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Tauopathies are a class of neurodegenerative diseases, including Alzheimer’s disease (AD), Frontotemporal Dementia (FTD), Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), and many others where microtubule-associated protein tau (MAPT or tau) is hyperphosphorylated and aggregated to form insoluble paired helical filaments (PHFs) and ultimately neurofibrillary tangles (NFTs). Autophagic-endolysosomal networks (AELN) play important roles in tau clearance. Excessive soluble neurotoxic forms of tau and tau hyperphosphorylated at specific sites are cleared through the ubiquitin-proteasome system (UPS), Chaperon-mediated Autophagy (CMA), and endosomal microautophagy (e-MI). On the other hand, intra-neuronal insoluble tau aggregates are often degraded within lysosomes by macroautophagy. AELN defects have been observed in AD, FTD, CBD, and PSP, and lysosomal dysfunction was shown to promote the cleavage and neurotoxicity of tau. Moreover, several AD risk genes (e.g., PICALM, GRN, and BIN1) have been associated with dysregulation of AELN in the late-onset sporadic AD. Conversely, tau dissociation from microtubules interferes with retrograde transport of autophagosomes to lysosomes, and that tau fragments can also lead to lysosomal dysfunction. Recent studies suggest that tau is not merely an intra-neuronal protein, but it can be released to brain parenchyma via extracellular vesicles, like exosomes and ectosomes, and thus spread between neurons. Extracellular tau can also be taken up by microglial cells and astrocytes, either being degraded through AELN or propagated via exosomes. This article reviews the complex roles of AELN in the degradation and transmission of tau, potential diagnostic/therapeutic targets and strategies based on AELN-mediated tau clearance and propagation, and the current state of drug development targeting AELN and tau against tauopathies.

Two key pathological hallmarks of neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), are the accumulation of misfolded protein aggregates and the chronic progressive neuroinflammation that they trigger. Numerous original research and reviews have provided a comprehensive understanding of how aggregated proteins (amyloid β, pathological tau, and α-synuclein) contribute to the disease, including driving sterile inflammation, in part, through the aggregation of multi-protein inflammasome complexes and the ASC speck [composed of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), Apoptosis-associated speck-like protein containing a C-terminal caspase activation and recruitment domain (ASC), and inflammatory caspase-1] involved in innate immunity. Here, we provide a unique perspective on the crosstalk between the aggregation-prone proteins involved in AD/PD and the multi-protein inflammasome complex/ASC speck that fuels feed-forward exacerbation of each other, driving neurodegeneration. Failed turnover of protein aggregates (both AD/PD related aggregates and the ASC speck) by protein degradation pathways, prionoid propagation of inflammation by the ASC speck, cross-seeding of protein aggregation by the ASC speck, and pro-aggregatory cleavage of proteins by caspase-1 are some of the mechanisms that exacerbate disease progression. We also review studies that provide this causal framework and highlight how the ASC speck serves as a platform for the propagation and spreading of inflammation and protein aggregation that drives AD and PD.

Neurodegenerative diseases, characterized by the progressive loss of neuronal structure and function, are among the most devastating health challenges of the modern era (1). Disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) share few common pathological hallmarks: neurodegeneration, neuroinflammation, and impaired brain integrity/connectivity (2). This complex interplay of immune-mediated responses in the central nervous system (CNS) integrity has emerged as a pivotal contributor to neuronal damage and disease progression (3). The growing body of research on this topic underscores the importance of unraveling the mechanisms of neuroinflammation and restoring brain homeostasis, which will pave the way for innovative therapeutic strategies.This Research Topic, titled Neuroinflammation and Neurodegenerative Diseases, comprises fourteen insightful contributions from leading researchers. Collectively, these studies explore the molecular and cellular underpinnings of neuroinflammation, the diagnostic potential of biomarkers, and promising therapeutic avenues. Additional insights are provided on how peripherally-derived risk factors [such as type 2 diabetes mellitus (T2DM), osteoarthritis, and Coronavirus Disease 2019 (COVID-19)] can have an impact on brain integrity/neuroinflammation. This editorial highlights the key themes and findings presented in this collection.Unraveling Molecular MechanismsAmong variety of neurodegenerative phenotypes, understanding the molecular basis of neuroinflammation is crucial for identifying therapeutic targets. Several studies in this collection shed light on these mechanisms. For instance, the potential role of Calcitonin Gene Related Peptide (CGRP) in synucleinopathies offers insights into the molecular mediators of neuroinflammation(4). Likewise, the study on α-Synuclein-mediated mitochondrial translocation of cofilin-1 elucidates how mitochondrial dysfunction and oxidative stress are intertwined in PD pathology (5). The reciprocal roles of retro-elements in regulating memory and immunity, as discussed in one article, further deepen our understanding of the genetic and epigenetic interplay in neurodegeneration (6). Such findings underscore the intricate molecular networks driving oxidative stress and neuroinflammatory processes.Inflammatory Biomarkers and DiagnosticsThe pursuit of reliable biomarkers for early diagnosis and disease monitoring remains a cornerstone of neurodegenerative research. The diagnostic values of plasma cell-free nuclear DNA (cf-nDNA) and cell-free mitochondrial DNA (cf-mtDNA) for PD and multiple system atrophy, as explored in one study, highlight the promise of liquid biopsy approaches (7). Another study associates higher serum lipoprotein-associated phospholipase A₂ (Lp-PLA2) levels with cognitive impairment in PD patients, emphasizing the role of systemic inflammation markers in CNS diseases (8).Many peripheral causes can impact neuronal integrity and trigger neuroinflammation. For example, comprehensive magnetic resonance imaging (MRI) assessments revealing subtle brain findings in non-hospitalized post-COVID patients with cognitive impairment extend the discussion to post-viral neuroinflammatory syndromes (9). Similarly, Zhou et al. observed significant abnormalities in the connectivity and topology of large brain functional networks in T2DM patients. Liu et al. has observed a positive correlation between patients with osteoarthritis and Parkinson’s disease. This underscores the relevance of neuroinflammation in broader contexts, including long-term sequelae of infectious, metabolic, and other peripheral degenerative diseases. Therapeutic Approaches and InterventionsTargeted therapies to mitigate neuroinflammation hold transformative potential for patients with neurodegenerative diseases. The neuroprotective effects of the aqueous extract of Swietenia macrophylla leaf in a PD murine model (10), along with the cognitive and mood-enhancing properties of diethyl butylmalonate in 5×familial Alzheimer’s disease (FAD) mice, exemplify novel pharmacological interventions (11).Non-pharmacological approaches also show promise. The regulation of microglia through physical exercise, as highlighted in one study, underscores the potential of lifestyle modifications as adjunctive therapies (12). These findings align with broader efforts to identify holistic and accessible therapeutic options.Neuroprotective StrategiesPreserving neuronal integrity amidst the challenges of neuroinflammation is a primary objective in neurodegenerative research. The impact of sleep, anxiety, and depression on traumatic brain injury outcomes, analyzed in another contribution, offers insights into the broader psychosocial dimensions of neuroprotection (13).Additionally, the spatiotemporal consistency analysis of cerebral small vessel disease via resting-state functional MRI (rs-fMRI) provides a window into the vascular contributions to neurodegeneration, emphasizing the need for integrated neurovascular protective strategies (14). Looking AheadThis collection represents a significant step forward in our understanding of neurodegenerative diseases with specific emphasis on neuroinflammation, metabolic condition, and peripheral diseases (Fig. 1). The findings bridge gaps between basic science and translational research, providing a roadmap for future investigations. By identifying actionable targets and validating therapeutic interventions, these studies lay the groundwork for innovative solutions to one of modern medicine’s most pressing challenges.We extend our gratitude to all contributors for their invaluable insights and encourage continued interdisciplinary collaboration in this field. Together, we aspire to translate these scientific advances into tangible benefits for patients and their families, ultimately transforming the landscape of neurodegenerative disease management.

Background The presence of hyperphosphorylated microtubule-associated protein tau is strongly correlated with cognitive decline and neuroinflammation in Alzheimer’s disease and related tauopathies. However, the role of inflammation and anti-inflammatory interventions in tauopathies is unclear. Our goal was to determine if removing anti-inflammatory interleukin-10 (IL-10) during an acute inflammatory challenge has any effect on neuronal tau pathology. Methods We induce systemic inflammation in Il10- deficient ( Il10 − / − ) versus Il10 + /+ (Non-Tg) control mice using a single intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) to examine microglial activation and abnormal hyperphosphorylation of endogenous mouse tau protein. Tau phosphorylation was quantified by Western blotting and immunohistochemistry. Microglial morphology was quantified by skeleton analysis. Cytokine expression was determined by multiplex electro chemiluminescent immunoassay (MECI) from Meso Scale Discovery (MSD). Results Our findings show that genetic deletion of Il10 promotes enhanced neuroinflammation and tau phosphorylation. First, LPS-induced tau hyperphosphorylation was significantly increased in Il10 − / − mice compared to controls. Second, LPS-treated Il10 − / − mice showed signs of neurodegeneration. Third, LPS-treated Il10 − / − mice showed robust IL-6 upregulation and direct treatment of primary neurons with IL-6 resulted in tau hyperphosphorylation on Ser396/Ser404 site. Conclusions These data support that loss of IL-10 activates microglia, enhances IL-6, and leads to hyperphosphorylation of tau on AD-relevant epitopes in response to acute systemic inflammation.

With increased research funding for Alzheimer’s disease (AD) and related disorders across the globe, large amounts of data are being generated. Several studies employed machine learning methods to understand the ever-growing omics data to enhance early diagnosis, map complex disease networks, or uncover potential drug targets. We describe results based on a Target Central Resource Database protein knowledge graph and evidence paths transformed into vectors by metapath matching. We extracted features between specific genes and diseases, then trained and optimized our model using XGBoost, termed MPxgb(AD). To determine our MPxgb(AD) prediction performance, we examined the top twenty predicted genes through an experimental screening pipeline. Our analysis identified potential AD risk genes: FRRS1, CTRAM, SCGB3A1, FAM92B/CIBAR2 , and TMEFF2 . FRRS1 and FAM92B are considered dark genes, while CTRAM , SCGB3A1 , and TMEFF2 are connected to TREM2-TYROBP, IL-1β-TNFα, and MTOR-APP AD-risk nodes, suggesting relevance to the pathogenesis of AD. Jessica Binder et al. developed a machine learning model to discover potential drug targets for Alzheimer’s disease. They validated their 20 top candidates in several in vitro models, and highlight FRRS1 , CTRAM , SCGB3A1 , FAM92B/CIBAR2 , and TMEFF2 as potential AD risk genes.

Pathological accumulation of microtubule associated protein tau in neurons is a major neuropathological hallmark of Alzheimer's disease (AD) and related tauopathies. Several attempts have been made to promote clearance of pathological tau (p-Tau) from neurons. Transcription factor EB (TFEB) has shown to clear p-Tau from neurons via autophagy. However, sustained TFEB activation and autophagy can create burden on cellular bioenergetics and can be deleterious. Here, we modified previously described two-plasmid systems of Light Activated Protein (LAP) from bacterial transcription factor-EL222 and Light Responsive Element (LRE) to encode TFEB. Upon blue-light (465 nm) illumination, the conformation changes in LAP induced LRE-driven expression of TFEB, its nuclear entry, TFEB-mediated expression of autophagy-lysosomal genes and clearance of p-Tau from neuronal cells and AD patient-derived human iPSC-neurons. Turning the blue-light off reversed the expression of TFEB-target genes and attenuated p-Tau clearance. Together, these results suggest that optically regulated TFEB expression unlocks the potential of opto-therapeutics to treat AD and other dementias.

Smoke from wildland fires has been shown to produce neuroinflammation in preclinical models, characterized by neural infiltrations of neutrophils and monocytes, as well as altered neurovascular endothelial phenotypes. To address the longevity of such outcomes, the present study examined the temporal dynamics of neuroinflammation and metabolomics after inhalation exposures from biomass-derived smoke. 2-month-old female C57BL/6 J mice were exposed to wood smoke every other day for 2 weeks at an average exposure concentration of 0.5 mg/m 3 . Subsequent serial euthanasia occurred at 1-, 3-, 7-, 14-, and 28-day post-exposure. Flow cytometry of right hemispheres revealed two endothelial populations of CD31 Hi and CD31 Med expressors, with wood smoke inhalation causing an increased proportion of CD31 Hi . These populations of CD31 Hi and CD31 Med were associated with an anti-inflammatory and pro-inflammatory response, respectively, and their inflammatory profiles were largely resolved by the 28-day mark. However, activated microglial populations (CD11b + /CD45 low ) remained higher in wood smoke-exposed mice than controls at day 28. Infiltrating neutrophil populations decreased to levels below controls by day 28. However, the MHC-II expression of the peripheral immune infiltrate remained high, and the population of neutrophils retained an increased expression of CD45, Ly6C, and MHC-II. Utilizing an unbiased approach examining the metabolomic alterations, we observed notable hippocampal perturbations in neurotransmitter and signaling molecules, such as glutamate, quinolinic acid, and 5-α-dihydroprogesterone. Utilizing a targeted panel designed to explore the aging-associated NAD + metabolic pathway, wood smoke exposure drove fluctuations and compensations across the 28-day time course, ending with decreased hippocampal NAD + abundance on day 28. Summarily, these results indicate a highly dynamic neuroinflammatory environment, with potential resolution extending past 28 days, the implications of which may include long-term behavioral changes, systemic and neurological sequalae directly associated with wildfire smoke exposure.

The early detection and tracing of anomalous operations in battery packs are critical to improving performance and ensuring safety. This paper presents a data-driven approach for online anomaly detection in battery packs that uses real-time voltage and temperature data from multiple Li-ion battery cells. Mean-based residuals are generated for cell groups and evaluated using Principal Component Analysis. The evaluated residuals are then thresholded using a cumulative sum control chart to detect anomalies. The mild external short circuits associated with cell balancing are detected in the voltage signals and necessitate voltage retraining after balancing. Temperature residuals prove to be critical, enabling anomaly detection of module balancing events within 14 min that are unobservable from the voltage residuals. Statistical testing of the proposed approach is performed on the experimental data from a battery electric locomotive injected with model-based anomalies. The proposed anomaly detection approach has a low false-positive rate and accurately detects and traces the synthetic voltage and temperature anomalies. The performance of the proposed approach compared with direct thresholding of mean-based residuals shows a 56% faster detection time, 42% fewer false negatives, and 60% fewer missed anomalies while maintaining a comparable false-positive rate.

Background Wildland fires in the United States have increased in frequency and scale over the past 30 years exposing millions of people to hazardous air pollutants. Among others, aging individuals are particularly vulnerable to the effects of wildfire smoke. In this study, we assessed the neurobiological impacts of wood smoke (WS) on aged mice and the potential of anti-aging therapeutics to mitigate these impacts. Methods Female C57BL/6 J mice, aged 18 months, were divided into 10 groups and exposed to either filtered air (FA; 5 groups) or biomass derived WS (5 groups) for 4 h/day, every other day, for 14 days (7 exposures total) with an average particulate matter (PM) concentration of 448 µg/m 3 per exposure. One FA control group and one WS exposed group were euthanized 24 h after the last exposure. The remaining 8 groups (4 FA and 4 WS exposed) were treated with either vehicle control, resveratrol and nicotinamide mononucleotide (RNMN), dasatinib and quercetin (DQ), or both RNMN and DQ (RNDQ) for 10 weeks. Results A significant reduction in NAD + within the prefrontal cortex was observed following the 14-day exposure to WS along with a reduction in serotonin. Serotonin reductions were observed up to 10 weeks post-exposure and co-occurred with neuroinflammation and behavioral alterations, including increased immobility in a forced swim test. RNMN conferred the greatest mitigating effect after WS exposure, while RNDQ treatment resulted in an upregulation of markers associated with aging in the brain. While the metabolic shift in the PFC following WS exposure was relatively modest, mice exposed to FA and vehicle control (10 weeks of natural aging) exhibited the greatest metabolic shift, including perturbed nicotinamide metabolism. Conclusion Taken together, these findings highlight that subacute (14-day) exposure to WS results in persistent neurometabolomic and behavioral alterations in an aged mouse model and that intervention with RNMN may be a useful strategy to mitigate the adverse neurological outcomes observed. Further studies are needed to assess the specific impact of either resveratrol or NMN in isolation and to fully elucidate age-specific, as well as sex- and species-determinant, WS exposure response pathways.