Translational Neurodegeneration最新文献

A wealth of pre-clinical reports and data derived from human subjects and brain autopsies suggest that microbial infections are relevant to Alzheimer's disease (AD). This has inspired the hypothesis that microbial infections increase the risk or even trigger the onset of AD. Multiple models have been developed to explain the increase in pathogenic microbes in AD patients. Although this hypothesis is well accepted in the field, it is not yet clear whether microbial neuroinvasion is a cause of AD or a consequence of the pathological changes experienced by the demented brain. Along the same line, the gut microbiome has also been proposed as a modulator of AD. In this review, we focus on human-based evidence demonstrating the elevated abundance of microbes and microbe-derived molecules in AD hosts as well as their interactions with AD hallmarks. Further, the direct-purpose and potential off-target effects underpinning the efficacy of anti-microbial treatments in AD are also addressed.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. More than 200 years after its first clinical description, PD remains a serious affliction that affects a growing proportion of the population. Prevailing treatments only alleviate symptoms; there is still neither a cure that targets the neurodegenerative processes nor therapies that modify the course of the disease. Over the past decades, several animal models have been developed to study PD. Although no model precisely recapitulates the pathology, they still provide valuable information that contributes to our understanding of the disease and the limitations of our treatment options. This review comprehensively summarizes the different animal models available for Parkinson's research, with a focus on those induced by drugs, neurotoxins, pesticides, genetic alterations, α-synuclein inoculation, and viral vector injections. We highlight their characteristics and ability to reproduce PD-like phenotypes. It is essential to realize that the strengths and weaknesses of each model and the induction technique at our disposal are determined by the research question being asked. Our review, therefore, seeks to better aid researchers by ensuring a concrete discernment of classical and novel animal models in PD research.

Background: The current diagnosis of Alzheimer's disease (AD) is based on a series of analyses which involve clinical, instrumental and laboratory findings. However, signs, symptoms and biomarker alterations observed in AD might overlap with other dementias, resulting in misdiagnosis.

Methods: Here we describe a new diagnostic approach for AD which takes advantage of the boosted sensitivity in biomolecular detection, as allowed by seed amplification assay (SAA), combined with the unique specificity in biomolecular recognition, as provided by surface-enhanced Raman spectroscopy (SERS).

Results: The SAA-SERS approach supported by machine learning data analysis allowed efficient identification of pathological Aβ oligomers in the cerebrospinal fluid of patients with a clinical diagnosis of AD or mild cognitive impairment due to AD.

Conclusions: Such analytical approach can be used to recognize disease features, thus allowing early stratification and selection of patients, which is fundamental in clinical treatments and pharmacological trials.

Background: Gaining more information about the reciprocal associations between different biomarkers within the ATN (Amyloid/Tau/Neurodegeneration) framework across the Alzheimer's disease (AD) spectrum is clinically relevant. We aimed to conduct a comprehensive head-to-head comparison of plasma and positron emission tomography (PET) ATN biomarkers in subjects with cognitive complaints.

Methods: A hospital-based cohort of subjects with cognitive complaints with a concurrent blood draw and ATN PET imaging (¹⁸F-florbetapir for A, ¹⁸F-Florzolotau for T, and ¹⁸F-fluorodeoxyglucose [¹⁸F-FDG] for N) was enrolled (n = 137). The β-amyloid (Aβ) status (positive versus negative) and the severity of cognitive impairment served as the main outcome measures for assessing biomarker performances.

Results: Plasma phosphorylated tau 181 (p-tau181) level was found to be associated with PET imaging of ATN biomarkers in the entire cohort. Plasma p-tau181 level and PET standardized uptake value ratios of AT biomarkers showed a similarly excellent diagnostic performance for distinguishing between Aβ+ and Aβ- subjects. An increased tau burden and glucose hypometabolism were significantly associated with the severity of cognitive impairment in Aβ+ subjects. Additionally, glucose hypometabolism - along with elevated plasma neurofilament light chain level - was related to more severe cognitive impairment in Aβ- subjects.

Conclusion: Plasma p-tau181, as well as ¹⁸F-florbetapir and ¹⁸F-Florzolotau PET imaging can be considered as interchangeable biomarkers in the assessment of Aβ status in symptomatic stages of AD. ¹⁸F-Florzolotau and ¹⁸F-FDG PET imaging could serve as biomarkers for the severity of cognitive impairment. Our findings have implications for establishing a roadmap to identifying the most suitable ATN biomarkers for clinical use.

Alzheimer's disease (AD) is a major subtype of neurodegenerative dementia caused by long-term interactions and accumulation of multiple adverse factors, accompanied by dysregulation of numerous intracellular signaling and molecular pathways in the brain. At the cellular and molecular levels, the neuronal cellular milieu of the AD brain exhibits metabolic abnormalities, compromised bioenergetics, impaired lipid metabolism, and reduced overall metabolic capacity, which lead to abnormal neural network activity and impaired neuroplasticity, thus accelerating the formation of extracellular senile plaques and intracellular neurofibrillary tangles. The current absence of effective pharmacological therapies for AD points to the urgent need to investigate the benefits of non-pharmacological approaches such as physical exercise. Despite the evidence that regular physical activity can improve metabolic dysfunction in the AD state, inhibit different pathophysiological molecular pathways associated with AD, influence the pathological process of AD, and exert a protective effect, there is no clear consensus on the specific biological and molecular mechanisms underlying the advantages of physical exercise. Here, we review how physical exercise improves crucial molecular pathways and biological processes associated with metabolic disorders in AD, including glucose metabolism, lipid metabolism, Aβ metabolism and transport, iron metabolism and tau pathology. How metabolic states influence brain health is also presented. A better knowledge on the neurophysiological mechanisms by which exercise improves AD metabolism can contribute to the development of novel drugs and improvement of non-pharmacological interventions.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective degeneration of upper and lower motor neurons. The pathogenesis of ALS remains largely unknown; however, inflammation of the spinal cord is a focus of ALS research and an important pathogenic process in ALS. Prostaglandin E₂ (PGE₂) is a major lipid mediator generated by the arachidonic-acid cascade and is abundant at inflammatory sites. PGE₂ levels are increased in the postmortem spinal cords of ALS patients and in ALS model mice. Beneficial therapeutic effects have been obtained in ALS model mice using cyclooxygenase-2 inhibitors to inhibit the biosynthesis of PGE₂, but the usefulness of this inhibitor has not yet been proven in clinical trials. In this review, we present current evidence on the involvement of PGE₂ in the progression of ALS and discuss the potential of microsomal prostaglandin E synthase (mPGES) and the prostaglandin receptor E-prostanoid (EP) 2 as therapeutic targets for ALS. Signaling pathways involving prostaglandin receptors mediate toxic effects in the central nervous system. In some situations, however, the receptors mediate neuroprotective effects. Our recent studies demonstrated that levels of mPGES-1, which catalyzes the final step of PGE₂ biosynthesis, are increased at the early-symptomatic stage in the spinal cords of transgenic ALS model mice carrying the G93A variant of superoxide dismutase-1. In addition, in an experimental motor-neuron model used in studies of ALS, PGE₂ induces the production of reactive oxygen species and subsequent caspase-3-dependent cytotoxicity through activation of the EP2 receptor. Moreover, this PGE₂-induced EP2 up-regulation in motor neurons plays a role in the death of motor neurons in ALS model mice. Further understanding of the pathophysiological role of PGE₂ in neurodegeneration may provide new insights to guide the development of novel therapies for ALS.

Background: Lysosomal dysfunction has been implicated in a number of neurodegenerative diseases such as Parkinson's disease (PD). Various molecular, clinical and genetic studies have highlighted a central role of lysosomal pathways and proteins in the pathogenesis of PD. Within PD pathology the synaptic protein alpha-synuclein (αSyn) converts from a soluble monomer to oligomeric structures and insoluble amyloid fibrils. The aim of this study was to unravel the effect of αSyn aggregates on lysosomal turnover, particularly focusing on lysosomal homeostasis and cathepsins. Since these enzymes have been shown to be directly involved in the lysosomal degradation of αSyn, impairment of their enzymatic capacity has extensive consequences.

Methods: We used patient-derived induced pluripotent stem cells and a transgenic mouse model of PD to examine the effect of intracellular αSyn conformers on cell homeostasis and lysosomal function in dopaminergic (DA) neurons by biochemical analyses.

Results: We found impaired lysosomal trafficking of cathepsins in patient-derived DA neurons and mouse models with αSyn aggregation, resulting in reduced proteolytic activity of cathepsins in the lysosome. Using a farnesyltransferase inhibitor, which boosts hydrolase transport via activation of the SNARE protein ykt6, we enhanced the maturation and proteolytic activity of cathepsins and thereby decreased αSyn protein levels.

Conclusions: Our findings demonstrate a strong interplay between αSyn aggregation pathways and function of lysosomal cathepsins. It appears that αSyn directly interferes with the enzymatic function of cathepsins, which might lead to a vicious cycle of impaired αSyn degradation. Lysosomal trafficking of cathepsin D (CTSD), CTSL and CTSB is disrupted when alpha-synuclein (αSyn) is aggregated. This results in a decreased proteolytic activity of cathepsins, which directly mediate αSyn clearance. Boosting the transport of the cathepsins to the lysosome increases their activity and thus contributes to efficient αSyn degradation.

Lysosomal acidification dysfunction has been implicated as a key driving factor in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Multiple genetic factors have been linked to lysosomal de-acidification through impairing the vacuolar-type ATPase and ion channels on the organelle membrane. Similar lysosomal abnormalities are also present in sporadic forms of neurodegeneration, although the underlying pathogenic mechanisms are unclear and remain to be investigated. Importantly, recent studies have revealed early occurrence of lysosomal acidification impairment before the onset of neurodegeneration and late-stage pathology. However, there is a lack of methods for organelle pH monitoring in vivo and a dearth of lysosome-acidifying therapeutic agents. Here, we summarize and present evidence for the notion of defective lysosomal acidification as an early indicator of neurodegeneration and urge the critical need for technological advancement in developing tools for lysosomal pH monitoring and detection both in vivo and for clinical applications. We further discuss current preclinical pharmacological agents that modulate lysosomal acidification, including small molecules and nanomedicine, and their potential clinical translation into lysosome-targeting therapies. Both timely detection of lysosomal dysfunction and development of therapeutics that restore lysosomal function represent paradigm shifts in targeting neurodegenerative diseases.

Background: The isolated rapid-eye-movement sleep behavior disorder (iRBD) is a prodromal condition of Lewy body disease including Parkinson's disease and dementia with Lewy bodies (DLB). We aim to investigate the longitudinal evolution of DLB-related cortical thickness signature in a prospective iRBD cohort and evaluate the possible predictive value of the cortical signature index in predicting dementia-first phenoconversion in individuals with iRBD.

Methods: We enrolled 22 DLB patients, 44 healthy controls, and 50 video polysomnography-proven iRBD patients. Participants underwent 3-T magnetic resonance imaging (MRI) and clinical/neuropsychological evaluations. We characterized DLB-related whole-brain cortical thickness spatial covariance pattern (DLB-pattern) using scaled subprofile model of principal components analysis that best differentiated DLB patients from age-matched controls. We analyzed clinical and neuropsychological correlates of the DLB-pattern expression scores and the mean values of the whole-brain cortical thickness in DLB and iRBD patients. With repeated MRI data during the follow-up in our prospective iRBD cohort, we investigated the longitudinal evolution of the cortical thickness signature toward Lewy body dementia. Finally, we analyzed the potential predictive value of cortical thickness signature as a biomarker of phenoconversion in iRBD cohort.

Results: The DLB-pattern was characterized by thinning of the temporal, orbitofrontal, and insular cortices and relative preservation of the precentral and inferior parietal cortices. The DLB-pattern expression scores correlated with attentional and frontal executive dysfunction (Trail Making Test-A and B: R = - 0.55, P = 0.024 and R = - 0.56, P = 0.036, respectively) as well as visuospatial impairment (Rey-figure copy test: R = - 0.54, P = 0.0047). The longitudinal trajectory of DLB-pattern revealed an increasing pattern above the cut-off in the dementia-first phenoconverters (Pearson's correlation, R = 0.74, P = 6.8 × 10^-4) but no significant change in parkinsonism-first phenoconverters (R = 0.0063, P = 0.98). The mean value of the whole-brain cortical thickness predicted phenoconversion in iRBD patients with hazard ratio of 9.33 [1.16-74.12]. The increase in DLB-pattern expression score discriminated dementia-first from parkinsonism-first phenoconversions with 88.2% accuracy.

Conclusion: Cortical thickness signature can effectively reflect the longitudinal evolution of Lewy body dementia in the iRBD population. Replication studies would further validate the utility of this imaging marker in iRBD.