scholarly journals Microglial ApoD Induced NLRC4 Inflammasome Activation Promotes Alzheimer’s Disease Progression

2021 ◽  
Author(s):  
Yaliang Yu ◽  
Jianzhou Lv ◽  
Dan Ma ◽  
Ya Han ◽  
Yaheng Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Critical Role ◽  
Microglia Activation ◽  
Inflammatory Factors ◽  
Inflammasome Activation ◽  
Cellular Interactions ◽  
Brain Functions ◽  
Chronic Neuroinflammation

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disease with no effective therapies. It’s well-known that chronic neuroinflammation plays a critical role in the onset and progression of AD. Proper neuronal-microglial interactions are essential for brain functions. However, as the main existence of immune cells, determining the role of microglia in Alzheimer’s neuroinflammation and the associated molecular basis has been challenging. Herein, the inflammatory factors in the sera of AD patients were detected and the association with microglia activation was analyzed. The mechanism regarding the microglial inflammation was investigated. The IL6 and TNF-α were found to be significantly increased in the AD stage. Further analysis revealed microglia were extensively activated in AD cerebra releasing mounts of cytokines to impair the neural stem cells (NSCs) function. Moreover, ApoD induced NLRC4 inflammasome was activated in microglia, which gave rise to the proinflammatory phenotype. Targeting the microglial ApoD promoted NSCs self-renewal and inhibited neuron apoptosis. These findings demonstrate the critical role of ApoD in microglial inflammasome activation, and for the first time reveal that microglia-induced inflammation suppresses neuronal proliferation. Our studies establish the cellular basis for microglia activation in AD progression, and shed lights on cellular interactions important for AD treatment.

scholarly journals Role of Neuron and Glia in Alzheimer’s Disease and Associated Vascular Dysfunction

2021 ◽  
Vol 13 ◽  
Author(s):  
Sanghamitra Bandyopadhyay
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Large Scale ◽  
Vascular Dysfunction ◽  
Critical Role ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Cell Types ◽  
Cellular Interactions

Amyloidogenicity and vascular dysfunction are the key players in the pathogenesis of Alzheimer’s disease (AD), involving dysregulated cellular interactions. An intricate balance between neurons, astrocytes, microglia, oligodendrocytes and vascular cells sustains the normal neuronal circuits. Conversely, cerebrovascular diseases overlap neuropathologically with AD, and glial dyshomeostasis promotes AD-associated neurodegenerative cascade. While pathological hallmarks of AD primarily include amyloid-β (Aβ) plaques and neurofibrillary tangles, microvascular disorders, altered cerebral blood flow (CBF), and blood-brain barrier (BBB) permeability induce neuronal loss and synaptic atrophy. Accordingly, microglia-mediated inflammation and astrogliosis disrupt the homeostasis of the neuro-vascular unit and stimulate infiltration of circulating leukocytes into the brain. Large-scale genetic and epidemiological studies demonstrate a critical role of cellular crosstalk for altered immune response, metabolism, and vasculature in AD. The glia associated genetic risk factors include APOE, TREM2, CD33, PGRN, CR1, and NLRP3, which correlate with the deposition and altered phagocytosis of Aβ. Moreover, aging-dependent downregulation of astrocyte and microglial Aβ-degrading enzymes limits the neurotrophic and neurogenic role of glial cells and inhibits lysosomal degradation and clearance of Aβ. Microglial cells secrete IGF-1, and neurons show a reduced responsiveness to the neurotrophic IGF-1R/IRS-2/PI3K signaling pathway, generating amyloidogenic and vascular dyshomeostasis in AD. Glial signals connect to neural stem cells, and a shift in glial phenotype over the AD trajectory even affects adult neurogenesis and the neurovascular niche. Overall, the current review informs about the interaction of neuronal and glial cell types in AD pathogenesis and its critical association with cerebrovascular dysfunction.

scholarly journals Alzheimer's disease and periodontitis - an elusive link

2014 ◽  
Vol 60 (2) ◽  
pp. 173-180 ◽  
Author(s):  
Abhijit N. Gurav
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inflammatory Cytokines ◽  
Critical Role ◽  
Anaerobic Bacteria ◽  
Systemic Infection ◽  
Low Grade ◽  
Inflammatory Status ◽  
Pro Inflammatory Cytokines

Alzheimer's disease is the preeminent cause and commonest form of dementia. It is clinically characterized by a progressive descent in the cognitive function, which commences with deterioration in memory. The exact etiology and pathophysiologic mechanism of Alzheimer's disease is still not fully understood. However it is hypothesized that, neuroinflammation plays a critical role in the pathogenesis of Alzheimer's disease. Alzheimer's disease is marked by salient inflammatory features, characterized by microglial activation and escalation in the levels of pro-inflammatory cytokines in the affected regions. Studies have suggested a probable role of systemic infection conducing to inflammatory status of the central nervous system. Periodontitis is common oral infection affiliated with gram negative, anaerobic bacteria, capable of orchestrating localized and systemic infections in the subject. Periodontitis is known to elicit a "low grade systemic inflammation" by release of pro-inflammatory cytokines into systemic circulation. This review elucidates the possible role of periodontitis in exacerbating Alzheimer's disease. Periodontitis may bear the potential to affect the onset and progression of Alzheimer's disease. Periodontitis shares the two important features of Alzheimer's disease namely oxidative damage and inflammation, which are exhibited in the brain pathology of Alzheimer's disease. Periodontitis can be treated and hence it is a modifiable risk factor for Alzheimer's disease.

scholarly journals Prostacyclin Promotes Degenerative Pathology in a Model of Alzheimer’s disease

2020 ◽  
Author(s):  
Tasha R. Womack ◽  
Craig Vollert ◽  
Odochi Nwoko ◽  
Monika Schmitt ◽  
Sagi Montazari ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Chronic Neuroinflammation ◽  
Model Of Alzheimer’S Disease ◽  
Amyloid Accumulation ◽  
Prostaglandin H ◽  
The Brain

AbstractAlzheimer’s disease (AD) is a progressive neurodegenerative disorder that is the most common cause of dementia in aged populations. A substantial amount of data demonstrates that chronic neuroinflammation can accelerate neurodegenerative pathologies, while epidemiological and experimental evidence suggests that the use of anti-inflammatory agents may be neuroprotective. In AD, chronic neuroinflammation results in the upregulation of cyclooxygenase and increased production of prostaglandin H2, a precursor for many vasoactive prostanoids. While it is well-established that many prostaglandins can modulate the progression of neurodegenerative disorders, the role of prostacyclin (PGI2) in the brain is poorly understood. We have conducted studies to assess the effect of elevated prostacyclin biosynthesis in a mouse model of AD. Upregulated prostacyclin expression significantly worsened multiple measures associated with amyloid disease pathologies. Mice overexpressing both amyloid and PGI2 exhibited impaired learning and memory and increased anxiety-like behavior compared with non-transgenic and PGI2 control mice. PGI2 overexpression accelerated the development of amyloid accumulation in the brain and selectively increased the production of soluble amyloid-β 42. PGI2 damaged the microvasculature through alterations in vascular length and branching; amyloid expression exacerbated these effects. Our findings demonstrate that chronic prostacyclin expression plays a novel and unexpected role that hastens the development of the AD phenotype.

scholarly journals New Insights on the Role of Manganese in Alzheimer’s Disease and Parkinson’s Disease

2019 ◽  
Vol 16 (19) ◽  
pp. 3546 ◽  
Author(s):  
Airton Cunha Martins ◽  
Patricia Morcillo ◽  
Omamuyovwi Meashack Ijomone ◽  
Vivek Venkataramani ◽  
Fiona Edith Harrison ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Parkinson’S Disease ◽  
Alzheimer's Disease ◽  
Parkinson's Disease ◽  
Critical Role ◽  
Essential Trace Element ◽  
Neuronal Function ◽  
Therapy Options ◽  
Physiological Processes

Manganese (Mn) is an essential trace element that is naturally found in the environment and is necessary as a cofactor for many enzymes and is important in several physiological processes that support development, growth, and neuronal function. However, overexposure to Mn may induce neurotoxicity and may contribute to the development of Alzheimer’s disease (AD) and Parkinson’s disease (PD). The present review aims to provide new insights into the involvement of Mn in the etiology of AD and PD. Here, we discuss the critical role of Mn in the etiology of these disorders and provide a summary of the proposed mechanisms underlying Mn-induced neurodegeneration. In addition, we review some new therapy options for AD and PD related to Mn overload.

scholarly journals Platycodigenin as Potential Drug Candidate for Alzheimer’s Disease via Modulating Microglial Polarization and Neurite Regeneration

Molecules ◽  
2019 ◽  
Vol 24 (18) ◽  
pp. 3207 ◽  
Author(s):  
Zhiyou Yang ◽  
Baiping Liu ◽  
Long-en Yang ◽  
Cai Zhang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cortical Neurons ◽  
Neuronal Survival ◽  
Critical Role ◽  
Mitogen Activated Protein Kinase ◽  
Inflammatory Factors ◽  
Primary Microglia ◽  
Microglial Polarization ◽  
Anti Inflammatory

Neuroinflammatory microenvironment, regulating neurite regrowth and neuronal survival, plays a critical role in Alzheimer’s disease (AD). During neuroinflammation, microglia are activated, inducing the release of inflammatory or anti-inflammatory factors depending on their polarization into classical M1 microglia or alternative M2 phenotype. Therefore, optimizing brain microenvironment by small molecule-targeted microglia polarization and promoting neurite regeneration might be a potential therapeutic strategy for AD. In this study, we found platycodigenin, a naturally occurring triterpenoid, promoted M2 polarization and inhibited M1 polarization in lipopolysaccharide (LPS)-stimulated BV2 and primary microglia. Platycodigenin downregulated pro-inflammatory molecules such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6 and nitric oxide (NO), while upregulated anti-inflammatory cytokine IL-10. Further investigation confirmed that platycodigenin inhibited cyclooxygenase-2 (Cox2) positive M1 but increased Ym1/2 positive M2 microglial polarization in primary microglia. In addition, platycodigenin significantly decreased LPS-induced the hyperphosphorylation of mitogen-activated protein kinase (MAPK) p38 and nuclear factor-κB (NF-κB) p65 subunits. Furthermore, the inactivation of peroxisome proliferators-activated receptor γ (PPARγ) induced by LPS was completely ameliorated by platycodigenin. Platycodigenin also promoted neurite regeneration and neuronal survival after Aβ treatment in primary cortical neurons. Taken together, our study for the first time clarified that platycodigenin effectively ameliorated LPS-induced inflammation and Aβ-induced neurite atrophy and neuronal death.

scholarly journals Glycogen Synthase Kinase-3β: A Mediator of Inflammation in Alzheimer's Disease?

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Jari Koistinaho ◽  
Tarja Malm ◽  
Gundars Goldsteins
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glycogen Synthase ◽  
Immune Defense ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Normal Brain ◽  
Brain Functions ◽  
The Brain

Proliferation and activation of microglial cells is a neuropathological characteristic of brain injury and neurodegeneration, including Alzheimer's disease. Microglia act as the first and main form of immune defense in the nervous system. While the primary function of microglia is to survey and maintain the cellular environment optimal for neurons in the brain parenchyma by actively scavenging the brain for damaged brain cells and foreign proteins or particles, sustained activation of microglia may result in high production of proinflammatory mediators that disturb normal brain functions and even cause neuronal injury. Glycogen synthase kinase-3βhas been recently identified as a major regulator of immune system and mediates inflammatory responses in microglia. Glycogen synthase kinase-3βhas been extensively investigated in connection to tau and amyloidβtoxicity, whereas reports on the role of this enzyme in neuroinflammation in Alzheimer's disease are negligible. Here we review and discuss the role of glycogen synthase-3βin immune cells in the context of Alzheimer's disease pathology.

scholarly journals May “Mitochondrial Eve” and Mitochondrial Haplogroups Play a Role in Neurodegeneration and Alzheimer's Disease?

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Elena Caldarazzo Ienco ◽  
Costanza Simoncini ◽  
Daniele Orsucci ◽  
Loredana Petrucci ◽  
Massimiliano Filosto ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Critical Role ◽  
Protective Role ◽  
Oxygen Species ◽  
Mitochondrial Haplogroups ◽  
Normal Ageing ◽  
Apoptotic Pathways ◽  
Mitochondrial Eve

Mitochondria, the powerhouse of the cell, play a critical role in several metabolic processes and apoptotic pathways. Multiple evidences suggest that mitochondria may be crucial in ageing-related neurodegenerative diseases. Moreover, mitochondrial haplogroups have been linked to multiple area of medicine, from normal ageing to diseases, including neurodegeneration. Polymorphisms within the mitochondrial genome might lead to impaired energy generation and to increased amount of reactive oxygen species, having either susceptibility or protective role in several diseases. Here, we highlight the role of the mitochondrial haplogroups in the pathogenetic cascade leading to diseases, with special attention to Alzheimer's disease.

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