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BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder influenced by age, sex, genetic factors, immune alterations, and infections. Multiple lines of evidence suggest that changes in antibody response are linked to AD pathology. METHODS: To elucidate the mechanisms underlying AD development, we investigated antibodies that target autoimmune epitopes using high-resolution epitope microarrays. Our study compared two groups: individuals with AD (n = 19) and non-demented (ND) controls (n = 19). To validate the results, we measured antibody levels in plasma samples from AD patients (n = 96), mild cognitive impairment (MCI; n = 91), and ND controls (n = 97). To further explore the invlovement of EBV, we performed epitope masking immunofluorescence microscopy analysis and tests to induce lytic replication using the B95-8 cell line. RESULTS: In this study, we analyzed high-resolution epitope-specific serum antibody levels in AD, revealing significant disparities in antibodies targeting multiple epitopes between the AD and control groups. Particularly noteworthy was the significant down-regulation of antibody (anti-DG#29) targeting an epitope of Epstein-Barr virus nuclear antigen 1 (EBNA1). This down-regulation increased AD risk in female patients (odds ratio up to 6.6), but not in male patients. Our investigation further revealed that the down-regulation of the antibody (anti-DG#29) is associated with EBV reactivation in AD, as indicated by the analysis of EBV VCA IgG or IgM levels. Additionally, our data demonstrated that the epitope region on EBNA1 for the antibody is hidden during the EBV lytic reactivation of B95-8 cells. CONCLUSION: Our findings suggest a potential relationship of EBV in the development of AD in female. Moreover, we propose that antibodies targeting the epitope (DG#29) of EBNA1 could serve as valuable indicators of AD risk in female.
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Enfermedad de Alzheimer , Anticuerpos Antivirales , Epítopos , Antígenos Nucleares del Virus de Epstein-Barr , Herpesvirus Humano 4 , Humanos , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/virología , Enfermedad de Alzheimer/sangre , Femenino , Masculino , Antígenos Nucleares del Virus de Epstein-Barr/inmunología , Anciano , Anticuerpos Antivirales/sangre , Epítopos/inmunología , Herpesvirus Humano 4/inmunología , Disfunción Cognitiva/inmunología , Anciano de 80 o más Años , Infecciones por Virus de Epstein-Barr/inmunología , Persona de Mediana EdadRESUMEN
Background: We previously demonstrated the validity of a regression model that included ethnicity as a novel predictor for predicting normative brain volumes in old age. The model was optimized using brain volumes measured with a standard tool FreeSurfer. Objective: Here we further verified the prediction model using newly estimated brain volumes from Neuro I, a quantitative brain analysis system developed for Korean populations. Methods: Lobar and subcortical volumes were estimated from MRI images of 1,629 normal Korean and 786 Caucasian subjects (age range 59-89) and were predicted in linear regression from ethnicity, age, sex, intracranial volume, magnetic field strength, and scanner manufacturers. Results: In the regression model predicting the new volumes, ethnicity was again a substantial predictor in most regions. Additionally, the model-based z-scores of regions were calculated for 428 AD patients and the matched controls, and then employed for diagnostic classification. When the AD classifier adopted the z-scores adjusted for ethnicity, the diagnostic accuracy has noticeably improved (AUCâ=â0.85, ΔAUCâ=â+â0.04, Dâ=â4.10, pâ<â0.001). Conclusions: Our results suggest that the prediction model remains robust across different measurement tool, and ethnicity significantly contributes to the establishment of norms for brain volumes and the development of a diagnostic system for neurodegenerative diseases.
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Enfermedad de Alzheimer , Encéfalo , Imagen por Resonancia Magnética , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Alzheimer/etnología , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/diagnóstico , Pueblo Asiatico , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Tamaño de los Órganos , Población Blanca , Pueblos del Este de AsiaRESUMEN
The gut-brain axis (GBA) plays a significant role in various neurodegenerative disorders, such as Alzheimer's disease (AD), and the gut microbiome (GM) can bidirectionally communicate with the brain through the GBA. Thus, recent evidence indicates that the GM may affect the pathological features and the progression of AD in humans. The aim of our study was to elucidate the impact of probiotics on the pathological features of AD in a 5xFAD model. Probiotics (Bifidobacterium lactis, Levilactobacillus brevis, and Limosilactobacillus fermentum) were orally administered in 5xFAD mice to modify the GM composition. Additionally, freeze-dried food containing phosphatidylserine was used as the positive control. Behavioral pathogenesis was assessed through the cross maze and Morris water maze tests. Our findings revealed that probiotic administration resulted in significant improvements in spatial and recognition memories. Furthermore, the neuroprotective effects of probiotics were substantiated by a reduction in amyloid-ß accumulation in critical brain regions. Microglial activation in 5xFAD mice was also attenuated by probiotics in the hippocampus and cerebral cortex. Moreover, elevated tau phosphorylation in 5xFAD mice was ameliorated in the probiotics-treated group. The results highlight the potential use of probiotics as a neuroprotective intervention in AD.
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Amyloid-ß (Aß) oligomers are implicated in the onset of Alzheimer's disease (AD). Herein, quinoline-derived half-curcumin-dioxaborine (Q-OB) fluorescent probe was designed for detecting Aß oligomers by finely tailoring the hydrophobicity of the biannulate donor motifs in donor-π-acceptor structure. Q-OB shows a great sensing potency in dynamically monitoring oligomerization of Aß during amyloid fibrillogenesis in vitro. In addition, we applied this strategy to fluorometrically analyze Aß self-assembly kinetics in the cerebrospinal fluids (CSF) of AD patients. The fluorescence intensity of Q-OB in AD patients' CSF revealed a marked change of log (I/I0) value of 0.34 ± 0.13 (cognitive normal), 0.15 ± 0.12 (mild cognitive impairment), and 0.14 ± 0.10 (AD dementia), guiding to distinguish a state of AD continuum for early diagnosis of AD. These studies demonstrate the potential of our approach can expand the currently available preclinical diagnostic platform for the early stages of AD, aiding in the disruption of pathological progression and the development of appropriate treatment strategies.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Proteínas Amiloidogénicas , Proteínas tau/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeoRESUMEN
Alzheimer's Disease (AD) is one of the most common neurodegenerative disorders in elderly people. It is diagnosed by detecting amyloid beta (Aß) protein in cerebrospinal fluid (CSF) obtained by lumbar puncture or through expensive positron emission tomography (PET) imaging. Although blood-based diagnosis of AD offers a less invasive and cost-effective alternative, the quantification of Aß is technically challenging due to its low abundance in peripheral blood. To address this, we developed a compact yet highly sensitive microwell-based electrochemical sensor with a densely packed microelectrode array (20 by 20) for enhancing sensitivity. Employing microwells on the working and counter electrodes minimized the leakage current from the metallic conductors into the assay medium, refining the signal fidelity. We achieved a detection limit <10 fg/mL for Aß by elevating the signal-to-noise ratio, thus capable of AD biomarker quantification. Moreover, the microwell structure maintained the performance irrespective of variations in bead number, indicative of the sensor's robustness. The sensor's efficacy was validated through the analysis of Aß concentrations in plasma samples from 96 subjects, revealing a significant distinction between AD patients and healthy controls with an area under the receiver operating characteristic curve (AUC) of 0.85. Consequently, our novel microwell-based electrochemical biosensor represents a highly sensitive platform for detecting scant blood-based biomarkers, including Aß, offering substantial potential for advancing AD diagnostics.
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Enfermedad de Alzheimer , Técnicas Biosensibles , Humanos , Anciano , Péptidos beta-Amiloides , Tomografía de Emisión de Positrones/métodos , Biomarcadores/líquido cefalorraquídeo , Microelectrodos , Proteínas tau , Fragmentos de PéptidosRESUMEN
Brain age prediction is a practical method used to quantify brain aging and detect neurodegenerative diseases such as Alzheimer's disease (AD). However, very few studies have considered brain age prediction as a biomarker for the conversion of cognitively normal (CN) to mild cognitive impairment (MCI). In this study, we developed a novel brain age prediction model using brain volume and cortical thickness features. We calculated an acceleration of brain age (ABA) derived from the suggested model to estimate different diagnostic groups (CN, MCI, and AD) and to classify CN to MCI and MCI to AD conversion groups. We observed a strong association between ABA and the 3 diagnostic groups. Additionally, the classification models for CN to MCI conversion and MCI to AD conversion exhibited acceptable and robust performances, with area under the curve values of 0.66 and 0.76, respectively. We believe that our proposed model provides a reliable estimate of brain age for elderly individuals and can identify those at risk of progressing from CN to MCI. This model has great potential to reveal a diagnosis associated with a change in cognitive decline.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Anciano , Disfunción Cognitiva/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Envejecimiento/patología , Imagen por Resonancia Magnética/métodos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patologíaRESUMEN
The gut-brain axis encompasses a bidirectional communication pathway between the gastrointestinal microbiota and the central nervous system. There is some evidence to suggest that probiotics may have a positive effect on cognitive function, but more research is needed before any definitive conclusions can be drawn. Inflammation-induced by lipopolysaccharide (LPS) may affect cognitive function. To confirm the effect of probiotics on oxidative stress induced by LPS, the relative expression of antioxidant factors was confirmed, and it was revealed that the administration of probiotics had a positive effect on the expression of antioxidant-related factors. After oral administration of probiotics to mice, an intentional inflammatory response was induced through LPS i.p., and the effect on cognition was confirmed by the Morris water maze test, nitric oxide (NO) assay, and interleukin (IL)-1ß enzyme-linked immunosorbent assay performed. Experimental results, levels of NO and IL-1 ß in the blood of LPS i.p. mice were significantly decreased, and cognitive evaluation using the Morris water maze test showed significant values in the latency and target quadrant percentages in the group that received probiotics. This proves that intake of these probiotics improves cognitive impairment and memory loss through anti-inflammatory and antioxidant mechanisms.
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This study examined the single-nucleotide polymorphism heritability and genetic correlations of cognitive abilities and brain structural measures (regional subcortical volume and cortical thickness) in middle-aged and elderly East Asians (Korean) from the Gwangju Alzheimer's and Related Dementias cohort study. Significant heritability was found in memory function, caudate volume, thickness of the entorhinal cortices, pars opercularis, superior frontal gyri, and transverse temporal gyri. There were 3 significant genetic correlations between (i) the caudate volume and the thickness of the entorhinal cortices, (ii) the thickness of the superior frontal gyri and pars opercularis, and (iii) the thickness of the superior frontal and transverse temporal gyri. This is the first study to describe the heritability and genetic correlations of cognitive and neuroanatomical traits in middle-aged to elderly East Asians. Our results support the previous findings showing that genetic factors play a substantial role in the cognitive and neuroanatomical traits in middle to advanced age. Moreover, by demonstrating shared genetic effects on different brain regions, it gives us a genetic insight into understanding cognitive and brain changes with age, such as aging-related cognitive decline, cortical atrophy, and neural compensation.
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Encéfalo , Pueblos del Este de Asia , Anciano , Persona de Mediana Edad , Humanos , Estudios de Cohortes , Encéfalo/diagnóstico por imagen , Corteza Cerebral , Cognición , Imagen por Resonancia Magnética/métodosRESUMEN
Accurate parcellation of cortical regions is crucial for distinguishing morphometric changes in aged brains, particularly in degenerative brain diseases. Normal aging and neurodegeneration precipitate brain structural changes, leading to distinct tissue contrast and shape in people aged >60 years. Manual parcellation by trained radiologists can yield a highly accurate outline of the brain; however, analyzing large datasets is laborious and expensive. Alternatively, newly-developed computational models can quickly and accurately conduct brain parcellation, although thus far only for the brains of Caucasian individuals. To develop a computational model for the brain parcellation of older East Asians, we trained magnetic resonance images of dimensions 256 × 256 × 256 on 5,035 brains of older East Asians (Gwangju Alzheimer's and Related Dementia) and 2,535 brains of Caucasians. The novel N-way strategy combining three memory reduction techniques inception blocks, dilated convolutions, and attention gates was adopted for our model to overcome the intrinsic memory requirement problem. Our method proved to be compatible with the commonly used parcellation model for Caucasians and showed higher similarity and robust reliability in older aged and East Asian groups. In addition, several brain regions showing the superiority of the parcellation suggest that DeepParcellation has a great potential for applications in neurodegenerative diseases such as Alzheimer's disease.
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The diagnosis of Alzheimer's disease (AD) needs to be improved. We investigated if hippocampal subfield volume measured by structural imaging, could supply information, so that the diagnosis of AD could be improved. In this study, subjects were classified based on clinical, neuropsychological, and amyloid positivity or negativity using PET scans. Data from 478 elderly Korean subjects grouped as cognitively unimpaired ß-amyloid-negative (NC), cognitively unimpaired ß-amyloid-positive (aAD), mild cognitively impaired ß-amyloid-positive (pAD), mild cognitively impaired-specific variations not due to dementia ß-amyloid-negative (CIND), severe cognitive impairment ß-amyloid-positive (ADD+) and severe cognitive impairment ß-amyloid-negative (ADD-) were used. NC and aAD groups did not show significant volume differences in any subfields. The CIND did not show significant volume differences when compared with either the NC or the aAD (except L-HATA). However, pAD showed significant volume differences in Sub, PrS, ML, Tail, GCMLDG, CA1, CA4, HATA, and CA3 when compared with the NC and aAD. The pAD group also showed significant differences in the hippocampal tail, CA1, CA4, molecular layer, granule cells/molecular layer/dentate gyrus, and CA3 when compared with the CIND group. The ADD- group had significantly larger volumes than the ADD+ group in the bilateral tail, SUB, PrS, and left ML. The results suggest that early amyloid depositions in cognitive normal stages are not accompanied by significant bilateral subfield volume atrophy. There might be intense and accelerated subfield volume atrophy in the later stages associated with the cognitive impairment in the pAD stage, which subsequently could drive the progression to AD dementia. Early subfield volume atrophy associated with the ß-amyloid burden may be characterized by more symmetrical atrophy in CA regions than in other subfields. We conclude that the hippocampal subfield volumetric differences from structural imaging show promise for improving the diagnosis of Alzheimer's disease.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Imagen por Resonancia Magnética , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Atrofia/patología , Péptidos beta-Amiloides , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/patologíaRESUMEN
[This corrects the article DOI: 10.3389/fnut.2022.873623.].
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Objective: To examine the changes in body composition, water compartment, and bioimpedance in mild cognitive impairment (MCI) individuals. Methods: We obtained seven whole-body composition variables and seven pairs of segmental body composition, water compartment, and impedance variables for the upper and lower extremities from the segmental multi-frequency bioelectrical impedance analysis (BIA) of 939 elderly participants, including 673 cognitively normal (CN) people and 266 individuals with MCI. Participants' characteristics, anthropometric information, and the selected BIA variables were described and statistically compared between the CN participants and those with MCI. The correlations between the selected BIA variables and neuropsychological tests such as the Korean version of the Mini-Mental State Examination and Seoul Neuropsychological Screening Battery - Second Edition were also examined before and after controlling for age and sex. Univariate and multivariate logistic regression analyses with estimated odds ratios (ORs) were conducted to investigate the associations between these BIA variables and MCI prevalence for different sexes. Results: Participants with MCI were slightly older, more depressive, and had significantly poorer cognitive abilities when compared with the CN individuals. The partial correlations between the selected BIA variables and neuropsychological tests upon controlling for age and sex were not greatly significant. However, after accounting for age, sex, and the significant comorbidities, segmental lean mass, water volume, resistance, and reactance in the lower extremities were positively associated with MCI, with ORs [95% confidence interval (CI)] of 1.33 (1.02-1.71), 1.33 (1.03-1.72), 0.76 (0.62-0.92), and 0.79 (0.67-0.93), respectively; with presumably a shift of water from the intracellular area to extracellular space. After stratifying by sex, resistance and reactance in lower extremities remained significant only in the women group. Conclusion: An increase in segmental water along with segmental lean mass and a decrease in body cell strength due to an abnormal cellular water distribution demonstrated by reductions in resistance and reactance are associated with MCI prevalence, which are more pronounced in the lower extremities and in women. These characteristic changes in BIA variables may be considered as an early sign of cognitive impairment in the elderly population.
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Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia. Amyloid-ß (Aß) has long been considered a key cause of neurodegeneration in the AD brain. Although the mechanisms underlying Aß-induced neurodegeneration are not fully understood, a number of recent studies have suggested that intracellular calcium overload mediates this process. In this study, we focused on the cellular function of phospholipase C-ß1 (PLCB1), which regulates calcium signaling by mediating hydrolysis of phosphatidylinositol 4,5-bisphosphate through G-protein coupled receptor pathways. First, we confirmed that acetylcholine-induced calcium release from intracellular stores of SH-SY5Y cells was significantly increased with Aß42 oligomer treatment. We further found that PLCB1 expression was upregulated in Aß42-treated cells, and PLCB1 overexpression in SH-SY5Y cells elicited the calcium overload observed in Aß-treated cells. In addition, Aß42 oligomer-induced calcium overload in SH-SY5Y cells was alleviated by knockdown of PLCB1, indicating that PLCB1 plays an essential role in the neurotoxic process initiated by Aß. The elevation of PLCB1 expression was confirmed in the brain tissues from the 5× familial AD (5×FAD) model mice. These findings suggest that PLCB1 may represent a potential therapeutic target for protecting neuronal cells against excitotoxicity in AD progression.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Calcio , Neuroblastoma , Fosfolipasa C beta , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Calcio/metabolismo , Línea Celular Tumoral , Humanos , Ratones , Neuroblastoma/metabolismo , Fragmentos de Péptidos/metabolismo , Fosfolipasa C beta/biosíntesisRESUMEN
INTRODUCTION: Basic studies suggest that olfactory dysfunction and functional near-infrared spectroscopy (fNIRS) can be used as tools for the diagnosis of mild cognitive impairment (MCI); however, real-world evidence is lacking. We investigated the potential diagnostic efficacy of olfactory-stimulated fNIRS for early detection of MCI and/or Alzheimer disease (AD). METHODS: We conducted a patient-level, single-group, diagnostic interventional trial involving elderly volunteers (age >60 years) suspected of declining cognitive function. Patients received open-label olfactory-stimulated fNIRS for measurement of oxygenation difference in the orbitofrontal cortex. All participants underwent amyloid PET, MRI, Mini-Mental State Examination (MMSE), and Seoul Neuropsychological Screening Battery (SNSB). RESULTS: Of 97 subjects, 28 (28.9%) were cognitively normal, 32 (33.0%) had preclinical AD, 21 (21.6%) had MCI, and 16 (16.5%) had AD. Olfactory-stimulated oxygenation differences in the orbitofrontal cortex were associated with cognitive impairment; the association was more pronounced with cognitive severity. Olfactory-stimulated oxygenation difference was associated with MMSE (adjusted ß [aß] 1.001; 95% CI 0.540-1.463), SNSB language and related function (aß, 1.218; 95% CI, 0.020-2.417), SNSB memory (aß, 1.963; 95% CI, 0.841-3.084), SNSB frontal/executive function (aß, 1.715; 95% CI, 0.401-3.029) scores, standard uptake value ratio from amyloid PET (aß, -10.083; 95% CI, -19.063 to -1.103), and hippocampal volume from MRI (aß, 0.002; 95% CI, 0.001-0.004). Olfactory-stimulated oxygenation difference in the orbitofrontal cortex was superior in diagnosing MCI and AD (AUC, 0.909; 95% CI, 0.848-0.971), compared to amyloid PET (AUC, 0.793; 95% CI, 0.694-0.893) or MRI (AUC, 0.758; 95% CI, 0.644-0.871). DISCUSSION: Our trial showed that olfactory-stimulated oxygenation differences in the orbitofrontal cortex detected by fNIRS were associated with cognitive impairment and cognitive-related objectives. This novel approach may be a potential diagnostic tool for patients with MCI and/or AD. TRIAL REGISTRATION: CRIS number, KCT0006197 .
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Enfermedad de Alzheimer , Disfunción Cognitiva , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Amiloide , Péptidos beta-Amiloides , Disfunción Cognitiva/diagnóstico por imagen , Humanos , Pruebas de Estado Mental y Demencia , Persona de Mediana Edad , Pruebas Neuropsicológicas , Espectroscopía Infrarroja CortaRESUMEN
Alzheimer disease (AD) is a leading cause of dementia that has gained prominence in our aging society. Yet, the complexity of diagnosing AD and measuring its invasiveness poses an obstacle. To this end, blood-based biomarkers could mitigate the inconveniences that impede an accurate diagnosis. We developed models to diagnose AD and measure the severity of neurocognitive impairment using blood protein biomarkers. Multiple reaction monitoring-mass spectrometry, a highly selective and sensitive approach for quantifying targeted proteins in samples, was used to analyze blood samples from 4 AD groups: cognitive normal control, asymptomatic AD, prodromal AD), and AD dementia. Multimarker models were developed using 10 protein biomarkers and apolipoprotein E genotypes for amyloid beta and 10 biomarkers with Korean Mini-Mental Status Examination (K-MMSE) score for predicting Alzheimer disease progression. The accuracies for the AD classification model and AD progression monitoring model were 84.9% (95% CI 82.8 to 87.0) and 79.1% (95% CI 77.8 to 80.5), respectively. The models were more accurate in diagnosing AD, compared with single APOE genotypes and the K-MMSE score. Our study demonstrates the possibility of predicting AD with high accuracy by blood biomarker analysis as an alternative method of screening for AD.
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Enfermedad de Alzheimer/sangre , Biomarcadores/sangre , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Femenino , Humanos , Masculino , Espectrometría de Masas , Pruebas de Estado Mental y Demencia , Modelos EstadísticosRESUMEN
Potential biomarkers for Alzheimer's disease (AD) include amyloid ß1-42 (Aß1-42), t-Tau, p-Tau181, neurofilament light chain (NFL), and neuroimaging biomarkers. Their combined use is useful for diagnosing and monitoring the progress of AD. Therefore, further development of a combination of these biomarkers is essential. We investigated whether plasma NFL/Aß1-42 can serve as a plasma-based primary screening biomarker reflecting brain neurodegeneration and amyloid pathology in AD for monitoring disease progression and early diagnosis. We measured the NFL and Aß1-42 concentrations in the CSF and plasma samples and performed correlation analysis to evaluate the utility of these biomarkers in the early diagnosis and monitoring of AD spectrum disease progression. Pearson's correlation analysis was used to analyse the associations between the fluid biomarkers and neuroimaging data. The study included 136 participants, classified into five groups: 28 cognitively normal individuals, 23 patients with preclinical AD, 22 amyloid-negative patients with amnestic mild cognitive impairment, 32 patients with prodromal AD, and 31 patients with AD dementia. With disease progression, the NFL concentrations increased and Aß1-42 concentrations decreased. The plasma and CSF NFL/Aß1-42 were strongly correlated (r = 0.558). Plasma NFL/Aß1-42 was strongly correlated with hippocampal volume/intracranial volume (r = 0.409). In early AD, plasma NFL/Aß1-42 was associated with higher diagnostic accuracy than the individual biomarkers. Moreover, in preclinical AD, plasma NFL/Aß1-42 changed more rapidly than the CSF t-Tau or p-Tau181 concentrations. Our findings highlight the utility of plasma NFL/Aß1-42 as a non-invasive plasma-based biomarker for early diagnosis and monitoring of AD spectrum disease progression.
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Established genetic risk factors for Alzheimer's disease (AD) account for only a portion of AD heritability. The aim of this study was to identify novel associations between genetic variants and AD-specific brain atrophy. We conducted genome-wide association studies for brain magnetic resonance imaging measures of hippocampal volume and entorhinal cortical thickness in 2643 Koreans meeting the clinical criteria for AD (n = 209), mild cognitive impairment (n = 1449) or normal cognition (n = 985). A missense variant, rs77359862 (R274W), in the SHANK-associated RH Domain Interactor (SHARPIN) gene was associated with entorhinal cortical thickness (p = 5.0 × 10-9) and hippocampal volume (p = 5.1 × 10-12). It revealed an increased risk of developing AD in the mediation analyses. This variant was also associated with amyloid-ß accumulation (p = 0.03) and measures of memory (p = 1.0 × 10-4) and executive function (p = 0.04). We also found significant association of other SHARPIN variants with hippocampal volume in the Alzheimer's Disease Neuroimaging Initiative (rs3417062, p = 4.1 × 10-6) and AddNeuroMed (rs138412600, p = 5.9 × 10-5) cohorts. Further, molecular dynamics simulations and co-immunoprecipitation indicated that the variant significantly reduced the binding of linear ubiquitination assembly complex proteins, SHPARIN and HOIL-1 Interacting Protein (HOIP), altering the downstream NF-κB signaling pathway. These findings suggest that SHARPIN plays an important role in the pathogenesis of AD.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/genética , Estudio de Asociación del Genoma Completo , Humanos , Imagen por Resonancia Magnética , Proteínas del Tejido Nervioso , UbiquitinasRESUMEN
Lipocalin-2 (LCN2) is an inflammatory protein with diverse functions in the brain. Although many studies have investigated the mechanism of LCN2 in brain injuries, the effect of LCN2 on amyloid-toxicity-related memory deficits in a mouse model of Alzheimer's disease (AD) has been less studied. We investigated the role of LCN2 in human AD patients using a mouse model of AD. We created an AD mouse model by injecting amyloid-beta oligomer (AßO) into the hippocampus. In this model, animals exhibited impaired learning and memory. We found LCN2 upregulation in the human brain frontal lobe, as well as a positive correlation between white matter ischemic changes and serum LCN2. We also found increased astrocytic LCN2, microglia activation, iron accumulation, and blood-brain barrier disruption in AßO-treated hippocampi. These findings suggest that LCN2 is involved in a variety of amyloid toxicity mechanisms, especially neuroinflammation and oxidative stress.
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BACKGROUND: Diabetic individuals have increased circulating inflammatory mediators which are implicated as underlying causes of neuroinflammation and memory deficits. Tonicity-responsive enhancer-binding protein (TonEBP) promotes diabetic neuroinflammation. However, the precise role of TonEBP in the diabetic brain is not fully understood. METHODS: We employed a high-fat diet (HFD)-only fed mice or HFD/streptozotocin (STZ)-treated mice in our diabetic mouse models. Circulating TonEBP and lipocalin-2 (LCN2) levels were measured in type 2 diabetic subjects. TonEBP haploinsufficient mice were used to investigate the role of TonEBP in HFD/STZ-induced diabetic mice. In addition, RAW 264.7 macrophages were given a lipopolysaccharide (LPS)/high glucose (HG) treatment. Using a siRNA, we examined the effects of TonEBP knockdown on RAW264 cell' medium/HG-treated mouse hippocampal HT22 cells. RESULTS: Circulating TonEBP and LCN2 levels were higher in experimental diabetic mice or type 2 diabetic patients with cognitive impairment. TonEBP haploinsufficiency ameliorated the diabetic phenotypes including adipose tissue macrophage infiltrations, neuroinflammation, blood-brain barrier leakage, and memory deficits. Systemic and hippocampal LCN2 proteins were reduced in diabetic mice by TonEBP haploinsufficiency. TonEBP (+ / -) mice had a reduction of hippocampal heme oxygenase-1 (HO-1) expression compared to diabetic wild-type mice. In particular, we found that TonEBP bound to the LCN2 promoter in the diabetic hippocampus, and this binding was abolished by TonEBP haploinsufficiency. Furthermore, TonEBP knockdown attenuated LCN2 expression in lipopolysaccharide/high glucose-treated mouse hippocampal HT22 cells. CONCLUSIONS: These findings indicate that TonEBP may promote neuroinflammation and cognitive impairment via upregulation of LCN2 in diabetic mice.
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Disfunción Cognitiva/sangre , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Tipo 2/sangre , Lipocalina 2/sangre , Factores de Transcripción NFATC/sangre , Enfermedades Neuroinflamatorias/sangre , Animales , Cognición/fisiología , Disfunción Cognitiva/etiología , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/psicología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/psicología , Dieta Alta en Grasa , Aprendizaje por Laberinto/fisiología , Ratones , Enfermedades Neuroinflamatorias/etiología , Células RAW 264.7RESUMEN
Alzheimer's disease (AD) is the most common form of dementia in the elderly population, but its underlying cause has not been fully elucidated. Recent studies have shown that microRNAs (miRNAs) play important roles in regulating the expression levels of genes associated with AD development. In this study, we analyzed miRNAs in plasma and cerebrospinal fluid (CSF) from AD patients and cognitively normal (including amyloid positive) individuals. miR-1273g-3p was identified as an AD-associated miRNA and found to be elevated in the CSF of early-stage AD patients. The overexpression of miR-1273g-3p enhanced amyloid beta (Aß) production by inducing oxidative stress and mitochondrial impairments in AD model cell lines. A biotin-streptavidin pull-down assay demonstrated that miR-1273g-3p primarily interacts with mitochondrial genes, and that their expression is downregulated by miR-1273g-3p. In particular, the miR-1273g-3p-target gene TIMM13 showed reduced expression in brain tissues from human AD patients. These results suggest that miR-1273g-3p expression in an early stage of AD notably contributes to Aß production and mitochondrial impairments. Thus, miR-1273g-3p might be a biomarker for early diagnosis of AD and a potential therapeutic target to prevent AD progression.