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Signal Transduction and Targeted Therapy Sep 2023Microglia activation is observed in various neurodegenerative diseases. Recent advances in single-cell technologies have revealed that these reactive microglia were with... (Review)
Review
Microglia activation is observed in various neurodegenerative diseases. Recent advances in single-cell technologies have revealed that these reactive microglia were with high spatial and temporal heterogeneity. Some identified microglia in specific states correlate with pathological hallmarks and are associated with specific functions. Microglia both exert protective function by phagocytosing and clearing pathological protein aggregates and play detrimental roles due to excessive uptake of protein aggregates, which would lead to microglial phagocytic ability impairment, neuroinflammation, and eventually neurodegeneration. In addition, peripheral immune cells infiltration shapes microglia into a pro-inflammatory phenotype and accelerates disease progression. Microglia also act as a mobile vehicle to propagate protein aggregates. Extracellular vesicles released from microglia and autophagy impairment in microglia all contribute to pathological progression and neurodegeneration. Thus, enhancing microglial phagocytosis, reducing microglial-mediated neuroinflammation, inhibiting microglial exosome synthesis and secretion, and promoting microglial conversion into a protective phenotype are considered to be promising strategies for the therapy of neurodegenerative diseases. Here we comprehensively review the biology of microglia and the roles of microglia in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies and Huntington's disease. We also summarize the possible microglia-targeted interventions and treatments against neurodegenerative diseases with preclinical and clinical evidence in cell experiments, animal studies, and clinical trials.
Topics: Animals; Neurodegenerative Diseases; Microglia; Neuroinflammatory Diseases; Protein Aggregates; Alzheimer Disease
PubMed: 37735487
DOI: 10.1038/s41392-023-01588-0 -
Australian Journal of General Practice Aug 2023Dementia is a debilitating neurological condition that affects millions of patients and families worldwide and remains a significant public health concern. Understanding...
BACKGROUND
Dementia is a debilitating neurological condition that affects millions of patients and families worldwide and remains a significant public health concern. Understanding the underlying neurobiology and pathophysiology of dementia is an important step towards finding effective treatment options.
OBJECTIVE
This article provides an overview of the pathophysiological processes of the most common types of dementia in older adults and highlights some of the developments in the research of biomarkers.
DISCUSSION
The most common forms of late-onset dementia are Alzheimer's disease, dementia with Lewy bodies, vascular dementia and frontotemporal dementia. The pathophysiology of dementia is broadly characterised by the aggregation of misfolded proteins (such as amyloid-β plaques and neurofibrillary tangles in Alzheimer's disease) and cerebrovascular disease. Mixed neuropathologies are frequently detected in the brains of older people with dementia and have important clinical implications.
Topics: Humans; Aged; Alzheimer Disease; Neurofibrillary Tangles; Brain
PubMed: 37532448
DOI: 10.31128/AJGP-02-23-6736 -
Annals of Clinical and Translational... Jun 2023LRRK2 variants are implicated in both familial and sporadic PD. LRRK2-PD has a generally benign clinical presentation and variable pathology, with inconsistent presence... (Review)
Review
LRRK2 variants are implicated in both familial and sporadic PD. LRRK2-PD has a generally benign clinical presentation and variable pathology, with inconsistent presence of Lewy bodies and marked Alzheimer's disease pathology. The mechanisms underlying LRRK2-PD are still unclear, but inflammation, vesicle trafficking, lysosomal homeostasis, and ciliogenesis have been suggested, among others. As novel therapies targeting LRRK2 are under development, understanding the role and function of LRRK2 in PD is becoming increasingly important. Here, we outline the epidemiological, pathophysiological, and clinical features of LRRK2-PD, and discuss the arising therapeutic approaches targeting LRRK2 and possible future directions for research.
Topics: Humans; Parkinson Disease; Lewy Bodies; Alzheimer Disease; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
PubMed: 37021623
DOI: 10.1002/acn3.51776 -
Journal of Neuroinflammation Jan 2024Some studies have shown that gut microbiota may be associated with dementia. However, the causal effects between gut microbiota and different types of dementia and...
BACKGROUND
Some studies have shown that gut microbiota may be associated with dementia. However, the causal effects between gut microbiota and different types of dementia and whether cytokines act as a mediator remain unclear.
METHODS
Gut microbiota, cytokines, and five dementia types, including Alzheimer's disease (AD), frontotemporal dementia (FTD), dementia with Lewy body (DLB), vascular dementia (VD), and Parkinson's disease dementia (PDD) were identified from large-scale genome-wide association studies (GWAS) summary data. We used Mendelian randomization (MR) to investigate the causal relationships between gut microbiota, cytokines, and five types of dementia. Inverse variance weighting (IVW) was used as the main statistical method. In addition, we explored whether cytokines act as a mediating factor in the pathway from gut microbiota to dementia.
RESULTS
There were 20 positive and 16 negative causal effects between genetic liability in the gut microbiota and dementia. Also, there were five positive and four negative causal effects between cytokines and dementias. Cytokines did not act as mediating factors.
CONCLUSIONS
Gut microbiota and cytokines were causally associated with five types of dementia, and cytokines seemed not to be the mediating factors in the pathway from gut microbiota to dementia.
Topics: Humans; Gastrointestinal Microbiome; Cytokines; Genome-Wide Association Study; Mendelian Randomization Analysis; Parkinson Disease; Alzheimer Disease; Frontotemporal Dementia
PubMed: 38178103
DOI: 10.1186/s12974-023-02999-0 -
Neuroscience and Biobehavioral Reviews Jul 2023Despite decades of research, we do not definitively know how people sometimes see things that are not there. Eight models of complex visual hallucinations have been... (Review)
Review
Despite decades of research, we do not definitively know how people sometimes see things that are not there. Eight models of complex visual hallucinations have been published since 2000, including Deafferentation, Reality Monitoring, Perception and Attention Deficit, Activation, Input, and Modulation, Hodological, Attentional Networks, Active Inference, and Thalamocortical Dysrhythmia Default Mode Network Decoupling. Each was derived from different understandings of brain organisation. To reduce this variability, representatives from each research group agreed an integrated Visual Hallucination Framework that is consistent with current theories of veridical and hallucinatory vision. The Framework delineates cognitive systems relevant to hallucinations. It allows a systematic, consistent, investigation of relationships between the phenomenology of visual hallucinations and changes in underpinning cognitive structures. The episodic nature of hallucinations highlights separate factors associated with the onset, persistence, and end of specific hallucinations suggesting a complex relationship between state and trait markers of hallucination risk. In addition to a harmonised interpretation of existing evidence, the Framework highlights new avenues of research, and potentially, new approaches to treating distressing hallucinations.
Topics: Humans; Hallucinations; Brain; Attention Deficit Disorder with Hyperactivity
PubMed: 37141962
DOI: 10.1016/j.neubiorev.2023.105208 -
Nature Medicine Jun 2023Abnormal α-synuclein aggregation is a key pathological feature of a group of neurodegenerative diseases known as synucleinopathies, which include Parkinson's disease...
Abnormal α-synuclein aggregation is a key pathological feature of a group of neurodegenerative diseases known as synucleinopathies, which include Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy (MSA). The pathogenic β-sheet seed conformation of α-synuclein is found in various tissues, suggesting potential as a biomarker, but few studies have been able to reliably detect these seeds in serum samples. In this study, we developed a modified assay system, called immunoprecipitation-based real-time quaking-induced conversion (IP/RT-QuIC), which enables the detection of pathogenic α-synuclein seeds in the serum of individuals with synucleinopathies. In our internal first and second cohorts, IP/RT-QuIC showed high diagnostic performance for differentiating PD versus controls (area under the curve (AUC): 0.96 (95% confidence interval (CI) 0.95-0.99)/AUC: 0.93 (95% CI 0.84-1.00)) and MSA versus controls (AUC: 0.64 (95% CI 0.49-0.79)/AUC: 0.73 (95% CI 0.49-0.98)). IP/RT-QuIC also showed high diagnostic performance in differentiating individuals with PD (AUC: 0.86 (95% CI 0.74-0.99)) and MSA (AUC: 0.80 (95% CI 0.65-0.97)) from controls in a blinded external cohort. Notably, amplified seeds maintained disease-specific properties, allowing the differentiation of samples from individuals with PD versus MSA. In summary, here we present a novel platform that may allow the detection of individuals with synucleinopathies using serum samples.
Topics: Humans; alpha-Synuclein; Synucleinopathies; Parkinson Disease; Multiple System Atrophy; Biomarkers; Lewy Body Disease
PubMed: 37248302
DOI: 10.1038/s41591-023-02358-9