Search Results (455)

Background: A limited number of studies have investigated the role of environmental chemicals in the etiology of mild cognitive impairment (MCI). We performed a cross-sectional study of the association between exposure to selected trace elements and the biomarkers of cognitive decline. Methods: During 2019–2021, we recruited 128 newly diagnosed patients with MCI from two Neurology Clinics in Northern Italy, i.e., Modena and Reggio Emilia. At baseline, we measured serum and cerebrospinal fluid (CSF) concentrations of cadmium, copper, iron, manganese, and zinc using inductively coupled plasma mass spectrometry. With immuno-enzymatic assays, we estimated concentrations of β-amyloid 1-40, β-amyloid 1-42, Total Tau and phosphorylated Tau181 proteins, neurofilament light chain (NfL), and the mini-mental state examination (MMSE) to assess cognitive status. We used spline regression to explore the shape of the association between exposure and each endpoint, adjusted for age at diagnosis, educational attainment, MMSE, and sex. Results: In analyses between the serum and CSF concentrations of trace metals, we found monotonic positive correlations between copper and zinc, while an inverse association was observed for cadmium. Serum cadmium concentrations were inversely associated with amyloid ratio and positively associated with Tau proteins. Serum iron concentrations showed the opposite trend, while copper, manganese, and zinc displayed heterogeneous non-linear associations with amyloid ratio and Tau biomarkers. Regarding CSF exposure biomarkers, only cadmium consistently showed an inverse association with amyloid ratio, while iron was positively associated with Tau. Cadmium concentrations in CSF were not appreciably associated with serum NfL levels, while we observed an inverted U-shaped association with CSF NfL, similar to that observed for copper. In CSF, zinc was the only trace element positively associated with NfL at high concentrations. Conclusions: In this cross-sectional study, high serum cadmium concentrations were associated with selected biomarkers of cognitive impairment. Findings for the other trace elements were difficult to interpret, showing complex and inconsistent associations with the neurodegenerative endpoints examined. Full article

Uterine infections reduce ruminant reproductive efficiency. Reproductive dysfunction caused by infusion of Gram-negative bacteria is characterized by the failure of embryo implantation and reduced conception rates. Lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria, is highly abortogenic. In this study, the effects of LPS infusion on the endometrial receptivity of sheep were studied during three critical periods of embryo implantation. The results showed that LPS infusion on d12, d16, and d20 of pregnancy in vivo interfered with the expression of prostaglandins (PGs) and affected the expression of adhesion-related factors (ITGB1/3/5, SPP1), key implantation genes (HOXA10, HOXA11 and LIF), and progestational elongation genes (ISG15, RSAD2 and CXCL10) during embryo implantation. In addition, after LPS infusion on d12, d16, and d20, the phosphorylation level of STAT1 significantly decreased and the protein expression level of IRF9 significantly increased on d12, suggesting that LPS infusion in sheep impairs endometrial receptivity through the JAK2/STAT1 pathway. Sheep endometrial epithelial cells were treated with 17 β-estrogen, progesterone, and/or interferon-tau in vitro to mimic the receptivity of the endometrium during early pregnancy for validation. LPS and the p-STAT1 inhibitor fludarabine were both added to the model, which resulted in reduced p-STAT1 protein expression, significant inhibition of PGE2/PGF2α, and significant suppression of the expression of key embryo implantation genes. Collectively, these results indicate that LPS infusion in sheep on d12, d16, and d20 impairs endometrial receptivity through the JAK2/STAT1 pathway, which is responsible for LPS-associated pregnancy failure. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with cognitive dysfunction, memory decline, and behavioral disturbance, and it is pathologically characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. Although various hypotheses have been proposed to explain the pathogenesis of AD, including the amyloid beta hypothesis, oxidative stress hypothesis, and abnormal phosphorylation of tau proteins, the exact pathogenic mechanisms underlying AD remain largely undefined. Furthermore, effective curative treatments are very limited. Epidemiologic studies provide convincing evidence for a significant association between type 2 diabetes and AD. Here, we showed energy metabolism using glucose, lactate, ketone bodies, and lipids as energy substrates in a normal brain, and changes in such energy metabolism due to type 2 diabetes. We also showed the influences of such altered energy metabolism due to type 2 diabetes on the pathology of AD. Furthermore, we comprehensively searched for risk factors related with type 2 diabetes for AD and showed possible therapeutic interventions based on considering risk factors and altered brain energy metabolism due to type 2 diabetes for the development of AD. Full article

The predominant neurodegenerative diseases, Alzheimer’s disease, Parkinson’s disease, dementia with Lewy Bodies, Huntington’s disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are rarely pure diseases but, instead, show a diversity of mixed pathologies. At some level, all of them share a combination of one or more different toxic biomarker proteins: amyloid beta (Aβ), phosphorylated Tau (pTau), alpha-synuclein (αSyn), mutant huntingtin (mHtt), fused in sarcoma, superoxide dismutase 1, and TAR DNA-binding protein 43. These toxic proteins share some common attributes, making them potentially universal and simultaneous targets for therapeutic intervention. First, they all form toxic aggregates prior to taking on their final forms as contributors to plaques, neurofibrillary tangles, Lewy bodies, and other protein deposits. Second, the primary enzyme that directs their aggregation is transglutaminase 2 (TGM2), a brain-localized enzyme involved in neurodegeneration. Third, TGM2 binds to calmodulin, a regulatory event that can increase the activity of this enzyme threefold. Fourth, the most common mixed pathology toxic biomarkers (Aβ, pTau, αSyn, nHtt) also bind calmodulin, which can affect their ability to aggregate. This review examines the potential therapeutic routes opened up by this knowledge. The end goal reveals multiple opportunities that are immediately available for universal therapeutic treatment of the most devastating neurodegenerative diseases facing humankind. Full article

Alzheimer’s disease (AD), which is characterized by deterioration in cognitive function and neuronal death, is the most prevalent age-related progressive neurodegenerative disease. Clinical and experimental research has revealed that gut microbiota dysbiosis may be present in AD patients. The changed gut microbiota affects brain function and behavior through several mechanisms, including tau phosphorylation and increased amyloid deposits, neuroinflammation, metabolic abnormalities, and persistent oxidative stress. The lack of effective treatments to halt or reverse the progression of this disease has prompted a search for non-pharmaceutical tools. Modulation of the gut microbiota may be a promising strategy in this regard. This review aims to determine whether specific dietary interventions, particularly antioxidant vitamins, either obtained from the diet or as supplements, may support the formation of beneficial microbiota in order to prevent AD development by contributing to the systemic reduction of chronic inflammation or by acting locally in the gut. Understanding their roles would be beneficial as it may have the potential to be used as a future therapy option for AD patients. Full article

Background/Objectives: Cognitive impairment represents a core and prodromal clinical feature of cerebral amyloid angiopathy (CAA). We sought to assess specific cognitive domains which are mainly affected among patients with CAA and to investigate probable associations with neuroimaging markers and Cerebrospinal Fluid (CSF) biomarkers. Methods: Thirty-five patients fulfilling the Boston Criteria v1.5 or v2.0 for the diagnosis of probable/possible CAA were enrolled in this prospective cohort study. Brain Magnetic Resonance Imaging and CSF biomarker data were collected. Every eligible participant underwent a comprehensive neurocognitive assessment. Spearman’s rank correlation tests were used to identify possible relationships between the Addenbrooke’s Cognitive Examination—Revised (ACE-R) sub-scores and other neurocognitive test scores and the CSF biomarker and neuroimaging parameters among CAA patients. Moreover, linear regression analyses were used to investigate the effects of CSF biomarkers on the ACE-R total score and Mini-Mental State Examination (MMSE) score, based on the outcomes of univariate analyses. Results: Cognitive impairment was detected in 80% of patients, and 60% had a coexistent Alzheimer’s disease (AD) pathology based on CSF biomarker profiles. Notable correlations were identified between increased levels of total tau (t-tau) and phosphorylated tau (p-tau) and diminished performance in terms of overall cognitive function, especially memory. In contrast, neuroimaging indicators, including lobar cerebral microbleeds and superficial siderosis, had no significant associations with cognitive scores. Among the CAA patients, those without AD had superior neurocognitive test performance, with significant differences observed in their ACE-R total scores and memory sub-scores. Conclusions: The significance of tauopathy in cognitive impairment associated with CAA may be greater than previously imagined, underscoring the necessity for additional exploration of the non-hemorrhagic facets of the disease and new neuroimaging markers. Full article

Background/Objectives: Progressive Supranuclear Palsy (PSP) is a tauopathy showing a marked symptoms overlap with Parkinson’s Disease (PD). PSP pathology suggests that tau protein might represent a valuable biomarker to distinguish between the two diseases. Here, we investigated the presence and diagnostic value of six different tau species (total tau, 4R-tau isoform, tau aggregates, p-tau202, p-tau231 and p-tau396) in serum from 13 PSP and 13 PD patients and 12 healthy controls (HCs). Methods: ELISA commercial kits were employed to assess all the tau species except for t-tau, which was assessed by a single molecule array (SIMOA)-based commercial kit. Possible correlations between tau species and biological and clinical features of our cohorts were also evaluated. Results: Among the six tau species tested, only p-tau396 was detectable in serum. Concentration of p-tau396 was significantly higher in both PSP and PD groups compared to HC, but PSP and PD patients showed largely overlapping values. Moreover, serum concentration of p-tau396 strongly correlated with disease severity in PSP and not in PD. Conclusions: Overall, we identified serum p-tau396 as the most expressed phosphorylated tau species in serum and as a potential tool for assessing PSP clinical staging. Moreover, we demonstrated that other p-tau species may be present at too low concentrations in serum to be detected by ELISA, suggesting that future work should focus on other biological matrices. Full article

Background: The levels of β-amyloid precursor protein (β-APP), tau protein, and phosphorylation of tau (p-tau) protein were examined by quantitative immunohistochemistry in the spinal cord sections of mice suffering from experimental autoimmune encephalomyelitis (EAE) in the successive phases of the disease: onset, peak, and chronic. Methods: EAE was induced in C57BL/6 mice by immunization with MOG35–55 peptide. The degree of pathological changes was assessed in cross-sections of the entire spinal cord. Results: β-APP expression was observed in the white matter and colocalized with some Iba-1-positive macrophages/microglia. It increased in the peak phase of EAE and remained at the same level in the chronic phase. During the onset and peak phases of EAE, expression of tau protein was observed in nerve fibers and nerve cell perikaryons, with a predominance of nerve fibers, whereas in the chronic phase, tau was labeled mainly in the perikaryons of nerve cells, with its content significantly decreased. P-tau immunostaining was seen only in nerve fibers. Conclusions: The expression of p-tau increased with the progression of EAE, reaching the maximum in the chronic phase. The correlation between these proteins and neurodegeneration/neuroinflammation highlights their potential roles in the progression of neurodegenerative mechanisms in MS. Full article

Background/Objectives: Alzheimer’s disease (AD), a leading cause of dementia, lacks effective long-term treatments. Current therapies offer temporary relief or fail to halt its progression and are often inaccessible due to cost. AD involves multiple pathological processes, including amyloid beta (Aβ) deposition, insulin resistance, tau protein hyperphosphorylation, and systemic inflammation accelerated by gut microbiota dysbiosis originating from a leaky gut. Given this context, exploring alternative therapeutic interventions capable of addressing the multifaceted components of AD etiology is essential. Methods: This study suggests D-Pinitol (DPIN) as a potential treatment modifier for AD. DPIN, derived from carob pods, demonstrates insulin-sensitizing, tau hyperphosphorylation inhibition, and antioxidant properties. To test this hypothesis, we studied whether chronic oral administration of DPIN (200 mg/kg/day) could reverse the AD-like disease progression in the 5×FAD mice. Results: Results showed that treatment of 5×FAD mice with DPIN improved cognition, reduced hippocampal Aβ and hyperphosphorylated tau levels, increased insulin-degrading enzyme (IDE) expression, enhanced pro-cognitive hormone circulation (such as ghrelin and leptin), and normalized the PI3K/Akt insulin pathway. This enhancement may be mediated through the modulation of cyclin-dependent kinase 5 (CDK5). DPIN also protected the gut barrier and microbiota, reducing the pro-inflammatory impact of the leaky gut observed in 5×FAD mice. DPIN reduced bacterial lipopolysaccharide (LPS) and LPS-associated inflammation, as well as restored intestinal proteins such as Claudin-3. This effect was associated with a modulation of gut microbiota towards a more balanced bacterial composition. Conclusions: These findings underscore DPIN’s promise in mitigating cognitive decline in the early AD stages, positioning it as a potential disease modifier. Full article

Background: Parkinson’s disease (PD) is the second most common neurodegenerative disease, primarily affecting the middle-aged to elderly population. Among its nonmotor symptoms, cognitive decline (CD) is a precursor to dementia and represents a critical target for early risk assessment and diagnosis. Accurate CD prediction is crucial for timely intervention and tailored management of at-risk patients. This study used machine learning (ML) techniques to predict the CD risk over five-year in early-stage PD. Methods: Data from the Early Parkinson’s Disease Longitudinal Singapore (2014 to 2018) was used to predict CD defined as a one-unit annual decrease or a one-unit decline in Montreal Cognitive Assessment over two consecutive years. Four ML methods—AutoScore, Random Forest, K-Nearest Neighbors and Neural Network—were applied using baseline demographics, clinical assessments and blood biomarkers. Results: Variable selection identified key predictors of CD, including education year, diastolic lying blood pressure, diastolic standing blood pressure, systolic lying blood pressure, Hoehn and Yahr scale, body mass index, phosphorylated tau at threonine 181, total tau, Neurofilament light chain and suppression of tumorigenicity 2. Random Forest was the most effective, achieving an AUC of 0.93 (95% CI: 0.89, 0.97), using 10-fold cross-validation. Conclusions: Here, we demonstrate that ML-based models can identify early-stage PD patients at high risk for CD, supporting targeted interventions and improved PD management. Full article

Alcohol consumption is believed to affect Alzheimer’s disease (AD) risk, but the contributing mechanisms are not well understood. A potential mediator of the proposed alcohol-AD connection is autophagy, a degradation pathway that maintains organelle and protein homeostasis. Autophagy is regulated through the activity of Transcription factor EB (TFEB), which promotes lysosome and autophagy-related gene expression. The purpose of this study is to explore whether chronic alcohol consumption worsens the age-related decline in TFEB-mediated lysosomal biogenesis in the brain and exacerbates cognitive decline associated with aging. To explore the effect of alcohol on brain TFEB and autophagy, we exposed young (3-month-old) and aged (23-month-old) mice to two alcohol-feeding paradigms and assessed biochemical, transcriptome, histology, and behavioral endpoints. In young mice, alcohol decreased hippocampal nuclear TFEB staining but increased SQSTM1/p62, LC3-II, ubiquitinated proteins, and phosphorylated Tau. Hippocampal TFEB activity was lower in aged mice than it was in young mice, and Gao-binge alcohol feeding did not worsen the age-related reduction in TFEB activity. Morris Water and Barnes Maze spatial memory tasks were used to characterize the effects of aging and chronic alcohol exposure (mice fed alcohol for 4 weeks). The aged mice showed worse spatial memory acquisition in both tests. Alcohol feeding slightly impaired spatial memory in the young mice, but had little effect or even slightly improved spatial memory acquisition in the aged mice. In conclusion, aging produces greater reductions in brain autophagy flux and impairment of spatial memory than alcohol consumption. Full article

Citrus fruits contain several bioactive components. Among them, one of the major components is 3,5,6,7,8,3′,4′-heptamethoxyflavone (HMF), which has previously shown protective effects in the brain in some disease models; moreover, HMF has been shown to penetrate the brain. In recent years, inflammation has been identified as a defense response in the body; however, a chronic inflammatory response may trigger several diseases. Inflammation in the peripheral tissues spreads to the brain and is suggested to be closely associated with diseases of the central nervous system. HMF has shown anti-inflammatory effects in the hippocampus following global cerebral ischemia; however, its effects on acute and chronic inflammation in the brain remain unclear. Therefore, in the present study, we examined the effects of HMF in a mouse model of systemic inflammation induced by lipopolysaccharide (LPS) administration. In this study, HMF suppressed LPS-induced microglial activation in the brains of acute inflammation model mice two days after LPS administration. In addition, 24 days after the administration of LPS in a chronic inflammation model, HMF promoted BDNF production and neurogenesis in the brain, which also tended to suppress tau protein phosphorylation at Ser396. These results suggest that HMF has anti-inflammatory and neurotrophic effects in the brains of model mice with lipopolysaccharide-induced systemic inflammation. Full article

Alzheimer’s disease (AD) is a complex multifactorial neurodegenerative disease. With the escalating aging of the global population, the societal burden of this disease is increasing. Although drugs are available for the treatment of AD, their efficacy is limited and there remains no effective cure. Therefore, the identification of safe and effective prevention and treatment strategies is urgently needed. Functional factors in foods encompass a variety of natural and safe bioactive substances that show potential in the prevention and treatment of AD. However, current research focused on the use of these functional factors for the prevention and treatment of AD is in its initial stages, and a complete theoretical and application system remains to be determined. An increasing number of recent studies have found that functional factors such as polyphenols, polysaccharides, unsaturated fatty acids, melatonin, and caffeine have positive effects in delaying the progression of AD and improving cognitive function. For example, polyphenols exhibit antioxidant, anti-inflammatory, and neuroprotective effects, and polysaccharides promote neuronal growth and inhibit inflammation and oxidative stress. Additionally, unsaturated fatty acids inhibit Aβ production and Tau protein phosphorylation and reduce neuroinflammation, and melatonin has been shown to protect nerve cells and improve cognitive function by regulating mitochondrial homeostasis and autophagy. Caffeine has also been shown to inhibit inflammation and reduce neuronal damage. Future research should further explore the mechanisms of action of these functional factors and develop relevant functional foods or nutritional supplements to provide new strategies and support for the prevention and treatment of AD. Full article

The clinical spectrum of Alzheimer’s disease (AD) ranges dynamically from asymptomatic and mild cognitive impairment (MCI) to mild, moderate, or severe AD. Although a few disease-modifying treatments, such as lecanemab and donanemab, have been developed, current therapies can only delay disease progression rather than halt it entirely. Therefore, the early detection of MCI and the identification of MCI patients at high risk of progression to AD remain urgent unmet needs in the super-aged era. This study utilized transcriptomics data from cognitively unimpaired (CU) individuals, MCI, and AD patients in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort and leveraged machine learning models to identify biomarkers that differentiate MCI from CU and also distinguish AD from MCI individuals. Furthermore, Cox proportional hazards analysis was conducted to identify biomarkers predictive of the progression from MCI to AD. Our machine learning models identified a unique set of gene expression profiles capable of achieving an area under the curve (AUC) of 0.98 in distinguishing those with MCI from CU individuals. A subset of these biomarkers was also found to be significantly associated with the risk of progression from MCI to AD. A linear mixed model demonstrated that plasma tau phosphorylated at threonine 181 (pTau181) and neurofilament light chain (NFL) exhibit the prognostic value in predicting cognitive decline longitudinally. These findings underscore the potential of integrating machine learning (ML) with transcriptomic profiling in the early detection and prognostication of AD. This integrated approach could facilitate the development of novel diagnostic tools and therapeutic strategies aimed at delaying or preventing the onset of AD in at-risk individuals. Future studies should focus on validating these biomarkers in larger, independent cohorts and further investigating their roles in AD pathogenesis. Full article

An aberrant recapitulation of a developmental mechanism driven by a 14 mer peptide (‘T14’) derived from acetylcholinesterase (AChE) has been implicated in Alzheimer’s disease. T14 was suggested as an upstream driver of neurodegeneration due to its ability to stimulate the production of phosphorylated tau and amyloid beta. The activation of this mechanism in adulthood is thought to be brought upon by insult to the primarily vulnerable subcortical nuclei. Here, we show that oxidative stress, induced by high glucose and confirmed by an analysis of antioxidant enzyme mRNA expression, increased the levels of T14 peptide in PC12 cells. This increase in T14 corresponded with an increase in the mRNA expression of AChE and a decrease in the cell viability. The increase in T14 could be blocked by the cyclic form of T14, NBP14, which prevented any cytotoxic effects. These observations suggest that oxidative stress can directly trigger the inappropriate activation of T14 in the adult brain through the upregulation of Ache mRNA. Full article