Although the existence of proteasomes in human blood, termed circulating proteasomes (c-proteasomes), has been reported previously, their origin and pathophysiological functions remain largely unknown.Given that c-proteasome activity was significantly reduced in Alzheimer's disease model mice and relatively high frequency of mild cognitive impairment (MCI) is accompanied by chronic tinnitus in aged patients, we examined whether c-proteasome activity in human plasma was associated with cognitive function in patients with chronic tinnitus.c-Proteasome activity in the plasma of tinnitus patients (N = 55) was measured with fluorogenic reporter substrate, suc-LLVY-AMC. To assess MCI, the Montreal Cognitive Assessment was conducted with a cut-off score of 22/23. All patients underwent audiological and psychoacoustic analyses. Levels of c-proteasomes, Aβ42, and Aβ40 were measured using ELISA, and their association with c-proteasome activity was evaluated.The activity of circulating proteasomes was significantly lower in patients with chronic tinnitus and MCI (p = 0.042), whereas activities of other plasma enzymes showed little correlation. In addition, c-proteasome activity was negatively associated with the level of plasma Aβ and was directly dependent on its own concentration in the plasma of patients with chronic tinnitus.Our current work provides a new perspective for understanding the potential relationship between circulating proteasomes in the plasma and cognitive dysfunction, suggesting a novel, non-invasive biomarker in the context of MCI diagnosis.
Alzheimer's disease (AD), which is the most common type of dementia, is characterized by the deposition of extracellular amyloid plaques. To understand the pathophysiology of the AD brain, the assessment of global proteomic dynamics is required. Since the hippocampus is a major region affected in the AD brain, we performed hippocampal analysis and identified proteins that are differentially expressed between wild-type and 5XFAD model mice via LC-MS methods. To reveal the relationship between proteomic changes and the progression of amyloid plaque deposition in the hippocampus, we analyzed the hippocampal proteome at two ages (5 and 10 months). We identified 9,313 total proteins and 1411 differentially expressed proteins (DEPs) in 5- and 10-month-old wild-type and 5XFAD mice. We designated a group of proteins showing the same pattern of changes as amyloid beta (Aβ) as the Aβ-responsive proteome. In addition, we examined potential biomarkers by investigating secretory proteins from the Aβ-responsive proteome. Consequently, we identified vitamin K-dependent protein S (PROS1) as a novel microglia-derived biomarker candidate in the hippocampus of 5XFAD mice. Moreover, we confirmed that the PROS1 level in the serum of 5XFAD mice increases as the disease progresses. An increase in PROS1 is also observed in the sera of AD patients and shows a close correlation with AD neuroimaging markers in humans. Therefore, our quantitative proteome data obtained from 5XFAD model mice successfully predicted AD-related biological alterations and suggested a novel protein biomarker for AD.
We recently developed a multiplex diagnostic kit, QPLEX™ Alz plus assay kit, which captures amyloid-β1-40, galectin-3 binding protein, angiotensin-converting enzyme, and periostin simultaneously using microliters of peripheral blood and utilizes an optimized algorithm for screening Alzheimer’s disease (AD) by correlating with cerebral amyloid deposition. Owing to the demand for early AD detection, we investigate the potential of our kit for the early clinical diagnosis of AD. A total of 1395 participants were recruited, and their blood samples were analyzed with the QPLEX™ kit. The average of QPLEX™ algorithm values in each group increased gradually in the order of the clinical progression continuum of AD: cognitively normal (0.382 ± 0.150), subjective cognitive decline (0.452 ± 0.130), mild cognitive impairment (0.484 ± 0.129), and AD (0.513 ± 0.136). The algorithm values between each group showed statistically significant differences among groups divided by Mini-Mental State Examination and Clinical Dementia Rating. The QPLEX™ algorithm values could be used to distinguish the clinical continuum of AD or cognitive function. Because blood-based diagnosis is more accessible, convenient, and cost- and time-effective than cerebral spinal fluid or positron emission tomography imaging-based diagnosis, the QPLEX™ kit can potentially be used for health checkups and the early clinical diagnosis of AD.
Abstract The deposition of beta-amyloid (Aβ) in the brain precedes the onset of symptoms such as cognitive impairment in Alzheimer’s disease (AD); therefore, the early detection of Aβ accumulation is crucial. We previously reported the applicability of the QPLEX TM Alz plus assay kit for the prescreening of Aβ accumulation. Here, we tested the specific application of the kit in a large cohort of cognitively normal (CN) individuals of varying ages for the early detection of Aβ accumulation. We included a total of 221 CN participants with or without brain Aβ. The QPLEX TM biomarkers were characterized based on age groups (1 st –3 rd tertile) and across various brain regions with cerebral amyloid deposition. The 3 rd tertile group (>65 years) was found to be the most suitable age group for the application of our assay kit. Receiver operating characteristic curve analysis showed that the area under the curve (AUC, discrimination power) was 0.878 with 69.7% sensitivity and 98.4% specificity in the 3 rd tertile group. Additionally, specific correlations between biomarkers and cerebral amyloid deposition in four different brain regions revealed an overall correlation with general amyloid deposition, consistent with previous findings. Furthermore, the combinational panel with plasma Aβ1–42 levels maximized the discrimination efficiency and achieved an AUC of 0.921 with 95.7% sensitivity and 67.3% specificity. Thus, we suggest that the QPLEX TM Alz plus assay is useful for prescreening brain Aβ levels in CN individuals, especially those aged >65 years, to prevent disease progression via the early detection of disease initiation.
Alzheimer's disease (AD) is the leading cause of dementia, and many studies have focused on finding effective blood biomarkers for the accurate diagnosis of this disease. Predicting cerebral amyloid deposition is considered the key for AD diagnosis because a cerebral amyloid deposition is the hallmark of AD pathogenesis. Previously, blood biomarkers were discovered to predict cerebral amyloid deposition, and further efforts have been made to increase their sensitivity and specificity. In this study, we analyzed blood-test factors (BTFs) that can be commonly measured in medical health check-ups from 149 participants with cognitively normal, 87 patients with mild cognitive impairment, and 64 patients with clinically diagnosed AD dementia with brain amyloid imaging data available. We demonstrated that four factors among regular health check-up blood tests, cortisol, triglyceride/high-density lipoprotein cholesterol ratio, alanine aminotransferase, and free triiodothyronine, showed either a significant difference by or correlation with cerebral amyloid deposition. Furthermore, we made a prediction model for Pittsburgh compound B-positron emission tomography positivity, using BTFs and the previously discovered blood biomarkers, the QPLEXTM Alz plus assay kit biomarker panel, and the area under the curve was significantly increased up to 0.845% with 69.4% sensitivity and 90.6% specificity. These results show that BTFs could be used as co-biomarkers and that a highly advanced prediction model for amyloid plaque deposition could be achieved by the combinational use of diverse biomarkers.
Alzheimer's disease (AD), characterized by progressive cognitive decline, is the most prevalent neurodegenerative disease in the elderly. Cerebral β-amyloid (Aβ) deposition is the major pathological hallmark of AD. Recent studies also have shown that the serum level of phosphorus correlates to the risk of incident dementia. To date, however, the linkage between cerebral Aβ deposition and the serum phosphorus level or factors from routine blood test (FRBT) remains unknown. In this study, we analyzed the levels of serum phosphorus in 109 mild cognitive impairment (MCI) and 73 AD dementia (ADD) subjects. Also, other FRBT (triiodothyronine III, cholesterol, cortisol, ALT-S) were used as covariates. All subjects underwent Pittsburgh compound B positron emission tomography (PiB-PET) imaging to measure cerebral Aβ deposition. The results with Aβ deposition was compared with the serum levels of phosphorus or FRBT. The subjects with cerebral Aβ deposition showed significantly different levels of serum phosphorus, triiodothyronine III, cholesterol, cortisol, and ALT-S than those without Aβ deposition. Multiple regression analyses showed that a low level of serum phosphorus correlated with cerebral Aβ deposition, even when age, sex, apolipoprotein E ε4 genotype, and MMSE z-score were controlled for. Serum levels of other ions, including calcium, iron, zinc, and copper, showed no such correlation. Our results suggest that combined model of phosphorus with other FRBTs may be used as an easily accessible blood biomarker for cerebral Aβ deposition in a cognitively impaired population.
Other SectionsABSTRACTINTRODUCTIONPRO-INFLAMMATORY CYTOKINES IN ADANTI-INFLAMMATORY CYTOKINES IN ADTHE ROLE OF INTESTINAL CYTOKINES (BRAIN-GUT AXIS) IN ADPOTENTIAL USE OF BLOOD IMMUNE CELLS AS BIOMARKERS FOR ADCOMPLEMENTS AS BIOMARKERS FOR ADCONCLUSIONACKNOWLEDGEMENTSCONFLICTS OF INTERESTFIGURETABLEREFERENCES
Abstract Microglia play a crucial role in synaptic elimination by engulfing dystrophic neurons via triggering receptors expressed on myeloid cells 2 (TREM2). They are also involved in the clearance of beta‐amyloid (Aβ) plaques in Alzheimer's disease (AD); nonetheless, the driving force behind TREM2‐mediated phagocytosis of beta‐amyloid (Aβ) plaques remains unknown. Here, using advanced 2D/3D/4D co‐culture systems with loss‐of‐function mutations in TREM2 (a frameshift mutation engineered in exon 2) brain organoids/microglia/assembloids, it is identified that the clearance of Aβ via TREM2 is accelerated by externalized phosphatidylserine (ePtdSer) generated from dystrophic neurons surrounding the Aβ plaques. Moreover, it is investigated whether microglia from both sporadic (CRISPR‐Cas9‐based APOE4 lines) and familial ( APP NL‐G‐F / MAPT double knock‐in mice) AD models show reduced levels of TREM2 and lack of phagocytic activity toward ePtdSer‐positive Aβ plaques. Herein new insight is provided into TREM2‐dependent microglial phagocytosis of Aβ plaques in the context of the presence of ePtdSer during AD progression.
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