Neurological diseases are a major health concern, and brain injury is a typical pathological process in various neurological disorders. Different biomarkers in the blood or the cerebrospinal fluid are associated with specific physiological and pathological processes. They are vital in identifying, diagnosing, and treating brain injuries. In this review, we described biomarkers for neuronal cell body injury (neuron-specific enolase, ubiquitin C-terminal hydrolase-L1, αII-spectrin), axonal injury (neurofilament proteins, tau), astrocyte injury (S100β, glial fibrillary acidic protein), demyelination (myelin basic protein), autoantibodies, and other emerging biomarkers (extracellular vesicles, microRNAs). We aimed to summarize the applications of these biomarkers and their related interests and limits in the diagnosis and prognosis for neurological diseases, including traumatic brain injury, status epilepticus, stroke, Alzheimer's disease, and infection. In addition, a reasonable outlook for brain injury biomarkers as ideal detection tools for neurological diseases is presented.
Humans ; Biomarkers/cerebrospinal fluid* ; Nervous System Diseases/diagnosis* ; Brain Injuries/metabolism* ; Phosphopyruvate Hydratase/cerebrospinal fluid* ; Glial Fibrillary Acidic Protein/blood* ; S100 Calcium Binding Protein beta Subunit/blood* ; tau Proteins/cerebrospinal fluid* ; Ubiquitin Thiolesterase/blood* ; Myelin Basic Protein/cerebrospinal fluid* ; Neurofilament Proteins/blood* ; MicroRNAs/blood* ; Brain Injuries, Traumatic/metabolism*

Neurodegenerative diseases constitute a group of chronic disorders characterized by the progressive loss of neurons. Major neurodegenerative conditions include Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis. Pathologically, these diseases are marked by the accumulation of aggregates formed by pathological proteins such as amyloid-β, tau, α-synuclein, and TAR DNA-binding protein 43. These proteins assemble into amyloid fibrils that undergo prion-like propagation and dissemination, ultimately inducing neurodegeneration. Understanding the biology of these protein aggregates is fundamental to elucidating the pathophysiology of neurodegenerative disorders. In this review, we summarize the molecular mechanisms underlying the aggregation and transmission of pathological proteins, the processes through which these protein aggregates trigger neurodegeneration, and the interactions between different pathological proteins. We also provide an overview of the current diagnostic approaches and therapeutic strategies targeting pathological protein aggregates.
Humans ; Neurodegenerative Diseases/metabolism* ; alpha-Synuclein/metabolism* ; Amyloid beta-Peptides/metabolism* ; tau Proteins/metabolism* ; Protein Aggregation, Pathological/metabolism* ; DNA-Binding Proteins/metabolism* ; Animals ; Protein Aggregates/physiology*

Hypoxic-ischemic brain damage (HIBD) is one of the main causes of disability in middle-aged and elderly people, as well as high mortality rates and long-term physical impairments in newborns. The pathological manifestations of HIBD include neuronal damage and loss of myelin sheaths. Tau protein is an important microtubule-associated protein in brain, exists in neurons and oligodendrocytes, and regulates various cellular activities such as cell differentiation and maturation, axonal transport, and maintenance of cellular cytoskeleton structure. Phosphorylation is a common chemical modification of Tau. In physiological condition, it maintains normal cell cytoskeleton and biological functions by regulating Tau structure and function. In pathological conditions, it leads to abnormal Tau phosphorylation and influences its structure and functions, resulting in Tauopathies. Studies have shown that brain hypoxia-ischemia could cause abnormal alteration in Tau phosphorylation, then participating in the pathological process of HIBD. Meanwhile, brain hypoxia-ischemia can induce oxidative stress and inflammation, and multiple Tau protein kinases are activated and involved in Tau abnormal phosphorylation. Therefore, exploring specific molecular mechanisms by which HIBD activates Tau protein kinases, and elucidating their relationship with abnormal Tau phosphorylation are crucial for future researches on HIBD related treatments. This review aims to focus on the mechanisms of the role of Tau phosphorylation in HIBD, and the potential relationships between Tau protein kinases and Tau phosphorylation, providing a basis for intervention and treatment of HIBD.
Humans ; tau Proteins/physiology* ; Phosphorylation ; Hypoxia-Ischemia, Brain/physiopathology* ; Animals ; Oxidative Stress

OBJECTIVES: To investigate the associations between Tau protein deposition and brain biochemical metabolites detected by proton magnetic resonance spectroscopy (¹H-MRS) in patients with advanced Alzheimer's disease (AD). METHODS: From April, 2022 to December, 2024, 64 Tau-positive AD patients and 29 healthy individuals underwent ¹⁸F-APN-1607 PET/MR and simultaneously acquired multi-voxel ¹H-MRS in the Department of Nuclear Medicine, Nanjing First Hospital. Visual analysis and voxel-based analysis of PET/MR data were performed to investigate the Tau protein deposition patterns in AD patients. Valid voxels within the ¹H-MRS field of view were selected, and their standardized uptake value ratio (SUVr) in PET and metabolite levels of N-acetylaspartate (NAA), choline (Cho), creatine (Cr), NAA/Cr, and Cho/Cr were recorded. The Tau-positive (Tau⁺) voxels and Tau-negative (Tau^-) voxels of the AD patients were compared for PET and ¹H-MRS parameters, and the correlations between the metabolites and Tau PET SUVr within Tau⁺ voxels were analyzed. RESULTS: Significant Tau protein deposition were observed in the AD patients, involving mainly the bilateral frontal lobes (30.07%), parietal lobes (29.96%), temporal lobes (21.07%), and occipital lobes (15.89%). A total of 1422 valid voxels in AD group (including 994 Tau⁺ and 428 Tau^- voxels) and 814 voxels in the control group were selected. The AD patients showed significantly decreased NAA level and increased SUVr compared with the control group (P<0.05). Subgroup analyses revealed that Tau⁺ voxels had higher SUVr and lower Cr and Cho/Cr than Tau^- voxels (P<0.05). Compared with the control group, Tau⁺ voxels exhibited higher SUVr and lower Cr (P<0.05), while Tau^- voxels showed lower NAA (P=0.004). No significant differences were found in Cho or NAA/Cr among the subgroups (P>0.05). Within Tau⁺ voxels, NAA, Cho, and Cr were negatively correlated with SUVr (P<0.001). CONCLUSIONS The patients with progressive AD have significant Tau protein deposition in the brain, which is correlated with alterations in metabolite levels. Decreased NAA is more prominent in early or pre-tau deposition stages, while Cr changes is more significant in the regions with Tau protein deposition, suggesting the potential of NAA and Cr as biomarkers for Tau protein deposition in AD for disease monitoring and treatment evaluation.
Humans ; Alzheimer Disease/diagnostic imaging* ; Aspartic Acid/metabolism* ; tau Proteins/metabolism* ; Creatine/metabolism* ; Brain/metabolism* ; Biomarkers/metabolism* ; Positron-Emission Tomography ; Male ; Female ; Proton Magnetic Resonance Spectroscopy ; Choline/metabolism* ; Aged ; Middle Aged

Vascular damage plays a significant role in the onset and progression of Alzheimer's disease (AD). However, the precise molecular mechanisms underlying the induction of neuronal injury by vascular damage remain unclear. The present study aimed to examine the impact of fibrinogen (Fg) on tau pathology. The results showed that Fg deposits in the brains of tau P301S transgenic mice interact with tau, enhancing the cytotoxicity of pathological tau aggregates and promoting tau phosphorylation and aggregation. Notably, Fg-modified tau fibrils caused enhanced neuronal apoptosis and synaptic damage compared to unmodified fibrils. Furthermore, intrahippocampal injection of Fg-modified tau fibrils worsened the tau pathology, neuroinflammation, synaptic damage, neuronal apoptosis, and cognitive dysfunction in tau P301S mice compared to controls. The present study provides compelling evidence linking Fg and tau, thereby connecting cerebrovascular damage to tau pathology in AD. Consequently, inhibiting Fg-mediated tau pathology could potentially impede the progression of AD.
Animals ; tau Proteins/metabolism* ; Alzheimer Disease/metabolism* ; Fibrinogen/metabolism* ; Mice, Transgenic ; Mice ; Disease Models, Animal ; Memory Disorders/metabolism* ; Male ; Mice, Inbred C57BL ; Brain/metabolism* ; Hippocampus/metabolism* ; Protein Aggregation, Pathological/metabolism* ; Apoptosis ; Phosphorylation

OBJECTIVES: This study aimed to investigate the potential mediating role of plasma phosphorylated tau217 (p-tau217) in the association between periodontitis and mild cognitive impairment (MCI). METHODS: In this case-control study, patients diagnosed with MCI in the Neurology Department of the First Affiliated Hospital of Shandong Second Medical University from November 2023 to May 2024 were selected as the case group (MCI group). Cognitively normal (CN) volunteers, matched for age and education level and recruited from the physical examination center during the same period, served as the control group (CN group). The general demographic data of the study participants were collected. The Beijing versions of the Montreal Cognitive Assessment (MoCA), clinical dementia rating (CDR), and activities of daily living scale (ADL) were used to assess neuropsychological functions. Clinical periodontal examinations were conducted, the periodontal inflamed surface area (PISA) was calculated, and the periodontitis stage was determined in accordance with the 2018 classification. Fasting elbow venous blood samples were collected in the morning, and blood biochemical indicators were measured. Plasma p-tau217 levels were detected using enzyme-linked immunosorbent assay (ELISA). Statistical analyses were performed using t-test, Mann-Whitney U test, chi-square test, partial correlation analysis, multivariate Logistic regression analysis, multiple linear regression analysis, restricted cubic spline (RCS) regression analysis, and mediation effect analysis. RESULTS: Among the 192 participants, 96 belong to the MCI group and 96 to the CN group. The prevalence of periodontitis was 63.5% in the MCI group and 43.8% in the CN group, with a statistically significant difference (χ²=7.561, P=0.006). The plasma p-tau217 levels in the MCI group were significantly higher than those in the CN group [7.00 (4.27-9.65) ng/mL versus 2.02 (0.80-3.81) ng/mL, Z=-8.108, P<0.001]. Partial correlation analysis revealed that plasma p-tau217 levels were positively correlated with all the clinical periodontal indices (all P<0.001). After adjustments for baseline covariates, multivariate Logistic regression indicated that periodontitis was an independent risk factor for MCI. Patients with periodontitis had a 1.977-fold higher MCI risk than those without periodontitis (OR=1.977, 95%CI: 1.088-3.594, P=0.025). Moreover, the MCI risk for stage Ⅰ/Ⅱ periodontitis and stage Ⅲ/Ⅳ periodontitis was 1.878 times (OR=1.878, 95%CI: 1.029-3.425, P=0.040) and 2.625 times (OR=2.625, 95%CI: 1.073-6.246, P=0.035) higher than that for patients without periodontitis, respectively. Trend test showed that the MCI risk increased with periodontitis severity (P_trend=0.016). After adjustments for baseline covariates, multiple linear regression analysis showed that periodontitis was an independent risk factor for increased plasma p-tau217 levels (β=3.309, 95%CI: 2.363-4.254, P<0.001). Compared with patients without periodontitis, those with stage Ⅰ/Ⅱ periodontitis (β=1.838, 95%CI: 0.869-2.806, P<0.001) and stage Ⅲ/Ⅳ periodontitis (β=5.539, 95%CI: 4.442-6.636, P<0.001) had significantly higher plasma p-tau217 levels. In addition, trend test indicated that plasma p-tau217 levels increased with periodontitis severity (P_trend<0.001). After adjustments for baseline covariates, RCS regression analysis further revealed that PISA had a positive linear dose-response relationship with MCI risk (P_overall=0.002, P_nonlinear=0.344) and plasma p-tau217 levels (P_overall<0.001, P_nonlinear=0.140). After adjustments for baseline covariates, mediation analysis showed that plasma p-tau217 mediated the association between periodontitis and MCI, with a mediation proportion of 13.99% (95% Bootstrap CI: 0.38%-49.39%, P=0.038). CONCLUSIONS Periodontitis was independently positively associated with MCI risk, and plasma p-tau217 plays a mediating role in this association.
Humans ; Cognitive Dysfunction/complications* ; tau Proteins/blood* ; Periodontitis/complications* ; Case-Control Studies ; Male ; Female ; Phosphorylation ; Aged ; Middle Aged ; Activities of Daily Living

The accumulation and spread of prion-like proteins is a key feature of neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, or Amyotrophic Lateral Sclerosis. In a process known as 'seeding', prion-like proteins such as amyloid beta, microtubule-associated protein tau, α-synuclein, silence superoxide dismutase 1, or transactive response DNA-binding protein 43 kDa, propagate their misfolded conformations by transforming their respective soluble monomers into fibrils. Cellular and molecular evidence of prion-like propagation in NDs, the clinical relevance of their 'seeding' capacities, and their levels of contribution towards disease progression have been intensively studied over recent years. This review unpacks the cyclic prion-like propagation in cells including factors of aggregate internalization, endo-lysosomal leaking, aggregate degradation, and secretion. Debates on the importance of the role of prion-like protein aggregates in NDs, whether causal or consequent, are also discussed. Applications lead to a greater understanding of ND pathogenesis and increased potential for therapeutic strategies.
Humans ; Prions ; Neurodegenerative Diseases/pathology* ; Amyloid beta-Peptides ; Alzheimer Disease ; alpha-Synuclein ; tau Proteins ; Parkinson Disease

Alzheimer's disease (AD) is a neurodegenerative disorder with an insidious onset, primarily characterized by a progressive decline in cognitive function. MCP-1 is a cytokine with chemotactic effects on monocytes, which can regulate their migration and infiltration and participate in disease progression. Increasing evidence suggests that MCP-1 plays a key role in the progression of Alzheimer's disease and has the potential to act as an early diagnostic marker and intervention target. This paper reviews the regulatory role of MCP-1 in neuroinflammation, beta-amyloid (Aβ) deposition and Tau pathology, and explores the potential of MCP-1 as a biomarker and intervention target for the early diagnosis of Alzheimer's disease.
Alzheimer Disease/metabolism* ; Humans ; Chemokine CCL2/genetics* ; Amyloid beta-Peptides/metabolism* ; Animals ; tau Proteins/metabolism* ; Biomarkers/metabolism*

Extracellular deposition of β-amyloid (Aβ) and intracellular hyperphosphorylated tau are the predominant pathological changes in Alzheimer's disease (AD). Increasing evidence demonstrates a critical role of a variety of small GTPases, namely Ras-related proteins (Rabs), in the pathogenesis of AD. As crucial regulators of intracellular membrane trafficking, alteration in Rab protein expression and function represents one of the primary factors contributing to the abnormal membrane trafficking in AD. Additionally, the Rab GTPases are also involved in the development of Aβ, tau and other pathological changes associated with AD. In this article, we conduct a comprehensive review on the primary functions of multiple Rab proteins and their involvement in the pathogenesis of AD.
Humans ; Alzheimer Disease ; rab GTP-Binding Proteins/metabolism* ; Amyloid beta-Peptides/metabolism* ; tau Proteins/metabolism*

Rats ; Animals ; Okadaic Acid/toxicity* ; PC12 Cells ; Triterpenes ; tau Proteins/metabolism* ; Phosphorylation