Dendrobium polysaccharides attenuate cognitive impairment in senescence-accelerated mouse prone 8 mice via modulation of microglial activation

Abstract Major depression is a prevalent illness that increases the risk of several neurological conditions. These include stroke, cardiovascular disease, and dementia including Alzheimer’s disease. In this review we ask whether certain types of depression and associated loneliness may be a harbinger of cognitive decline and possibly even dementia. We propose that chronic stress and inflammation combine to compromise vascular and brain function. The resulting increases in proinflammatory cytokines and microglial activation drive brain pathology leading to depression and mild cognitive impairment, which may progress to dementia. We present evidence that by treating the inflammatory changes, depression can be reversed in many cases. Importantly, there is evidence that anti-inflammatory and antidepressant treatments may reduce or prevent dementia in people with depression. Thus, we propose a model in which chronic stress and inflammation combine to increase brain permeability and cytokine production. This leads to microglial activation, white matter damage, neuronal and glial cell loss. This is first manifest as depression and mild cognitive impairment, but can eventually evolve into dementia. Further research may identify clinical subgroups with inflammatory depression at risk for dementia. It would then be possible to address in clinical trials whether effective treatment of the depression can delay the onset of dementia.

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Alzheimer´s Disease in the Perspective of Neuroimmunology

The Open Neurology Journal ◽

10.2174/1874205x01812010050 ◽

2018 ◽

Vol 12 (1) ◽

pp. 50-56 ◽

Cited By ~ 5

Author(s):

Ricardo B. Maccioni ◽

Andrea González ◽

Víctor Andrade ◽

Nicole Cortés ◽

José Pablo Tapia ◽

...

Keyword(s):

Cognitive Impairment ◽

Tau Protein ◽

Microglial Activation ◽

Neurodegenerative Disorder ◽

Vicious Cycle ◽

Considerable Research ◽

Dopaminergic Pathway ◽

The World ◽

Main Culprit

Background:Alzheimer’s Disease (AD) is a severe neurodegenerative disorder that includes the occurrence of behavioral disorders as well as memory and cognitive impairment as major symptoms. AD affects around 12% of the aged population in the world. Considerable research efforts have pointed to the role of innate immunity as the main culprit in the pathogenesis of AD. In this context, and according to with our neuroimmunomodulation theory, microglial activation modifies the cross-talks between microglia and neurons. We postulated that glial activation triggered by “damage signals” activates a pathological molecular cascade that finally leads to hyperphosphorylation and oligomerization of the tau protein. Interestingly, these modifications correlate with the gradual cognitive impairment of patients with the AD. Microglial activation is determined by the nature and strength of the stimulus. In the AD, a continuous activation state of microglia appears to generate neuronal injury and neurodegeneration, producing the outflow of pathological tau from the inner of neurons to the extraneuronal space. Released tau, together with the contribution of ApoE4 protein, would then produce reactivation of microglia, thus inducing a positive feedback that stimulates the vicious cycle in neurodegeneration.Conclusion:Nevertheless, from the pathophysiological perspective AD is significantly more than a loss of memory. In the initial stages of AD pathogenesis, variations in the dopaminergic pathway along with serotonin diminution play an important role. This may explain why depression is associated with the onset of AD. All these pathophysiological events take place together with immunomodulatory changes that trigger tau oligomerization in the course of neurofibrillary tangles formation. Interestingly, mood disorders appear to be followed by neuroinflammatory processes and structural/functional alterations that lead to cognitive impairment in the context of AD.

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CSF sTREM2 correlates with CSF tau in advancing Parkinson’s disease

10.1101/687269 ◽

2019 ◽

Author(s):

Edward N. Wilson ◽

Michelle S. Swarovski ◽

Patricia Linortner ◽

Marian Shahid ◽

Abigail J. Zuckerman ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Cognitive Decline ◽

Microglial Activation ◽

Soluble Form ◽

Motor Symptoms ◽

Cognitively Normal ◽

Csf Concentration

AbstractParkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease (AD) and affects 1% of the population above 60 years old. Although PD commonly manifests with motor symptoms, a majority of patients with PD subsequently develop cognitive impairment which often progresses to dementia, a major cause of morbidity and disability. PD is characterized by α-synuclein accumulation that frequently associates with amyloid beta (Aβ) and tau fibrils, the hallmarks of AD neuropathologic changes; this co-occurrence suggests that onset of cognitive decline in PD may be associated with appearance of pathologic Aβ and/or tau. Recent studies have highlighted the appearance of the soluble form of the Triggering Receptor Expressed on Myeloid cells 2 (sTREM2) receptor in CSF during development of AD. Given the known association of microglial activation with advancing PD, we investigated whether CSF and/or plasma sTREM2 increased with progression to PD dementia. We examined 165 participants consisting of 17 cognitively normal elderly, 45 PD patients with no cognitive impairment, 86 with mild cognitive impairment, and 17 with dementia. Stratification of subjects by CSF Aβ and tau levels revealed that CSF sTREM2 concentrations were elevated in PD subgroups with abnormal tau, but not Aβ, CSF concentration. These findings indicate that CSF sTREM2 could serve as a surrogate immune biomarker of neuronal injury in PD that is associated with cognitive decline.One sentence summaryCSF sTREM2 correlates with CSF tau in PD

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Qiang Xin 1 Formula Suppresses Excessive Pro-inflammatory Cytokine Responses and Microglia Activation to Prevent Cognitive Impairment and Emotional Dysfunctions in Experimental Sepsis

10.21203/rs.2.17972/v1 ◽

2019 ◽

Author(s):

Xuerui Wang ◽

Xiaolong Xu ◽

Yuhong Guo ◽

Po Huang ◽

Yanxiang Ha ◽

...

Keyword(s):

Cognitive Impairment ◽

Signaling Pathway ◽

Microglial Activation ◽

Inflammatory Cytokine ◽

Cell Activation ◽

Cytokine Production ◽

Behavioral Changes ◽

Microglia Cell ◽

Emotional Dysfunction

Abstract Background: Sepsis commonly leads to acute and long-term cognitive and affective impairments which are associated with increased mortality in patients. Neuroinflammation characterized by excessive cytokine release and immune cell activation underlies the behavioral changes associated with sepsis. We previously reported that the administration of a traditional Chinese herbal Qiang Xin 1 (QX1) formula improves survival in septic mice. This study was performed to better understand the effects and the mechanisms of QX1 formula treatment on behavioral changes in septic model. Methods: A preclinical septic model was induced by cecal ligation and puncture in mice. QX1 formula was orally administrated daily. Behavior test including Morris water maze, novel object recognition testing, elevated plus maze and open field testing was performed. Elisa, immunofluorescence, microarray analysis, and Real-time PCR were analyzed. Results: QX1 formula administration significantly improved survival, alleviated overall cognitive impairment and emotional dysfunction in septic mice. QX1 formula administration dramatically inhibited short and long-term excessive pro-inflammatory cytokine production both peripherally and centrally, and was accompanied by diminished microglial activation in septic mice. Biological processes including synaptic transmission, microglia cell activation, cytokine production, microglia cell polarization, as well as inflammatory responses related to signaling pathways including the MAPK signaling pathway and the NF-κB signaling pathway were altered prominently by QX1 formula treatment in the hippocampus of septic mice. In addition, QX1 formula administration decreased the expression of the M1 phenotype microglia gene markers such as Cd32, Socs3, and Cd68, while up-regulated M2 phenotype marker genes including Myc, Arg-1, and Cd206. Conclusions: QX1 formula administration attenuates cognitive deficits, emotional dysfunction, and reduces neuroinflammatory responses to improve survival in septic mice. Diminished microglial activation and altered microglial polarization are involved in the neuroprotective mechanism of QX1 formula.

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Sleep fragmentation, microglial aging, and cognitive impairment in adults with and without Alzheimer’s dementia

Science Advances ◽

10.1126/sciadv.aax7331 ◽

2019 ◽

Vol 5 (12) ◽

pp. eaax7331 ◽

Cited By ~ 9

Author(s):

Kirusanthy Kaneshwaran ◽

Marta Olah ◽

Shinya Tasaki ◽

Lei Yu ◽

Elizabeth M. Bradshaw ◽

...

Keyword(s):

Cognitive Impairment ◽

Older Persons ◽

Microglial Activation ◽

Marker Gene ◽

Sleep Fragmentation ◽

Sleep Disruption ◽

Religious Orders ◽

Marker Gene Expression ◽

Expression Of Genes ◽

Underlying Mechanisms

Sleep disruption is associated with cognitive decline and dementia in older adults; however, the underlying mechanisms are unclear. In rodents, sleep disruption causes microglial activation, inhibition of which improves cognition. However, data from humans are lacking. We studied participants in two cohort studies of older persons—the Rush Memory and Aging Project and the Religious Orders Study. We assessed sleep fragmentation by actigraphy and related this to cognitive function, to neocortical microglial marker gene expression measured by RNA sequencing, and to the neocortical density of microglia assessed by immunohistochemistry. Greater sleep fragmentation was associated with higher neocortical expression of genes characteristic of aged microglia, and a higher proportion of morphologically activated microglia, independent of chronological age- and dementia-related neuropathologies. Furthermore, these were, in turn, associated with worse cognition. This suggests that sleep fragmentation is accompanied by accelerated microglial aging and activation, which may partially underlie its association with cognitive impairment.

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Neuroinflammation trajectories precede cognitive impairment after experimental meningitis—evidence from an in vivo PET study

Journal of Neuroinflammation ◽

10.1186/s12974-019-1692-0 ◽

2020 ◽

Vol 17 (1) ◽

Cited By ~ 2

Author(s):

Vijayasree V. Giridharan ◽

Allan Collodel ◽

Jaqueline S. Generoso ◽

Giselli Scaini ◽

Rico Wassather ◽

...

Keyword(s):

Oxidative Stress ◽

Cognitive Impairment ◽

Microglial Activation ◽

Caspase 3 ◽

Cns Infection ◽

Control Group ◽

Caspase 9 ◽

Activation Markers

Abstract Background Bacterial meningitis is a devastating central nervous system (CNS) infection with acute and long-term neurological consequences, including cognitive impairment. The aim of this study was to understand the association between activated microglia-induced neuroinflammation and post-meningitis cognitive impairment. Method Meningitis was induced in male Wistar rats by injecting Streptococcus pneumoniae into the brain through the cisterna magna, and rats were then treated with ceftriaxone. Twenty-four hours and 10 days after meningitis induction, rats were imaged with positron emission tomography (PET) using [11C]PBR28, a specific translocator protein (TSPO) radiotracer, to determine in vivo microglial activation. Following imaging, the expression of TSPO, cardiolipin, and cytochrome c, inflammatory mediators, oxidative stress markers, and glial activation markers were evaluated in the prefrontal cortex and hippocampus. Ten days after meningitis induction, animals were subjected to behavioral tests, such as the open-field, step-down inhibitory avoidance, and novel object recognition tests. Results Both 24-h (acute) and 10-day (long-term) groups of rats demonstrated increased [11C]PBR28 uptake and microglial activation in the whole brain compared to levels in the control group. Although free from infection, 10-day group rats exhibited increased expression levels of cytokines and markers of oxidative stress, microglial activation (IBA-1), and astrocyte activation (GFAP) similar to those seen in the 24-h group. Acute meningitis induction also elevated TSPO, cytochrome c, and caspase-3 levels with no change in caspase-9 levels. Furthermore, upregulated levels of TSPO, cytochrome c, and caspase-3 and caspase-9 were observed in the rat hippocampus 10 days after meningitis induction with a simultaneous reduction in cardiolipin levels. Animals showed a cognitive decline in all tasks compared with the control group, and this impairment may be at least partially mediated by activating a glia-mediated immune response and upregulating TSPO. Conclusions TSPO-PET could potentially be used as an imaging biomarker for microglial activation and long-term cognitive impairment post-meningitis. Additionally, this study opens a new avenue for the potential use of TSPO ligands after infection-induced neurological sequelae.

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