Particulate Matter Exposure Exacerbates Amyloid-β Plaque Deposition and Gliosis in APP/PS1 Mice

2021 ◽  
Author(s):  
Bijayani Sahu ◽  
Amy R. Mackos ◽  
Angela M. Floden ◽  
Loren E. Wold ◽  
Colin K. Combs
Keyword(s):  
Air Pollution ◽  
Particulate Matter ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Plaque Deposition ◽  
Tnf Α ◽  
Plaque Load ◽  
Genetic And Environmental Factors ◽  
Particulate Matter Exposure

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques, neuroinflammation, and neuronal death. There are several well-established genetic and environmental factors hypothesized to contribute to AD progression including air pollution. However, the molecular mechanisms by which air pollution exacerbates AD are unclear. Objective: This study explored the effects of particulate matter exposure on AD-related brain changes using the APP/PS1 transgenic model of disease. Methods: Male C57BL/6;C3H wild type and APP/PS1 mice were exposed to either filtered air (FA) or particulate matter sized under 2.5 μm (PM2.5) for 6 h/day, 5 days/week for 3 months and brains were collected. Immunohistochemistry for Aβ, GFAP, Iba1, and CD68 and western blot analysis for PS1, BACE, APP, GFAP, and Iba1 were performed. Aβ ELISAs and cytokine arrays were performed on frozen hippocampal and cortical lysates, respectively. Results: The Aβ plaque load was significantly increased in the hippocampus of PM2.5-exposed APP/PS1 mice compared to their respective FA controls. Additionally, in the PM2.5-exposed APP/PS1 group, increased astrocytosis and microgliosis were observed as indicated by elevated GFAP, Iba1, and CD68 immunoreactivities. PM2.5 exposure also led to an elevation in the levels of PS1 and BACE in APP/PS1 mice. The cytokines TNF-α, IL-6, IL-1β, IFN-γ, and MIP-3α were also elevated in the cortices of PM2.5-exposed APP/PS1 mice compared to FA controls. Conclusion: Our data suggest that chronic particulate matter exposure exacerbates AD by increasing Aβ plaque load, gliosis, and the brain inflammatory status.

scholarly journals Particulate Matter Exposure Exacerbates Amyloid-β Plaque Deposition and Gliosis in APP/PS1 Mice

2021 ◽  
pp. 1-14
Author(s):  
Bijayani Sahu ◽  
Amy R. Mackos ◽  
Angela M. Floden ◽  
Loren E. Wold ◽  
Colin K. Combs
Keyword(s):  
Air Pollution ◽  
Particulate Matter ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Plaque Deposition ◽  
Inflammatory Status ◽  
Plaque Load ◽  
Genetic And Environmental Factors ◽  
Particulate Matter Exposure

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques, neuroinflammation, and neuronal death. There are several well-established genetic and environmental factors hypothesized to contribute to AD progression including air pollution. However, the molecular mechanisms by which air pollution exacerbates AD are unclear. Objective: This study explored the effects of particulate matter exposure on AD-related brain changes using the APP/PS1 transgenic model of disease. Methods: Male C57BL/6;C3H wild type and APP/PS1 mice were exposed to either filtered air (FA) or particulate matter sized under 2.5μm (PM2.5) for 6 h/day, 5 days/week for 3 months and brains were collected. Immunohistochemistry for Aβ, GFAP, Iba1, and CD68 and western blot analysis for PS1, BACE, APP, GFAP, and Iba1 were performed. Aβ ELISAs and cytokine arrays were performed on frozen hippocampal and cortical lysates, respectively. Results: The Aβ plaque load was significantly increased in the hippocampus of PM2.5-exposed APP/PS1 mice compared to their respective FA controls. Additionally, in the PM2.5-exposed APP/PS1 group, increased astrocytosis and microgliosis were observed as indicated by elevated GFAP, Iba1, and CD68 immunoreactivities. PM2.5 exposure also led to an elevation in the levels of PS1 and BACE in APP/PS1 mice. The cytokines TNF-α, IL-6, IL-1β, IFN-γ, and MIP-3α were also elevated in the cortices of PM2.5-exposed APP/PS1 mice compared to FA controls. Conclusion: Our data suggest that chronic particulate matter exposure exacerbates AD by increasing Aβ plaque load, gliosis, and the brain inflammatory status.

scholarly journals Repositioning of Immunomodulators: A Ray of Hope for Alzheimer’s Disease?

2020 ◽  
Vol 14 ◽  
Author(s):  
Antonio Munafò ◽  
Chiara Burgaletto ◽  
Giulia Di Benedetto ◽  
Marco Di Mauro ◽  
Rosaria Di Mauro ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune System ◽  
Neurodegenerative Disorder ◽  
Drug Repositioning ◽  
Amyloid Β ◽  
Deep Understanding ◽  
Current Status ◽  
Age Related ◽  
Tnf Α

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder characterized by cognitive decline and by the presence of amyloid β plaques and neurofibrillary tangles in the brain. Despite recent advances in understanding its pathophysiological mechanisms, to date, there are no disease-modifying therapeutic options, to slow or halt the evolution of neurodegenerative processes in AD. Current pharmacological treatments only transiently mitigate the severity of symptoms, with modest or null overall improvement. Emerging evidence supports the concept that AD is affected by the impaired ability of the immune system to restrain the brain’s pathology. Deep understanding of the relationship between the nervous and the immune system may provide a novel arena to develop effective and safe drugs for AD treatment. Considering the crucial role of inflammatory/immune pathways in AD, here we discuss the current status of the immuno-oncological, immunomodulatory and anti-TNF-α drugs which are being used in preclinical studies or in ongoing clinical trials by means of the drug-repositioning approach.

scholarly journals Influence of Woodsmoke Exposure on Molecular Mechanisms Underlying Alzheimer’s Disease: Existing Literature and Gaps in Our Understanding

2020 ◽  
Vol 13 ◽  
pp. 251686572095487
Author(s):  
Adam Schuller ◽  
Luke Montrose
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Air Pollution ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Ambient Air ◽  
The United States ◽  
Ambient Air Pollution ◽  
Current Status

Woodsmoke poses a significant health risk as a growing component of ambient air pollution in the United States. While there is a long history of association between woodsmoke exposure and diseases of the respiratory, circulatory, and cardiovascular systems, recent evidence has linked woodsmoke exposure to cognitive dysfunction, including Alzheimer’s disease dementia. Alzheimer’s disease is a progressive neurodegenerative disorder with largely idiopathic origins and no known cure. Here, we explore the growing body of literature which relates woodsmoke-generated and ambient air pollution particulate matter exposure to Alzheimer’s disease (AD) onset or exacerbation, in the context of an inflammation-centric view of AD. Epigenetic modifications, specifically changes in DNA methylation patterns, are well documented following woodsmoke exposure and have been shown to influence disease-favoring inflammatory cascades, induce oxidative stress, and modulate the immune response in vitro, in vivo, and in humans following exposure to air pollution. Though the current status of the literature does not allow us to draw definitive conclusions linking these events, this review highlights the need for additional work to fill gaps in our understanding of the directionality, causality, and susceptibility throughout the life course.

Impairment of the activity of the plasma membrane Ca2+-ATPase in Alzheimer's disease

2011 ◽  
Vol 39 (3) ◽  
pp. 819-822 ◽  
Author(s):  
Ana M. Mata ◽  
María Berrocal ◽  
M. Rosario Sepúlveda
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Plasma Membrane ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Inhibitory Effect ◽  
Amyloid Β Peptide ◽  
Aβ Amyloid

AD (Alzheimer's disease) is an age-associated neurodegenerative disorder where the accumulation of neurotoxic Aβ (amyloid β-peptide) in senile plaques is a typical feature. Recent studies point out a relationship between Aβ neurotoxicity and Ca2+ dyshomoeostasis, but the molecular mechanisms involved are still under discussion. The PMCAs (plasma membrane Ca2+-ATPases) are a multi-isoform family of proteins highly expressed in brain that is implicated in the maintenance of low intraneural Ca2+ concentration. Therefore the malfunction of this pump may also be responsible for Ca2+ homoeostasis failure in AD. We have found that the Ca2+-dependence of PMCA activity is affected in human brains diagnosed with AD, being related to the enrichment of Aβ. The peptide produces an inhibitory effect on the activity of PMCA which is isoform-specific, with the greatest inhibition of PMCA4. Besides, cholesterol blocked the inhibitory effect of Aβ, which is consistent with the lack of any Aβ effect on PMCA4 found in cholesterol-enriched lipid rafts isolated from pig brain. These observations suggest that PMCAs are a functional component of the machinery that leads to Ca2+ dysregulation in AD and propose cholesterol enrichment in rafts as a protector of the Aβ-mediated inhibition on PMCA.

scholarly journals Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery

Antioxidants ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1353
Author(s):  
Francesca Romana Buccellato ◽  
Marianna D’Anca ◽  
Chiara Fenoglio ◽  
Elio Scarpini ◽  
Daniela Galimberti
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Oxidative Damage ◽  
Molecular Mechanisms ◽  
Biomarker Discovery ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Antioxidant Defenses ◽  
Ageing Population

Alzheimer’s disease (AD) is a neurodegenerative disorder accounting for over 50% of all dementia patients and representing a leading cause of death worldwide for the global ageing population. The lack of effective treatments for overt AD urges the discovery of biomarkers for early diagnosis, i.e., in subjects with mild cognitive impairment (MCI) or prodromal AD. The brain is exposed to oxidative stress as levels of reactive oxygen species (ROS) are increased, whereas cellular antioxidant defenses are decreased. Increased ROS levels can damage cellular structures or molecules, leading to protein, lipid, DNA, or RNA oxidation. Oxidative damage is involved in the molecular mechanisms which link the accumulation of amyloid-β and neurofibrillary tangles, containing hyperphosphorylated tau, to microglia response. In this scenario, microglia are thought to play a crucial role not only in the early events of AD pathogenesis but also in the progression of the disease. This review will focus on oxidative damage products as possible peripheral biomarkers in AD and in the preclinical phases of the disease. Particular attention will be paid to biological fluids such as blood, CSF, urine, and saliva, and potential future use of molecules contained in such body fluids for early differential diagnosis and monitoring the disease course. We will also review the role of oxidative damage and microglia in the pathogenesis of AD and, more broadly, in neurodegeneration.

Sirt1 protects against thrombomodulin down-regulation and lung coagulation after particulate matter exposure

Blood ◽  
2012 ◽  
Vol 119 (10) ◽  
pp. 2422-2429 ◽  
Author(s):  
Zhuang Wu ◽  
Ming-Cheh Liu ◽  
Mei Liang ◽  
Jian Fu
Keyword(s):  
Particulate Matter ◽  
Molecular Mechanisms ◽  
Transcriptional Level ◽  
Class Iii ◽  
Plasminogen Activator Inhibitor 1 ◽  
Down Regulation ◽  
Knock Out ◽  
Fibrin Formation ◽  
Knock Out Mice ◽  
Particulate Matter Exposure

Abstract Exposure to ambient particulate matter (PM) air pollution has been reported to trigger inflammation and thrombosis. However, molecular mechanisms underlying the modulation of coagulation pathways in PM-induced thrombosis remain largely unknown. We report here that Sirt1, a member of class III histone deacetylase, controls lung inflammation and coagulation after PM exposure. Sirt1 knock-out mice exhibited aggravated lung vascular leakage and inflammation after PM exposure, which was correlated with increased NF-κB acetylation and activation. Furthermore, Sirt1 knock-out mice were highly susceptible to PM-induced lung coagulation as demonstrated by increased fibrin formation. The increased fibrin formation was associated with reduced tissue factor pathway inhibitor (TFPI) expression and increased plasminogen activator inhibitor-1 (PAI-1) activity in the lungs, thus favoring elevated coagulation and disrupted fibrinolysis responses. Thrombomodulin (TM), a central player of the anticoagulant protein C system, is regulated by Kruppel-like factor 2 (KLF2) at the transcriptional level. Our data show that PM exposure led to decreased lung KLF2 and TM expression in wild-type mice, and lung KLF2 and TM protein levels were further decreased in Sirt1 knock-out mice. Importantly, Sirt1 gene delivery inhibited TM and KLF2 down-regulation and reduced lung coagulation after PM exposure. Collectively, our studies indicate that Sirt1 functions as a suppressor of coagulation after particulate matter exposure.

scholarly journals Effects of particulate matter exposure on blood 5-hydroxymethylation: results from the Beijing truck driver air pollution study

Epigenetics ◽  
2015 ◽  
Vol 10 (7) ◽  
pp. 633-642 ◽  
Author(s):  
Marco Sanchez-Guerra ◽  
Yinan Zheng ◽  
Citlalli Osorio-Yanez ◽  
Jia Zhong ◽  
Yana Chervona ◽  
...  
Keyword(s):  
Air Pollution ◽  
Particulate Matter ◽  
Truck Driver ◽  
Pollution Study ◽  
Particulate Matter Exposure ◽  
Driver Air

scholarly journals Trichostatin A ameliorates Alzheimer’s disease-related pathology and cognitive deficits by increasing albumin expression and Aβ clearance in APP/PS1 mice

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Qiang Su ◽  
Tian Li ◽  
Pei-Feng He ◽  
Xue-Chun Lu ◽  
Qi Yu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Western Blotting ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Trichostatin A ◽  
Amyloid Β ◽  
Aβ Oligomers ◽  
Aβ Clearance

Abstract Background Alzheimer’s disease (AD) is an intractable neurodegenerative disorder in the elderly population, currently lacking a cure. Trichostatin A (TSA), a histone deacetylase inhibitor, showed some neuroprotective roles, but its pathology-improvement effects in AD are still uncertain, and the underlying mechanisms remain to be elucidated. The present study aims to examine the anti-AD effects of TSA, particularly investigating its underlying cellular and molecular mechanisms. Methods Novel object recognition and Morris water maze tests were used to evaluate the memory-ameliorating effects of TSA in APP/PS1 transgenic mice. Immunofluorescence, Western blotting, Simoa assay, and transmission electron microscopy were utilized to examine the pathology-improvement effects of TSA. Microglial activity was assessed by Western blotting and transwell migration assay. Protein-protein interactions were analyzed by co-immunoprecipitation and LC-MS/MS. Results TSA treatment not only reduced amyloid β (Aβ) plaques and soluble Aβ oligomers in the brain, but also effectively improved learning and memory behaviors of APP/PS1 mice. In vitro study suggested that the improvement of Aβ pathology by TSA was attributed to the enhancement of Aβ clearance, mainly by the phagocytosis of microglia, and the endocytosis and transport of microvascular endothelial cells. Notably, a meaningful discovery in the study was that TSA dramatically upregulated the expression level of albumin in cell culture, by which TSA inhibited Aβ aggregation and promoted the phagocytosis of Aβ oligomers. Conclusions These findings provide a new insight into the pathogenesis of AD and suggest TSA as a novel promising candidate for the AD treatment.

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