Solute carrier family 6 member 14 (SLC6A14/ATB0,+) is a broad-spectrum, Na+/Cl--dependent amino acid transporter. It mediates the active uptake of nearly all essential amino acids and serves as a critical metabolic hub under physiological and pathological conditions. To fully understand its potential as a therapeutic target for cancer intervention, this review systematically elucidates the structural biology, regulatory networks, and multifaceted roles of SLC6A14 in cancer. By examining the expression patterns of SLC6A14 in physiological and pathological situation, we demonstrate that it's significantly upregulated in various "amino acid-dependent" malignancies. It includes pancreatic cancer, colorectal cancer, and estrogen receptor-positive breast cancer, where it drives multiple signaling pathways and promotes tumor progression through diverse mechanisms. Beyond its classical metabolic functions, SLC6A14-mediated nutrient deprivation establishes a "nutrient-based immune evasion" mechanism, elucidating its potential for intervention in tumor immunity. Furthermore, we outline a dual-pronged therapeutic strategy for SLC6A14, including its use as a target for pharmacological inhibition and as a delivery channel for amino acid-conjugated prodrugs. Finally, we emphasize that successful clinical translation requires a shift from biomarker-driven patient stratification to mechanism-driven implementation. This highlights the central role of SLC6A14 as an intervenable target at the intersection of cancer metabolism, immune regulation, and targeted therapy.

Concerns about chronic exposure to titanium dioxide nanoparticles (TiO2-NPs) have increased because of their widespread use in consumer products and subsequent environmental release. Previous studies have shown that TiO2-NPs exert neurotoxic effects and may contribute to Parkinson's disease (PD)-related neurodegenerative processes. However, the molecular mechanisms underlying TiO2-NPs-induced neurotoxicity remain unclear. We investigated these effects and their potential mechanisms in A53T α-synuclein transgenic mice and SH-SY5Y cells. Repeated oral exposure to TiO2-NPs for two months dose-dependently aggravated motor dysfunction and neuronal degeneration in the substantia nigra pars compacta at 1, 10, and 50 mg/kg body weight. In SH‑SY5Y cells, exposure to TiO2‑NPs for 48 h at 0.01, 0.1, 1, 10, 50, and 100 mg/L reduced cell viability in a concentration-dependent manner, impaired mitochondrial function, increased reactive oxygen species (ROS) production and promoted apoptosis. Western blotting showed that TiO2-NPs inhibited PI3K/Akt signaling and altered mitochondrial apoptosis-related proteins, including Bcl-2, Bax, cytochrome C (Cyt C) and caspase-3. The PI3K agonist insulin-like growth factor-1 (IGF-1) partly attenuated these changes. These findings provide mechanistic evidence for TiO2-NPs-induced neurotoxicity and may support the health risk assessment and safe application of TiO2-NPs.

ABSTRACT Introduction Although sleep disturbance is closely linked to cognitive impairment, the specific sleep‐related characteristics driving this deficit remain undetermined, with the mechanistic contribution of biomarkers also poorly characterized. Accumulating evidence suggests that inflammation may contribute to cognitive decline, yet its mediating role in the sleep‐cognition relationship has not been fully clarified. Methods Based on the UK Biobank, four linear regression models (for reasoning, reaction time, visual memory, and numeric memory) and one logistic regression model (for prospective memory) were employed to analyze the relation between sleep features and cognitive impairment. Apart from that, the bootstrap mediation model and Mendelian randomization were utilized to investigate the causal association. Results Short sleep duration (β = −0.394, p = 0.020) and long sleep duration (β = −0.359, p = 0.014) correlated with poorer numeric memory performance, while moderate sleep quality (β = −0.071, p = 0.042) and work shift were linked to impaired reasoning, reaction time, visual memory, and prospective memory. Subgroup analyses stratified by age, sex, and BMI further supported these associations. In addition, C‐reactive protein (CRP) partially mediated the snoring‐reasoning ability association (PM: β = −0.071, p = 0.049), with MR analysis confirming a causal pathway, whereas snoring elevated CRP levels to impair reasoning, accounting for 32.1% of the observed relationship. Conclusion In this cohort study, abnormal sleep traits correlated with domain‐specific cognitive impairments, with CRP partially mediating the snoring‐reasoning association.

BACKGROUND AND AIMS:The aggregation of α-synuclein (α-syn) is a central event in Parkinson's disease (PD) pathogenesis. However, the cellular factors that initiate and accelerate the process are not fully understood. Synaptogyrin-3 (SYNGR3) is a synaptic vesicle protein whose role in α-syn pathology remains unexplored. This study investigated whether SYNGR3 is a key factor triggering the pathological process of PD. METHODS:This study investigated the expression of SYNGR3 in the brains of transgenic A53T α-syn mutant mouse line M83 (TgA53T) PD model mice using Western blot. The direct interaction between SYNGR3 and α-syn was assessed by GST pull-down assays. This study examined the effect of SYNGR3 on α-syn aggregation kinetics and fibril stability in vitro through the thioflavin T (Th T) assays and proteinase K (PK) digestion. By overexpressing or knocking down SYNGR3 in HEK-293 cells stably transfected with α-syn, primary neurons, and TgA53T mice, the effects of enhanced or deficient function of SYNGR3 on α-syn pathology, synaptic integrity, mitochondrial function, and motor behavior were evaluated. RESULTS:SYNGR3 levels were significantly elevated in an age-dependent manner in the striatum of TgA53T mice. The study found that SYNGR3 directly interacts with the central region of α-syn and accelerates its aggregation into fibrils that are more resistant to PK digestion. Overexpression of SYNGR3 exacerbated α-syn aggregation, synaptic protein loss, mitochondrial dysfunction, and apoptosis in cellular models. In vivo, SYNGR3 intensified α-syn pathology, dopaminergic neurodegeneration, and PD-like motor deficits. Conversely, knockdown of SYNGR3 effectively alleviated these pathological and behavioral impairments. CONCLUSION:This study identifies SYNGR3 as a novel and critical promoter of α-syn aggregation and neurotoxicity. These findings establish SYNGR3 as a key contributor to PD pathogenesis and highlight its potential as a therapeutic target for intervention.

Cancer poses serious health risks to humans. The solute carrier (SLC) family is crucial for cancer development regulation. As a member of this family, SLC7A7 forms a heterodimer with SLC3A2 to transport cationic and neutral amino acids (AA) across the membrane, thereby maintaining cellular AA homeostasis. A recent study resolved the crystal structure of SLC7A7 and identified the key residues involved in substrate binding of SLC7A7, providing important experimental evidence for the future development of small-molecule inhibitors of SLC7A7. In addition, multiple studies have revealed the expression regulation mechanism of SLC7A7 in human, mouse, and porcine cells, providing a basis for studying the regulatory mechanism of SLC7A7 expression in cancer cells. SLC7A7 is dysregulated in multiple cancers, including bladder cancer, non-small cell lung cancer, and hepatocellular carcinoma. SLC7A7 is involved in cancer proliferation and metastasis, with a notable impact on shaping the tumor microenvironment (TME) across multiple cancer types, making it a valuable target for further investigation. In this review, we discuss recent advances in understanding the structure, expression, and regulatory mechanisms of SLC7A7, focusing on its role in cancer development and the current research limitations. Furthermore, this review emphasizes the role of SLC7A7 in promoting cancer immune escape by influencing innate and adaptive immune cells in the TME and discusses its potential mechanisms of immune cell regulation.

INTRODUCTION:The blood-brain barrier (BBB) maintains brain homeostasis, and its dysfunction is a critical pathological mechanism for many neurological disorders. However, current BBB models lack functional brain parenchyma, hindering mechanistic studies of BBB-parenchyma interactions and limiting drug evaluation for barrier penetration and neural targeting. OBJECTIVES:To develop an integrated human blood-brain barrier-brain organoid-on-a-chip (BBOC) model that replicates physiological interaction and pathological disruption between the BBB and brain parenchyma. METHODS:A bioengineered BBB model was constructed on a millifluidic plate using human brain microvascular endothelial cells and pericytes under dynamic flow. Human brain organoids (hBOs) derived from pluripotent stem cells were co-cultured to form the BBOC model. Parenchymal pathology was induced by Aβ42 oligomers (Aβ42O) to examine their effects on BBB function and integrity. RESULTS:Conditioned medium and dynamic flow improved endothelial cell viability. Co-culture with hBOs significantly enhanced the engineered BBB function, increasing TEER values and reducing molecular permeability. Aβ42O-treated hBOs exhibited the pathological phenotypes of brain parenchyma, including notable neurite loss, impaired stem cell proliferation, increased cell apoptosis, and transcriptional upregulation of cytokine genes. The pathological hBOs disrupted the BBB, including decreased tight junction protein expression, increased barrier permeability, and impaired barrier integrity. CONCLUSION:The BBOC model reproduced physiological and pathological interactions between parenchyma and the BBB, collectively confirming that brain parenchymal states can modulate BBB integrity. Functionally, hBOs strengthened endothelial barrier integrity, indicating that parenchymal-derived signals actively promote the BBB maturation and stability. In contrast, pathological hBOs induced pericyte degeneration and tight junction disruption of BBB, demonstrating that pathological brain environments can impair BBB function. By bridging neurobiology and bioengineering, the BBOC model will facilitate investigations into neurological mechanisms and drug discovery for barrier penetration and neural targeting.

Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Rare, truncating variants in the sortilin-related receptor 1 (SORL1) gene are well established as high-risk factors for early-onset AD, although with incomplete penetrance. In this study, we identified a novel heterozygous frameshift variant in SORL1 (c.6152delA) in a Chinese family presenting with early-onset dementia characterized by progressive memory impairment and neuropsychiatric symptoms. The variant is extremely rare in gnomAD v4 and is predicted to introduce a premature termination codon. To investigate whether the truncated SORL1 transcript escapes nonsense-mediated mRNA decay (NMD) and to explore the potential cellular effects of residual truncated SORL1, the mutant SORL1 construct was expressed in SH-SY5Y cells and APPswe-expressing HEK293 cells. Additionally, SORL1 mRNA levels in the serum of the proband and her families were assessed by qRT-PCR. Confocal microscopy was used to examine amyloid precursor protein (APP) trafficking within early endosomes, late endosomes, and the trans-Golgi network, marked by EEA1, Rab7, and TGN46, respectively. Amyloid-β (Aβ40 and Aβ42) levels were quantified by ELISA. The results showed that SORL1 mRNA levels in the proband were reduced. And the SORL1 c.6152delA variant impaired the ability of SORL1 to retain APP within the Golgi–endosomal transport network, resulting in increased Aβ production. Overall, these findings indicate that the SORL1 c.6152delA frameshift variant is a significant risk factor for AD pathogenesis.

Early intervention is the most effective strategy to impede the progression of Alzheimer’s disease (AD), depending on the identification of early diagnostic biomarkers. Here, we isolate neuron-derived exosomes (NDEs) from plasma of familial AD (FAD), presymptomatic FAD (pre-FAD), and healthy controls (cognitively normal [CN]), followed by label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. A specific peptide from protein phosphatase 2 regulatory subunit B'β (PPP2R5C) shows a progressive decrease from CN to pre-FAD and FAD patients. This decline is further validated in plasma NDEs and brain tissue from amnestic mild cognitive impairment (aMCI) and sporadic AD (SAD) patients. Two independent cohorts confirm the early and differential diagnostic value of plasma PPP2R5C. Immunohistochemistry of Tau Braak-staged brains reveals PPP2R5C reduction preceding Tau hyperphosphorylation. Mechanistically, PPP2R5C interacts with Tau, reducing Tau levels and phosphorylation via unc-51-like kinase 1 (ULK1)-dependent autophagolysosomal activation and PP2A regulation. Our findings suggest that plasma PPP2R5C has the potential to serve as an ideal biomarker for the early diagnosis of AD.

Parkinson's disease is an age-related neurodegenerative disease that is characterized by the deposition of α-synuclein aggregates in the brain. Nevertheless, the molecular mechanisms that regulate α-synuclein aggregation have not yet been identified fully. TMEM106B is a lysosomal transmembrane protein that has been reported to be associated with brain ageing and neurodegenerative diseases, including Parkinson's disease. Here we show that TMEM106B is reduced in the brains of patients with Parkinson's disease. Knockout of Tmem106b increases the formation of α-synuclein aggregates in primary neurons and mouse brains. TMEM106B deficiency results in impaired lysosomal acidification, lipid metabolism disorders and lipid droplet deposition in neurons. Interestingly, lipid droplets promote α-synuclein aggregation, resulting in the formation of α-synuclein fibrils with enhanced seeding activity and neurotoxicity in comparison to α-synuclein fibrils formed in the absence of lipid droplets. TMEM106B deficiency also leads to retardation of α-synuclein degradation by reducing the enzymatic activity of the lysosomal protease cathepsin D. Taken together, these results indicate that TMEM106B deficiency contributes to Parkinson's disease pathogenesis by accelerating α-synuclein aggregation and halting α-synuclein degradation.

The pathogenicity of variants of uncertain significance in the LRRK2 gene remains underexplored. Investigating the LRRK2 variant spectrum in a large Chinese population cohort can provide deeper insights into its pathogenic mechanisms. This study examined the LRRK2 gene variants in 20,519 Chinese individuals, including 7,562 Parkinson’s disease (PD) patients, 3,077 Essential tremor (ET) patients, and 9880 healthy controls. We conducted a genetic analysis of low-frequency and common non-synonymous variants in the LRRK2 gene across the cohorts. A total of 287 low-frequency non-synonymous LRRK2 variants were identified in the PD and control cohorts. Among these, six reported pathogenic variants (p.R1325Q, p.R1441C, p.R1441H, p.V1447M, p.G2019S, p.I2020T) and three reported likely pathogenic variants (p.R1067Q, p.N1437D, p.R1728H) were enriched in PD cases, with a frequency of 0.71%. In contrast, only one pathogenic variant (p.R1325Q) and one likely pathogenic variant (p.R1067Q) were observed in healthy controls (0.11%), and the ET cohort exhibited similar variant distribution to controls (0.19%). Burden analysis and association analysis revealed novel likely pathogenic variants, including p.A312V, p.M968K, and p.R1320S as candidates. These novel variants were significantly more frequent in PD patients (0.79%) compared to healthy controls (0.20%) or ET patients (0.42%). Additionally, seven common missense variants of LRRK2 were identified, and significant associations with PD for p.A419V, p.R1628P, and p.G2385R were confirmed, but no common variants were linked to ET. This study provides the first comprehensive characterization of the LRRK2 variant spectrum in a large Chinese population, underscoring the pivotal role of LRRK2 in PD pathogenesis but not in ET. These findings advance the understanding of LRRK2 in neurodegenerative disorders and lay a foundation for personalized therapeutic strategies based on genetic profiling.

BACKGROUND:TATA-box binding protein associated factor 15 (TAF15) is a multifunctional DNA/RNA-binding protein that plays pivotal roles in transcription regulation, precursor mRNA splicing, and cellular stress responses. Accumulating evidence demonstrates that TAF15 is strongly implicated in two distinct pathological classes: neurodegenerative diseases and cancers. In neurodegenerative diseases including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), TAF15 undergoes abnormal cytoplasmic aggregation and mislocalization in neurons and glia, and TAF15 has been established as a candidate disease gene for ALS. In a wide range of cancers, TAF15 drives oncogenic transcriptional dysregulation either via wild-type protein dysfunction or the formation of oncogenic fusion proteins derived from chromosomal translocations. AIM OF REVIEW:A central unresolved question is how TAF15 contributes to two mechanistically distinct disease entities. This review aims to provide a mechanistically integrated analysis of the physiological and pathological functions of TAF15. We use TAF15's intrinsic molecular properties as a unifying framework to connect its roles in neurodegeneration and cancer. We also summarize key pathogenic mechanisms and emerging therapeutic strategies targeting TAF15, with the goal of proposing a novel conceptual perspective to guide future research. Key scientific concepts of review. TAF15 may act as a biologically relevant molecular link between neurodegeneration and cancer through its intrinsic molecular characteristics, such as nucleic acid binding, phase separation, and nucleocytoplasmic shuttling. The "localization determines outcome" hypothesis offers a unifying framework to explain the connection between the two diseases. TAF15 holds promise as a target for novel biomarkers and precision therapeutics across both disease areas. Deepening mechanistic studies of TAF15 will not only advance understanding of its dual pathological roles but also illuminate the largely unexplored molecular link between neurodegenerative diseases and cancers.

The aberrant aggregation of tau leads to loss of its physiological functions and gain of toxic functions, and plays a crucial role in the pathogenesis of tauopathies including Alzheimer’s disease (AD). Targeting tau aggregation is considered a promising strategy for treating tauopathies. The BRICHOS family consists of a variety of proteins containing the BRICHOS domain. Certain endogenous BRICHOS domains may inhibit the pathological aggregation of disease-associated proteins. However, the effects of the BRICHOS domains on tau aggregation remain unknown. Here we revealed that BRICHOS domains from integral membrane protein 2B (ITM2B), tenomodulin (TNMD), and out at first (OAF) bind to tau and inhibit its aggregation in vitro. Intravenous administration of TNMD BRICHOS alleviates tau aggregation, synaptic dysfunction, and memory deficits in Tau P301S transgenic mice. Thus, TNMD BRICHOS may serve as a potential therapeutic approach for the development of treatments for tauopathies.

Protein misfolding and propagation contribute to neurodegenerative diseases. Recently, cryogenic electron microscopy of insoluble amyloid fibrils derived from individuals with frontotemporal lobar degeneration (FTLD) revealed new species of amyloid fibrils, which are composed of aggregated TATA-binding protein-associated factor 15 (TAF15). However, it remains unknown whether TAF15 fibrils propagate in a prion-like manner and drive neurodegeneration. Here, we show that TAF15 forms amyloid fibrils that can self-propagate. Strikingly, a single injection of synthetic TAF15 pre-formed fibrils into the prefrontal cortex of wild-type mice led to the aggregation of endogenous TAF15 and cell-to-cell transmission of pathologic TAF15. TAF15 pathology was accompanied by progressive degeneration of cortical neurons, cognitive impairments, and anxiety- and depression-like behaviors. The detrimental effects of TAF15 fibrils were abolished by genetic deletion of endogenous TAF15. Together, these observations indicate that TAF15 aggregation drives neurodegeneration.

Parkinson's disease (PD) is characterized by progressive motor deficits and dopaminergic neuronal loss. Aberrant neuroinflammation contributes to neurodegeneration. Prompted by published case reports describing motor improvement following levofloxacin (LVFX) administration in patients with parkinsonian syndromes, as well as an additional clinical observation from our center, we investigated its effects in cellular and mouse models. In LPS-stimulated BV2 microglial cells, levofloxacin was associated with reduced activity of the TLR4/NF-κB/NLRP3 axis, reducing pro-inflammatory cytokine release and oxidative stress. TLR4 knockdown experiments suggested that TLR4 is involved in mediating this anti-inflammatory action. Conditioned medium from levofloxacin-treated microglia attenuated LPS-induced neuronal viability loss and apoptosis in SH-SY5Y cells. Furthermore, levofloxacin attenuated activation of the TLR4/NF-κB/NLRP3 pathway and glial activation in an LPS-induced mouse model of neuroinflammation. In an MPTP-induced mouse model of PD, levofloxacin alleviated dopaminergic neuronal degeneration and motor deficits. These findings are consistent with clinical observations and preclinical evidence and suggest that levofloxacin may have beneficial effects in models of PD-like pathology, at least in part, by modulating the neuroinflammatory TLR4/NF-κB/NLRP3 axis.

Human brain organoids (hBOs) have been recently regarded as neurobiologically relevant brain models and exponentially exploited in a variety of neuroscience research. However, the current gold-standard method for generating hBOs is intricate and laborious, resulting in hBOs with morphological variability and inconsistent batch-to-batch reproducibility. Despite several studies reporting simplified hBO culture methods, few of those methods was biologically validated with multiomic profiling, which is crucial for neurobiological studies. Here, we demonstrate an all-in-one millifluidic plate (AIOMP) with individually perfusable microchambers for hBOs, simplifying the culture process, improving the uniformity and reproducibility, and enabling long-term cultivation and real-time morphogenesis observation. Additionally, our comprehensive transcriptomic and proteomic analyses revealed that AIOMP increases neurogenesis and corticogenesis of hBOs, suggesting a stronger correlation between the AIOMP-generated hBOs and human fetal brain than those generated through conventional method. Metabolomic and neurophysiological results further support the maturation-enhancing effects of AIOMP on hBOs, showing improved neurotransmitter synthesis and electrophysiological functionality. Overall, the AIOMP approach offers a simplified, reproducible, and biologically validated method for hBOs generation and maturation, with potential applications in neurobiology, neurological disease research, and central nervous system drug assessment.

Neurodegenerative diseases (NDDs) that are characterized by the accumulation of alpha-synuclein (α-syn) aggregates in both neurons and the non-neuronal cells of the brain are called synucleinopathies. The most common synucleinopathies includes Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB). Significant progress has been made in the development of positron emission tomography (PET) radiotracers for synucleinopathies, yielding several α-syn tracers that have entered clinical studies. However, selective α-syn imaging still faces inherent challenges. This review provides a comprehensive overview of the progress in α-syn PET radiotracers from three angles: Alzheimer’s disease (AD)-derived scaffolds, representative compound scaffolds and analogs, and the identification of α-syn tracers through high-throughput screening (HTS). We discuss the characteristics, advantages, and limitations of the tracers for preclinical and clinical application. Finally, future directions in the development of radioligands for proteinopathies are discussed. There is no clinical available PET radiotracer for imaging α-syn aggregates, but these advances have laid a key foundation for non-invasive α-syn imaging and early diagnosis of synucleinopathies.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the aggregation of α-synuclein (α-syn) and the nigrostriatal dopaminergic neuronal degeneration. Depression is one of the most common non-motor symptoms of PD patients. However, the pathogenic connection between PD and depression is not well understood. Herein, we report that chronic stress upregulates the expression of α-syn in the mouse brain. Overexpression of α-syn in the hippocampus replicates depressive-like phenotypes, whereas the genetic deletion of α-syn enhances resistance to chronic stress. Furthermore, chronic stress in early life promoted the deposition of α-syn aggregates in a transgenic mouse model that overexpresses human A53T mutant α-syn (A53T mice). Chronic stress also exacerbated dopaminergic degeneration and motor impairments in A53T mice. Strikingly, α-syn inclusions were also observed in the brains of some aged non-transgenic mice subjected to chronic stress. Together, our findings suggest that chronic stress upregulates α-synuclein expression, resulting in depression-like behaviors and parkinsonism.

BACKGROUND:The migration of vascular smooth muscle cells (VSMCs) is critical for the development of atherosclerosis. However, the underlying molecular mechanisms are not completely understood. Here, we detected FAM49B (family with sequence similarity 49 member B) fragments in atherosclerotic plaques and identified their roles in VSMC migration and atherogenesis. METHODS:Transgenic mice such as Aep (asparagine endopeptidase)-/-, Aep-/-Apoe-/-, and VSMC-specific full-length FAM49B and FAM49B fragment overexpression by adenovirus gene transfer were used to determine the role of FAM49B fragments in atherosclerosis. In addition, the effects of compound 11, an AEP inhibitor, on the progression of atherosclerosis in Apoe-/- mice were analyzed. FAM49B fragments were identified by mass spectrometry. Moreover, the expression of FAM49B fragments in atherosclerotic plaques from mice and patients was analyzed by immunofluorescence and immunoblotting. RESULTS:The levels of FAM49B are increased in atherosclerotic lesions. Interestingly, FAM49B is cleaved by the cysteine protease AEP at residues N169 and N170, generating 2 fragments: FAM49B (1-169) and FAM49B (171-324). Both fragments are upregulated in VSMCs with the development of atherosclerotic plaques. The overexpression of full-length FAM49B inhibits the migration of human aortic VSMCs, whereas the overexpression of FAM49B fragments promotes VSMC migration. FAM49B fragments bind to Rac1 (Ras-related C3 botulinum toxin substrate 1) and increase its activity, thereby inducing actin polymerization and promoting cell migration. The overexpression of FAM49B fragments in mouse aortic VSMCs results in a higher atherosclerotic plaque burden, whereas the deletion of AEP blocks FAM49B fragmentation and decreases plaque size in mouse models of atherosclerosis. Furthermore, the administration of compound 11 blocked FAM49B fragmentation and alleviated atherosclerotic lesions. CONCLUSIONS:Our results indicate that AEP-derived FAM49B fragments facilitate Rac1-mediated VSMC migration and promote atherosclerosis progression. Inhibiting AEP-mediated FAM49B fragmentation may be a therapeutic strategy for atherosclerosis.

Overwhelming studies have demonstrated that implementing an early intervention is the most effective strategy to impede the advancement of Alzheimer's disease (AD), depending on the identification of early diagnostic biomarkers. In this study, we first employed proteomics to identify differentially expressed proteins in neuron-derived exosomes (NDEs) from plasma samples of 13 familial AD (FAD) patients, 10 pre-FAD patients, and 18 cognitively normal (CN) controls. These findings were subsequently validated using targeted mass spectrometry in a cohort of sporadic AD individuals. Enzyme-linked immunosorbent assay (ELISA) was utilized for further validation in a larger cohort comprising 74 AD patients, 76 individuals with amnestic mild cognitive impairment (aMCI), and 74 healthy controls. Additionally, the diagnostic performance of PPP2R5C was evaluated by analyzing 34 AD patients, 28 progressive supranuclear palsy (PSP) patients, and 37 frontotemporal dementia (FTD) patients. Meanwhile, the mechanism underlying PPP2R5C's role in AD pathogenesis was explored through in vitro and in vivo models. Our findings reveal a trend of decreased PPP2R5C protein levels in NDEs across FAD, pre-FAD, and CN (FAD < pre-FAD < CN), as well as a similar downward trend in plasma PPP2R5C levels within the AD cohort (AD < aMCI < CN, p  <0.05). Diagnostic accuracy was assessed using receiver operating characteristic (ROC) curve analysis. Plasma PPP2R5C demonstrated significant diagnostic ability for AD (AUC = 0.84, p  < 0.0001) and for aMCI (AUC = 0.74, p  < 0.0001). Mechanistically, we found that PPP2R5C interacts with Tau and attenuates both its total and phosphorylated levels, either by mediating the autophagolysosomal pathway or directly influencing PP2A activity. Furthermore, PPP2R5C-mediated autophagy was shown to be dependent on its binding activity to unc-51-like kinase 1 (ULK1). This study suggested that plasma PPP2R5C could be a novel and ideal biomarker for the early diagnosis of AD and its involvement in the pathogenesis of AD

PSEN1 E280A carrier for the APOE3 Christchurch variant (R136S) is protected against Alzheimer’s disease (AD) symptoms with a distinct anatomical pattern of Tau pathology. However, the molecular mechanism accounting for this protective effect remains incompletely understood. Here, we show that the ApoE3 R136S mutant strongly binds to Tau and reduces its uptake into neurons and microglia compared with ApoE3 wild type (WT), diminishing Tau fragmentation by asparagine endopeptidase (AEP), proinflammatory cytokines by Tau pre-formed fibrils (PFFs) or β-amyloid (Aβ), and neurotoxicity. Further, ApoE3 R136S demonstrates more robust effects in attenuating AEP activation and Tau PFF spreading in the brains of both 5xFAD and Tau P301S mice than in ApoE3 WT, leading to improved cognitive functions. Thus, our findings support the idea that ApoE3 R136S strongly binds Tau and decreases its cellular uptake, abrogating Tau pathology propagation in AD brains.