptomic analysis further indicates that SIRT2-deficient microglia exhibit altered expression of genes associated with aging and synaptic dysfunction. This phenotype was accompanied by increased phagocytosis of PSD95 and impaired long-term potentiation. These findings suggest that while SIRT2 inhibition in some contexts may be beneficial, targeted inhibition within microglia could accelerate AD progression, underscoring the need for cell-specific approaches when considering SIRT2 as a therapeutic target.

Alzheimer's disease (AD) is a progressive neurodegenerative condition that creates a significant global health challenge and profoundly affects patients and their families. Recent research has highlighted the critical role of microorganisms, particularly viral infections, in the pathogenesis of AD. The involvement of viral infections in AD pathogenesis is predominantly attributed to their ability to induce neuroinflammation and amyloid beta (Aβ) deposition in the brain. The extant research exploring the relationship between viruses and AD has focused largely on Herpesviridae family. Traces of Herpesviruses, such as Herpes Simplex Virus-1 and Epstein Barr Virus, have been found in the brains of patients with AD. These viruses are thought to contribute to the disease progression by triggering chronic inflammatory responses in the brain. They can remain dormant in the brain, and become reactivated due to stress, a secondary viral infection, or immune-senescence in older adults. This review focuses on the association between Herpesviridae and bacterial infections with AD. We explore the genetic factors that might regulate viral illness and discuss clinical trials investigating antiviral and anti-inflammatory agents as possible therapeutic strategies to mitigate cognitive decline in patients with AD. In summary, understanding the interplay between infections, genetic factors, and AD pathogenesis may pave the way for novel therapeutic approaches, facilitating better management and possibly even prevent this debilitating disease.

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.

Understanding the neurological impact of nanoplastic exposure has become an area of intensive research recently. This study examined the molecular and cellular mechanisms of how nanoplastics affect amyloid-beta (Aβ) clearance by microglia in the context of Alzheimer's disease (AD). Transmission electron microscopy and molecular dynamics simulations showed that polystyrene nanoplastics accelerated Aβ aggregation by forming a protein corona, promoting peptide fibrillization through hydrogen bonding and π-π interactions. Flow cytometry and endocytosis inhibition assays revealed that polystyrene nanoplastics impaired microglial uptake of Aβ while increasing their own cellular internalization, leading to microglial energy depletion and allowing Aβ aggregates to evade immune clearance. Additionally, proteomic analysis indicated that polystyrene nanoplastics disrupted microglial homeostasis, exacerbated neuroinflammation and metabolic dysregulation, and impaired the signalling pathway of ABC transporters critical for Aβ clearance in the AD brain. These findings suggest that nanoplastics contribute to AD pathology by impeding Aβ clearance and corrupting neuroimmune defense.

Alzheimer's Disease (AD) is an incurable and debilitating progressive, neurodegenerative disorder which is the leading cause of dementia worldwide. Neuropathologically, AD is characterized by the accumulation of Aβ amyloid plaques in the microenvironment of brain cells and neurovascular walls, chronic neuroinflammation, resulting in neuronal and synaptic loss, myelin and axonal failure, as well as significant reduction in adult hippocampal neurogenesis. The hippocampal formation is particularly vulnerable to this degenerative process, due to early dysfunction of the cholinergic circuit. Neurotrophic factors consist major regulatory molecules and their decline in AD is considered as an important cause of disease onset and progression. Novel pharmacological approaches are targeting the downstream pathways controlled by neurotrophins, such as nerve growth factor (NGF) receptors, TrkA and p75NTR, which enhance hippocampal neurogenic capacity and neuroprotective mechanisms, and potentially counteract the neurotoxic effects of amyloid deposition. BNN27 is a non-toxic, newly developed 17-spiro-steroid analog, penetrating the blood-brain-barrier (BBB) and mimicking the neuroprotective effects of NGF, acting as selective activator of its receptors, both TrkA and p75NTR, thus promoting survival of various neuronal cell types. Our present research aims at determining whether and which aspects of the AD-related pathology, BNN27 is able to alleviate, exploring the cellular and molecular AD components and link these changes with improvements in the cognitive performance of an animal AD model, the 5xFAD mice. Our results clearly indicate that BNN27 administration significantly reduced amyloid-β load in whole brain of the animals, enhanced adult hippocampal neurogenesis, restored cholinergic function and synaptogenesis, reducing inflammatory activation and leading to significant restoration of cognitive functions. BNN27 may represent a new lead multimodal molecule with neuroprotective, neurogenic and anti-neuroinflammatory actions for developing druggable anti-Alzheimeric agents. Proteomics data are available via ProteomeXchange with the identifier PXD044699.

Immunofluorescent staining is widely utilized in biomedical research. However, reliable and reproducible quantification remains challenging and often depend on the experience of the raters heavily. As a result, variations caused by different raters or the same rater at different times confound quantitative interpretations. In this study, we propose a histogram-based analytical method to explore the sources of signals at various intensities and, subsequently, identify the signals of interest using the histograms as a reference. Our method aims to alleviate inter-rater and intra-rater inconsistencies and improve the quantification of microscope images with immunofluorescent staining.•Identification of signal sources for image pixels at different intensities•Reduction of quantification variations using the proposed histogram-based analysis.

Alzheimer's disease (AD) is a neurodegenerative condition that affects memory and cognition, with a higher prevalence in women. Given the lack of effective treatment, physical activity stands out as a complementary approach to prevent or delay disease progression. While numerous studies on humans and animals indicate that aerobic exercise induces brain changes, the impact of resistance exercise (RE) on AD is not fully understood.

This study aimed to investigate the behavioral and molecular changes induced by RE in female transgenic mice with AD at the early and advanced stages of the disease.

Adult (initial phase - 7 to 8 months of age, n = 32) and adult/elderly (advanced phase - 22 to 23 months of age, n = 32) female mice (2xTg-AD) for the APPSWE/PS1dE9 mutation were subjected to a four-week RE protocol. Mobility, anxiety-like behavior, long-term memory (LTM), and depressive-like behavior were assessed. Beta-amyloid (βA) and cytokines were quantified using the ELISA technique.

There was a progressive increase in strength in both trained groups at different ages. RE reversed memory deficits only in adult AD animals and the anxiety-like behavior only in adult/elderly AD animals. RE reversed depressive-like behavior in adult and adult/elderly AD animals. RE reduced βA only in adult AD animals. RE modified the expression of several cytokines in animals in the early and advanced stage of AD.

RE can be a promising strategy to minimize the deleterious effects of AD; however, its effectiveness may be more limited to the early stages of the disease.

BackgroundNeuroinflammation actively contributes to the pathophysiology of Alzheimer's disease (AD); however, the value of neuroinflammatory biomarkers for disease-staging or predicting disease progression remains unclear.ObjectiveTo investigate diagnostic and prognostic utility of inflammatory biomarkers in combination with conventional AD biomarkers.MethodsData from 258 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) with cerebrospinal fluid (CSF) biomarkers of amyloid-β (Aβ), tau, and inflammation were analyzed. Clinically meaningful cognitive decline (CMCD) was defined as a ≥ 4-point increase on the Alzheimer's Disease Assessment Scale Cognitive Subscore 11. Predictor variables included demographics (D: age, sex, education), APOE4 status (A), inflammatory biomarkers (I), and classic AD biomarkers of Aβ and p-tau181 (C). Models incorporating inflammatory biomarkers assessed their contribution to improving baseline diagnostic classification and 1-year CMCD prediction.ResultsAt 1-year follow-up, 27.1% of participants experienced CMCD. Adding inflammatory biomarkers to models with D and A variables (DA model) improved classification of cognitively normal (CN) versus mild cognitive impairment (MCI) and CN versus Dementia (p < 0.001). Similarly, inflammatory markers enhanced classification in models including C (DAC model), for CN versus MCI (p < 0.01) and CN versus Dementia (p < 0.001). Predictive performance for CMCD was improved in individuals with MCI and dementia in both models (all p < 0.05). In addition, the DAI model outperformed the DAC model in predicting CMCD for MCI and Dementia groups (both p < 0.05).ConclusionsAddition of CSF inflammatory biomarkers to biomarkers of AD improves diagnostic accuracy of clinical disease stage at baseline and add incremental value to AD biomarkers for prediction of cognitive decline.

Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder characterized by neuronal loss leading to dementia and ultimately death. Whilst the loss of neurons is central to this disease, it is becoming clear that glia, specifically astrocytes, contribute to the onset and progression of neurodegeneration. The role of astrocytes in maintaining ion homeostasis in the extracellular milieu is fundamental for multiple brain functions, including synaptic plasticity and neuronal excitability, which are compromised during AD and affect neuronal signalling. In this study, we measured the astrocytic K+ clearance rate in the hippocampus and somatosensory cortex of a mouse model for AD during disease progression. Our results establish that astrocytic [K+]o (extracellular K+ concentration) clearance in the hippocampus is reduced in symptomatic 5xFAD mice, and this decrease is region-specific, as no significant alterations were detected in the superficial layers of the somatosensory cortex. The decrease in the [K+]o clearance rate correlated with a significant reduction in the expression and conductivity of Kir4.1 channels and a decline in the number of primary connected astrocytes. Moreover, astrocytes in the hippocampus of symptomatic 5xFAD mice demonstrated increased reactivity which was accompanied by an increased excitability and altered spiking profile of nearby neurons. These findings indicate that the supportive function astrocytes typically provide to nearby neurons is diminished during disease progression, which affects the neuronal circuit signalling in this area and provides a potential explanation for the increased vulnerability of neurons in AD. KEY POINTS: Astrocytic potassium clearance from the extracellular milleu is fundamental for multiple brain functions. Alterations in the clearance rate can affect the excitability and overall viability of neurons. A symptomatic mouse model for Alzheimer's disease (5xFAD) exhibits a significant decline in astrocytic K+ clearance at the hippocampus, but not the somatosensory cortex. The decrease in the clearance rate correlated with a reduction in the expression and conductivity of astrocytic Kir4.1 channels and a decrease in the number of primary connected astrocytes, specifically at the stratum lacunosum moleculare layer of the CA1 region. Astrocytes in the hippocampus of symptomatic 5xFAD mice displayed increased reactivity. The excitability profile and firing patterns of neurons at the hippocampus were affected by alterations in K+ homeostasis, indicating that the supportive function astrocytes typically provide to nearby neurons is diminished during progression of Alzheimer's disease.

Mitochondria, as central regulators of cellular processes such as energy production, apoptosis, and metabolic homeostasis, are essential to cellular function and health. The maintenance of mitochondrial integrity, especially through mitophagy-the selective removal of impaired mitochondria-is crucial for cellular homeostasis. Dysregulation of mitochondrial function, dynamics, and biogenesis is linked to neurodegenerative and metabolic diseases, notably Alzheimer's disease (AD), which is increasingly recognized as a metabolic disorder due to its shared pathophysiologic features: insulin resistance, oxidative stress, and chronic inflammation. In this review, we highlight recent advancements in pharmacological interventions, focusing on agents that modulate mitophagy, mitochondrial uncouplers that reduce oxidative phosphorylation, compounds that directly scavenge reactive oxygen species to alleviate oxidative stress, and molecules that ameliorate amyloid beta plaque accumulation and phosphorylated tau pathology. Additionally, we explore dietary and lifestyle interventions-MIND and ketogenic diets, caloric restriction, physical activity, hormone modulation, and stress management-that complement pharmacological approaches and support mitochondrial health. Our review underscores mitochondria's central role in the pathogenesis and potential treatment of neurodegenerative and metabolic diseases, particularly AD. By advocating for an integrated therapeutic model that combines pharmacological and lifestyle interventions, we propose a comprehensive approach aimed at mitigating mitochondrial dysfunction and improving clinical outcomes in these complex, interrelated diseases.

Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela of neuroinflammation includes the pathologic hyperphosphorylation of tau protein, an endogenous microtubule-associated protein that protects the integrity of neuronal cytoskeletons. Tau hyperphosphorylation results in protein misfolding and subsequent accumulation of tau tangles forming neurotoxic aggregates. These misfolded proteins are characteristic of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease and can lead to downstream neuroinflammatory processes, including assembly and activation of the inflammasome complex. Inflammasomes refer to a family of multimeric protein units that, upon activation, release a cascade of signaling molecules resulting in caspase-induced cell death and inflammation mediated by the release of interleukin-1β cytokine. One specific inflammasome, the NOD-like receptor protein 3, has been proposed to be a key regulator of tau phosphorylation where it has been shown that prolonged NOD-like receptor protein 3 activation acts as a causal factor in pathological tau accumulation and spreading. This review begins by describing the epidemiology and pathophysiology of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease. Next, we highlight neuroinflammation as an overriding theme and discuss the role of the NOD-like receptor protein 3 inflammasome in the formation of tau deposits and how such tauopathic entities spread throughout the brain. We then propose a novel framework linking traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease as inflammasome-dependent pathologies that exist along a temporal continuum. Finally, we discuss potential therapeutic targets that may intercept this pathway and ultimately minimize long-term neurological decline.

Traumatic brain injury (TBI) triggers a complex neuroinflammatory cascade, with microglia serving as key regulators of both pathological damage and tissue structural restoration. Despite extensive research, the precise temporal evolution of microglial activation and its implications for long-term neurological outcomes remain incompletely understood. Here, we provide a comprehensive review of the molecular and cellular mechanisms underlying microglial responses in TBI, highlighting their role in neuroinflammation, neurogenesis, and tissue remodeling. We systematically compare clinical and preclinical TBI classifications, lesion patterns, and animal modeling strategies, evaluating their translational relevance. Furthermore, we explore the limitations of the conventional M1/M2 dichotomy and emphasize recent insights from single-cell transcriptomic analyses that reveal distinct microglial subpopulations across different injury phases. Finally, we discuss current therapeutic strategies targeting microglial modulation and propose future directions for neuroimmune interventions in TBI. By integrating findings from experimental and clinical studies, this review aims to bridge mechanistic insights with therapeutic advancements, paving the way for precision-targeted neuroimmune therapies.

BackgroundThe involvement of microglia is likely to be pivotal in the pathogenesis of Alzheimer's disease (AD) by modulating the deposition of amyloid-β (Aβ) plaques. The deletion of Dedicator of cytokinesis 8 (DOCK8) has a protective effect in mouse with neurodegenerative diseases.ObjectiveTo explore the underlying mechanism of DOCK8 in AD.MethodsIn present study, we first the detected the expression of DOCK8 in the hippocampal tissue of APP/PS1 mice. Then, the expression of DOCK8 was knocked down in the hippocampal tissue of APP/PS1 mice, and the effects of DOCK8 down-regulation on cognitive function, the microglia migration around Aβ plaques, and the cell division cycle 42 (Cdc42)/p38 mitogen-activated protein kinase (MAPK) signaling pathway were detected. Next, the effects of DOCK8 knockdown on Aβ-induced migration and activation of BV-2 cells as well as the MAPK signaling pathway were detected. Finally, the transcriptional regulation of DOCK by transcription factor 3 (ATF3) was detected by a dual luciferase reporter assay.ResultsDOCK8 expression exerts a significant upregulation in the hippocampus of APP/PS1 mice. However, following the DOCK8 knockdown, there was a significant recovery in the results of the behavioral tests and a notable reduction in microglial expression. Moreover, the high expression of DOCK8 mediated by ATF3 successfully triggered the Cdc42/p38 MAPK signaling pathway, thereby enhancing the migration and recruitment of microglia towards senile plaques, accelerating the production of Aβ plaques.ConclusionsATF3-mediated high expression of DOCK8 accelerates the production of Aβ plaques, and participates in the pathogenesis of AD.

Neuroinflammation is associated with both early and late stages of the pathophysiology of Alzheimer's disease (AD). Fluid biomarkers are gaining significance in clinical practice for diagnosis in presymptomatic stages, monitoring, and disease prognosis. This systematic literature review (SLR) aimed to identify fluid biomarkers for neuroinflammation related to clinical stages across the AD continuum and examined long-term outcomes associated with changes in biomarkers.

The SLR was conducted per the Cochrane Handbook for Systematic Reviews of Interventions and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We used PubMed®, Embase®, and Cochrane Collaboration databases to search for articles in English (between 2012 and 2022) on AD or mild cognitive impairment due to AD, using "neuroinflammation" or other "immune" search strings. Two independent reviewers screened titles and examined data from full-text articles for the SLR.

After the initial screening, 54 studies were prioritized for data extraction based upon their relevance to the SLR research questions. Nine studies for YKL-40, seven studies for sTREM2, and 11 studies for GFAP examined the relationship between the neuroinflammatory biomarkers and the clinical stage of the disease. Nine longitudinal studies further explored the association of fluid biomarkers with long-term clinical outcomes of disease. Cerebrospinal fluid (CSF) levels of YKL-40 were elevated in patients with AD dementia, while CSF sTREM2 levels were more strongly associated with preclinical and early symptomatic stages of AD. Plasma GFAP levels remained consistently elevated both in patients with AD dementia and individuals in preclinical stages with β-amyloid pathology. Longitudinal changes in plasma GFAP appeared to be predictive of cognitive decline in patients over time.

Neuroinflammatory biomarkers are associated with AD progression. More longitudinal studies in the preclinical and MCI stages of AD are needed to validate fluid biomarkers for diagnosis, disease monitoring, and prognosis in clinical practice.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, accounting for ≈60-70% of all dementia cases worldwide. Microglial-mediated brain inflammation is thought to play key roles in AD progression. Clinical evidence and animal models have indicated that the ribosome-associated quality control (RQC) component Listerin is involved in the development of AD. How Listerin regulates the development and progression of AD is unknown. Here, it is demonstrated that Listerin can decrease brain inflammation and alleviate AD-related cognitive impairments. Microglial-specific knockout of Listerin exhibits deteriorative cognitive symptoms based on the extracellular Amyloid-β (Aβ) or Lipopolysaccharide (LPS) injection. Mechanistically, Listerin directly binds to Toll-like receptor 4 (TLR4) mRNA and facilitates the IRE1α-mediated cleavage and degradation of TLR4 mRNA, leading to the alleviation of TLR4-induced brain inflammation. Adenovirus-mediated overexpression of Listerin decelerates the disease progression in the mouse model of Aβ-mediated neurodegeneration. Thus, Listerin is an important suppressor of microglia-induced brain inflammation and may be a potential therapeutic target for AD treatment.

The hippocampus is highly affected in neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). The relationship between neuropathology and atrophy in hippocampal subfields is complex due to differences in the selective neuronal vulnerability to distinct protein aggregates that underlie cognitive impairment. The aim of the current study was to investigate the relation between hippocampal subfield volumes, neuropathological burden (amyloid-β, p-tau and α-synuclein) and cognitive performance in AD, PD and control brain donors, using a cross-disease and within-subject post-mortem in situ MRI and neuropathology approach.

A total of 60 brain donors, including 14 non-neurological controls, 27 AD and 19 PD, underwent post-mortem in situ MRI. From 3D-T1 images hippocampal subfield and entorhinal cortex volumes were derived using FreeSurfer-based subfield segmentation. Hippocampal tissue was obtained at subsequent autopsy, fixed and immunostained for amyloid-β, p-tau and pSer129-αSyn. Immunoreactivity in hippocampal subfields was quantified as area% load using QuPath. Clinical Dementia Rating scores were extracted from the clinical files when available.

AD showed atrophy and increased p-tau, but not amyloid-β, burden in the CA1, subiculum and entorhinal cortex compared to controls, however MRI and neuropathology did not correlate. Controls and PD had similar hippocampal subfield volumes and pathology load. In PD, p-tau pathology, rather than pSer129-αSyn, was associated with lower total hippocampal volume (r=-0.68, p = 0.045), predominantly in PD with dementia (PDD) (r=-0.99, p = 0.013). Cross-disease, volume loss of the subiculum (r=-0.68, p = 0.001) and entorhinal cortex (r=-0.73, p = 0.004) strongly associated with cognitive impairment. Moreover, p-tau pathology had the strongest effect on subfield atrophy, most pronounced in the subiculum (β=-0.570, p < 0.001), but could only explain 22-44% of the volumetric variance.

Even though p-tau was the strongest predictor of hippocampal subfield atrophy, AD-pathology (p-tau and amyloid-β) only partially accounted for volumetric differences in hippocampal subfields, highlighting the significance of other pathologies or mechanisms. The increased sensitivity of subicular and entorhinal cortical atrophy compared to total hippocampal atrophy highlights the potential clinical value of incorporating hippocampal subfield atrophy in monitoring disease progression.

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.

Aging is a multifactorial biological process characterized by the irreversible accumulation of molecular damage, leading to an increased risk of age-related diseases. With the global prominent rise in aging populations, elucidating the mechanisms underlying the aging process and developing strategies to combat age-related diseases have become a pressing priority. Extracellular vesicles (EVs) have gained significant attention due to their role in intercellular communication. EVs are known for their ability to deliver biocargoes, such as miRNA, proteins, and lipids, implicating their involvement in disease pathogenesis and intervention. In this review article, we explore the dual role of EVs in age-related diseases: contributing to the pathogenesis of diseases by transferring deleterious molecules, while also offering therapeutic ability by transferring beneficial molecules. We also highlight the application of EVs as biomarkers for early diagnosis of age-related diseases, paving the way for early intervention and precision medicine. Additionally, we discuss how analysing the composition of EVs cargo can provide insights into disease progression. Finally, we address the challenges and future perspectives of EV-based-therapy in clinical translation, including standardization of EVs isolation methods and improving cargo specificity.

Alzheimer's disease (AD), the most common cause of dementia, affects twice as many women as men. Moreover, sex is increasingly recognised as an important factor for AD, influencing symptom presentation, progression, disease biology, and treatment responses. In parallel, AD biomarkers are becoming more accessible with the discovery of specific and accurate blood-based biomarkers and their incorporation in AD diagnostic frameworks. This narrative review aimed to summarise sex differences in the concentration and interpretation of biofluid biomarkers for AD.

Biological sex may influence both the concentration and interpretation of biofluid biomarkers for AD pathology such as amyloid-β aggregation, tau neurofibrillary tangles, neurodegeneration, or neuroinflammation. While some biofluid biomarkers display consistent sex differences in absolute levels, most biomarker levels have not been found to differ consistently by sex. Nonetheless, even biomarkers that do not differ in absolute levels display sex-specific associations with clinically relevant variables such as brain atrophy, cognitive impairment, and disease progression.

Sex may influence the interpretation of AD biomarkers depending on their context of use, and more research is required to develop sex-specific guidelines. Future research should aim to study sex differences and sex-specific associations with variables of interest, as well as the underlying factors driving sex differences in AD.

Alzheimer's disease (AD) is a growing neurological disorder giving impact cognition and memory, posing a global health challenge with over 55 million individuals affected. It is the 7th foremost cause of dying worldwide, and its pervasiveness is expected to twofold in each five years, reaching 115 million by 2050. AD is characterized by neurofibrillary tangles, senile plaques, and oxidative stress, leading to synaptic failure and cognitive decline. Currently, there is no cure, and available FDA-approved drugs provide only symptomatic relief. The disease progresses through five phases- mild cognitive impairment (MCI), very severe, severe, moderate and mild AD. Research on AD focuses on various neurodegenerative pathways, including inflammation, oxidative stress, genetic factors, environmental variables, and amyloid-beta accumulation. Existing FDA-accepted drugs, like rivastigmine, memantine, galantamine, and donepezil, primarily address early symptoms but have limitations, including side effects and high costs. In this context, phytochemicals from plants, such as resveratrol, huperzine, quercetin, galantamine, and rosmarinic acid, show promise as potential treatments for AD and overcome the challenges and limitation of conventional treatment. These natural substances are being investigated for their ability to lower the risk of AD safely. However, there is a lack of comprehensive knowledge about their application, necessitating further research and clinical trials to explore their potential benefits and limitations. This review serves as an essential reference for advancing future studies on Alzheimer's disease. By thoroughly analyzing neurodegenerative pathways, addressing drug limitations, and highlighting the potential of phytochemicals, we establish a strong foundation for developing innovative therapeutic strategies. Closing the knowledge gap related to the use of phytochemicals in Alzheimer's management is not just important; it is critical for creating novel and more effective treatments for this challenging neurological condition.

Age-related macular degeneration (AMD) and Alzheimer's disease (AD), two prevalent neurodegenerative disorders, share overlapping pathophysiological features yet lack cross-disease therapeutic strategies. This study systematically investigates their parallel genes and shared molecular mechanisms to identify potential therapeutic targets for dry AMD, a condition with limited treatment options.

Transcriptomic datasets for AMD (GSE155154) and AD (GSE95587) were retrieved from the GEO database. AMD tissues were stratified into four subgroups: macular retina (MR), macular choroid/RPE/sclera (MCRS), peripheral retina (PR), and peripheral choroid/RPE/sclera (PCRS). Common differentially expressed genes (DEGs) were identified and analyzed via functional enrichment (GO, KEGG), gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) networks. Drug-gene interactions and competing endogenous RNA (ceRNA) networks were constructed to prioritize therapeutic targets. Key hub genes were experimentally validated in a sodium iodate-induced AMD murine model using RT-qPCR.

Comparative analysis revealed 89, 56, 4, and 130 common DEGs between AD and MR, MCRS, PR, and PCRS subgroups, respectively. Neuroactive ligand-receptor interactions were prioritized in MR/MCRS-AD analyses, while extracellular matrix organization emerged as the dominant pathway in PCRS-AD comparisons. GSEA identified conserved the TNFα signaling pathway via NF-κB across both diseases. PCRS exhibited consistent expression trends for shared genes and pathways with AD. Computational screening prioritized seven druggable targets (COL1A1, COL1A2, COL3A1, MMP2, MMP9, VCAN, ITGA5) with dual therapeutic potential, along with a reconstructed circRNA (circRNA_002179)-miRNA (miR-124)-mRNA (VCAN) regulatory axis. Experimental validation in a sodium iodate-induced AMD murine model confirmed region-specific dysregulation: hub genes were significantly downregulated in MCRS but upregulated in PCRS.

Our study delineates both convergent and divergent molecular landscapes of AMD and AD, with PCRS emerging as a critical locus for shared pathophysiology. These findings bridge a critical gap in understanding AMD-AD comorbidity, offering actionable strategies for targeted drug development.

Treatment-resistant depression (TRD) presents substantial clinical challenges, particularly in patients with Alzheimer's disease (AD) and older adults experiencing late-life depression. Traditional monoaminergic therapies often fail in this population due to neurodegenerative changes that impact receptor dynamics and neurotransmitter systems. Emerging evidence suggests that N-methyl-D-aspartate (NMDA) receptor antagonists, such as ketamine, esketamine, and arketamine, may offer new avenues for treatment. This review examines the potential of ketamine and its derivatives in treating TRD in older adults and individuals with AD, focusing on their mechanisms of action, clinical efficacy, and limitations in the context of neurodegenerative pathology. Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we conducted a systematic search of PubMed, Google Scholar, and Web of Science databases up until January 2025, with no year restrictions. Nineteen human clinical studies and eight preclinical studies met the inclusion criteria. Evidence suggests that ketamine may offer advantages over standard treatments for AD, potentially due to its broader mechanism of action compared to the NMDA antagonist memantine, as observed in animal models of AD. Clinical findings have demonstrated the rapid and robust antidepressant effects of ketamine and esketamine, alleviating depressive symptoms in both AD patients and older adults with TRD, indicating their potential as effective therapeutic options for these complex conditions.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by amyloid-beta (Aβ) accumulation and neuroinflammation. A previous multicenter, phase 2, double-blind, placebo-controlled trial randomized 179 participants into placebo or resveratrol over 52 weeks. Sub-analysis of CSF biomarkers of neuronal damage, inflammation, and microglial activity was performed in a subset of patients treated with a placebo (n = 21) versus resveratrol (n = 30). Markers of neuronal damage, including neuron-specific enolase and hyperphosphorylated neurofilaments, were reduced. Microglial activation was measured via a triggering receptor expressed on myeloid cells (TREM)-2 at baseline and after resveratrol treatment. Resveratrol significantly reduced CSF TREM2 levels and decreased inflammation and tissue damage, including matrix metalloprotease (MMP)-9. Cathepsin D, a lysosomal marker of autophagy, was reduced in the resveratrol group compared with placebo, while angiogenin, a marker of vascular angiogenesis, was increased. These data suggest that resveratrol may exert anti-inflammatory and neuroprotective effects in AD by reducing CSF TREM2 and other markers of neuronal damage. Further research is needed to assess the significance of these biomarker changes on clinical outcomes in patients with neurodegenerative diseases.

Alzheimer's disease is a neurodegenerative disorder characterized by two hallmarks: amyloid beta plaques and neurofibrillary tangles. The receptor for advanced glycation end products (RAGE) is a multi-ligand receptor involved in the pathophysiology of various diseases including cancer, diabetes, cardiovascular diseases, and Alzheimer's disease (AD). Therefore, targeting RAGE could be an effective strategy to block RAGE signaling pathways. The present study aims to identify potential RAGE inhibitors against AD through comprehensive in-silico approaches. A total of 708,580 compounds were screened from numerous databases using structure-based virtual screening and ADMET evaluation. Further, the molecules with good glide scores were assessed by molecular docking studies. Subsequently, the top six ligands were subjected to molecular dynamic (MD) simulations for 100 ns and binding free energy calculations to check their stability with RAGE (PDB: 6XQ3). The per-residue decomposition analysis revealed that specific residues namely, GLY_20, ALA_21, LYS_39, GLU_50, LYS_52, ARG_98, GLN_100, LYS_110, ASN_112, and ARG_198 played a key role in the binding process. Furthermore, the trajectory analysis (DCCM and PCA) analyzed the dominant motions of residues and predicted the stability of protein-ligand complexes. In conclusion, the Hit-6 compound could be a promising candidate for targeting RAGE and deserves further consideration as an anti-Alzheimer drug.

Alzheimer's disease (AD) is a progressive and neurodegenerative disease, predominantly causing dementia. Despite increasing clinical evidence suggesting the involvement of peripheral immune cells such as monocytes in AD pathology, the dynamic penetration and infiltration of monocytes crossing blood-brain barrier (BBB) and inducing neuroinflammation is largely understudied in an AD brain. Herein, we engineer BBB-like microphysiological system (BBB-MPS) models for recapitulating the dynamic penetration and infiltration of monocytes in an AD patient's brain. Each BBB-MPS model can be engineered by integrating a functional BBB-like structure on a human cortical organoid using a 3D-printed device within a well of a plate. By coculturing these BBB-MPS models with monocytes from AD patients and age-matched healthy donors, we found that AD monocytes exhibit significantly greater BBB penetration and brain infiltration compared to age-matched control monocytes. Moreover, we also tested the interventions including Minocycline and Bindarit, and found they can effectively inhibit AD monocyte infiltration, subsequently reducing neuroinflammation and neuronal apoptosis. We believe these scalable and user-friendly BBB-MPS models may hold promising potential in modeling and advancing therapeutics for neurodegenerative and neuroinflammatory diseases.

To investigate interleukin (IL)-34 and colony-stimulating factor (CSF)-1 levels in saliva, cerebrospinal fluid, and plasma in different stages of cognitive impairment. The study also examines the relationship between these biomarkers and periodontal status across different stages of cognitive impairment.

A total of 230 individuals diagnosed with Alzheimer's disease (AD, n = 52), mild cognitive impairment (MCI, n = 51), subjective cognitive impairment (SCI, n = 51), and controls (n = 76) were enrolled. Participants underwent clinical and radiological oral examinations. Cerebrospinal fluid samples were collected from all groups except controls. Stimulated saliva and blood were collected during oral examination. IL-34 and CSF-1 levels were assessed using enzyme-linked immunosorbent assays.

Salivary IL-34 levels were increased in AD compared to SCI (p = 0.010) and controls (p < 0.001), and in MCI compared to controls (p < 0.001). Elevated salivary CSF-1 levels were observed in AD compared to SCI (p = 0.003). Salivary IL-34 was inversely associated with Mini-Mental State Examination (MMSE) scores (p < 0.010) and body mass index (p = 0.040), while CSF-1 was associated with age (p = 0.015). IL-34 and CSF-1 levels did not differ in cerebrospinal fluid between groups, and periodontal status did not affect the levels in any biofluid measured.

Salivary IL-34 is increased in AD patients and is associated with MMSE scores.

Identifying reliable biomarkers for AD is crucial for early detection and intervention. This study suggests that salivary IL-34 could serve as a potential biomarker for AD.

Alzheimer's disease (AD) has significant public health concerns in the aging society. AD can compromise brain function and lead to severe neurological abnormalities associated with dementia. The human Apolipoprotein E (ApoE4) gene is a strong risk factor for AD. However, comprehensive analyses and improvements of mouse models expressing ApoE4 remain largely unexplored.

ApoE4 knock-in (KI) mice were used to investigate the role of humanized ApoE4 in hippocampal histological changes and cognitive impairment. Cerebrovascular perfusion, blood-brain barrier (BBB) integrity, microgliosis, and amyloid-beta 42 (Aβ42) accumulation were examined. Cognitive functions were assessed using the Morris water maze, Y-maze, and novel object recognition tests. Mirodenafil, a potent and selective phosphodiesterase 5 inhibitor (PDE5i), was orally administered to ApoE4 KI mice for 4 weeks. An in vitro BBB model and BV2 microglial cells were used to investigate endothelial permeability and inflammation.

ApoE4 KI mice exhibited not only reduced cerebrovascular perfusion and CLN-5 expression but also increased microgliosis and Aβ42 accumulation in the hippocampus. These phenomena were accompanied by impaired cognitive functions. Mirodenafil administration reversed the histological and behavioral alterations induced by ApoE4 KI. In vitro, mirodenafil treatment mitigated Aβ42-induced endothelial permeability and lipopolysaccharide-induced microglial inflammation.

These findings suggest that mirodenafil enhances cerebrovascular function, preserves BBB integrity, and mitigates neuroinflammation in ApoE4 KI mice, leading to cognitive improvement. PDE5 inhibition may serve as a promising therapeutic approach for addressing ApoE4-associated cerebrovascular and cognitive dysfunction.

Laryngeal dystonia (LD) is an isolated focal dystonia causing involuntary spasms in the laryngeal muscles that selectively impair speech production. LD is characterized as a functional and structural neural network disorder; however, the mechanistic aspects of network dysfunction in dystonia remain unknown.

We hypothesized that iron-induced abnormal metabolic processes may underlie microstructural neuronal damage, contributing to altered neural activity within the dystonic network and, subsequently, the development of the dystonic state.

We used 7 Tesla magnetic resonance imaging (MRI) at ultra-high field resolution for quantitative susceptibility mapping (QSM) of iron content, multi-echo multi-band resting-state functional MRI (fMRI) of brain activity and functional connectivity, positron emission tomography with [11C]flumazenil radioligand of GABAA neuroreceptor availability, and immunohistochemistry of postmortem brain tissue to investigate iron metabolism in LD patients and healthy controls.

The QSM analysis found increased iron content in primary sensorimotor and premotor cortices, inferior frontal, middle frontal, and middle temporal gyri, middle cingulate cortex, superior and inferior parietal lobules, insula, putamen, and cerebellum. Histopathology substantiated the neuroimaging findings by showing focal clusters of iron precipitates in these regions. Increased iron content in the supplementary motor area and middle cingulate cortex was associated with altered neural activity, while increased iron in the middle cingulate cortex, premotor cortex, and putamen had associations with GABAA receptor availability in LD patients.

Abnormal iron accumulations are likely to contribute to the imbalance of excitatory and inhibitory signaling within the dystonic neural network, leading to altered network dynamics that ultimately contribute to LD development. © 2025 International Parkinson and Movement Disorder Society.

Background/Objectives: Lipoxins, particularly Lipoxin A4 (LXA4), are endogenous lipid mediators with potent anti-inflammatory and pro-resolving properties, making them promising candidates for the treatment of inflammatory and neurodegenerative disorders. However, their therapeutic application is limited by poor stability and bioavailability. This study aimed to develop and characterize nanomicelles encapsulating LXA4 (nano-lipoxin A4) to improve its pharmacological efficacy against Alzheimer's disease (AD), a neurodegenerative condition marked by chronic inflammation and beta-amyloid (Aβ) accumulation. Methods: Nano-lipoxin A4 was synthesized using Pluronic F-127 as a carrier and characterized in terms of morphology, physicochemical stability, and in vitro activity against Aβ fibrils. Dissociation of Aβ fibrils was assessed via Thioflavin-T fluorescence assays and transmission electron microscopy. In vivo biodistribution and pharmacokinetic profiles were evaluated using technetium-99m-labeled nano-lipoxin A4 in rodent models. Hepatic biochemical parameters were also measured to assess potential systemic effects. Results: In vitro studies demonstrated that nano-lipoxin A4 effectively dissociated Aβ fibrils at concentrations of 50 nM and 112 nM. Electron microscopy confirmed the disruption of fibrillar structures. In vivo imaging revealed predominant accumulation in the liver and spleen, consistent with reticuloendothelial system uptake. Pharmacokinetic analysis showed a prolonged half-life (63.95 h) and low clearance rate (0.001509 L/h), indicating sustained systemic presence. Biochemical assays revealed elevated liver enzyme levels, suggestive of increased hepatic metabolism or potential hepatotoxicity. Conclusions: Nano-lipoxin A4 exhibits significant therapeutic potential for Alzheimer's disease through effective modulation of Aβ pathology and favorable pharmacokinetic characteristics. However, the elevation in liver enzymes necessitates further investigation into systemic safety to support clinical translation.

Neuroinflammation plays a crucial role in Alzheimer's disease (AD) pathogenesis. We investigated the relationship between cerebrospinal fluid (CSF) C-C chemokine ligand 25 (CCL25), an inflammatory regulator, and AD pathology and progression. We analyzed data on CSF CCL25, AD biomarkers (CSF β-amyloid [Aβ]42, phosphorylated tau [pTau]181, amyloid positron emission tomography [PET]), postmortem neuropathology, magnetic resonance imaging-based neurodegeneration, and cognitive function from 703 participants in the Alzheimer's Disease Neuroimaging Initiative cohort. We found that elevated CSF CCL25 levels were associated with cognitive impairment, abnormal Aβ and tau pathology, greater brain atrophy, and worse cognitive performance (all P < 0.05). Notably, CSF CCL25 exhibited nonlinear relationships with Aβ and tau pathology, reaching a plateau as AD pathology increased. CSF CCL25 showed acceptable diagnostic accuracy in distinguishing amyloid-positive/negative (A ±) and tau-positive/negative (T ±) participants (area under the curve [AUC] = 0.71-0.77) and autopsy-confirmed AD cases (AUC = 0.77), with optimal performance in differentiating A + T + from A-T- participants (AUC = 0.82-0.85 with age and sex adjustment). Longitudinally, higher baseline CSF CCL25 predicted accelerated amyloid accumulation, hippocampal atrophy, and cognitive decline. Mediation analyses revealed that CCL25 partially mediated associations between Aβ pathology and tau pathology (mediating effect: 54.5%), neurodegeneration (18.2%), and cognitive decline (7.4%). Among 37 CSF CCL and CXCL chemokines examined, 28 were associated with at least one AD-related outcome, with CCL25 demonstrating the strongest associations overall. These findings suggest that CSF CCL25 is involved in early AD pathological progression and may serve as an inflammatory biomarker for diagnosis and monitoring of disease progression in AD.

Alzheimer's disease, the most common form of dementia, is characterized by age-dependent amyloid beta (Ab) aggregation and accumulation, neuroinflammation, and cognitive deficits. Significantly, there are prominent sex differences in the risk, onset, progression, and severity of AD, as well as response to therapies, with disease burden disproportionately affecting women. Although menopause onset (i.e., perimenopause) may be a critical transition stage for AD susceptibility in women, the role of early ovarian decline in initial disease pathology, particularly key neuroinflammatory processes, is not well understood.

To study this, we developed a unique mouse model of perimenopausal AD by combining an accelerated ovarian failure (AOF) model of menopause induced by 4-vinylcyclohexene diepoxide (VCD) with the 5xFAD transgenic AD mouse model. To target early stages of disease progression, 5xFAD females were studied at a young age (∼4 months) and at the beginning stage of ovarian failure analogous to human perimenopause (termed "peri-AOF"), and compared to age-matched males. Assessment of neuropathology was performed by immunohistochemical labeling of Ab as well as markers of astrocyte and microglia activity in the hippocampus, a brain region involved in learning and memory that is deleteriously impacted during AD.

Our results show that genotype, AOF, and sex contributed to AD-like pathology. Aggregation of Ab was heightened in female 5xFAD mice and further increased at peri-AOF, with hippocampal subregion specificity. Further, select increases in glial activation also paralleled Ab pathology in distinct hippocampal subregions. However, cognitive function was not affected by peri-AOF.

These findings align with the hypothesis that perimenopause constitutes a period of susceptibility for AD pathogenesis in women.