Microglia in Alzheimer\u27s disease

Microglia are brain-resident myeloid cells that mediate key functions to support the CNS. Microglia express a wide range of receptors that act as molecular sensors, which recognize exogenous or endogenous CNS insults and initiate an immune response. In addition to their classical immune cell function, microglia act as guardians of the brain by promoting phagocytic clearance and providing trophic support to ensure tissue repair and maintain cerebral homeostasis. Conditions associated with loss of homeostasis or tissue changes induce several dynamic microglial processes, including changes of cellular morphology, surface phenotype, secretory mediators, and proliferative responses (referred to as an activated state ). Activated microglia represent a common pathological feature of several neurodegenerative diseases, including Alzheimer\u27s disease (AD). Cumulative evidence suggests that microglial inflammatory activity in AD is increased while microglial-mediated clearance mechanisms are compromised. Microglia are perpetually engaged in a mutual interaction with the surrounding environment in CNS; thus, diverse microglial reactions at different disease stages may open new avenues for therapeutic intervention and modification of inflammatory activities. In this Review, the role of microglia in the pathogenesis of AD and the modulation of microglia activity as a therapeutic modality will be discussed

PPARs in Alzheimer's Disease

Peroxisome proliferator-activated receptors (PPARs) are well studied for their peripheral physiological and pathological impact, but they also play an important role for the pathogenesis of various disorders of the central nervous system (CNS) like multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's, and Parkinson's disease. The observation that PPARs are able to suppress the inflammatory response in peripheral macrophages and in several models of human autoimmune diseases lead to the idea that PPARs might be beneficial for CNS disorders possessing an inflammatory component. The neuroinflammatory response during the course of Alzheimer's disease (AD) is triggered by the neurodegeneration and the deposition of the β-amyloid peptide in extracellular plaques. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been considered to delay the onset and reduce the risk to develop Alzheimer's disease, while they also directly activate PPARγ. This led to the hypothesis that NSAID protection in AD may be partly mediated by PPARγ. Several lines of evidence have supported this hypothesis, using AD-related transgenic cellular and animal models. Stimulation of PPARγ receptors by synthetic agonist (thiazolidinediones) inducing anti-inflammatory, anti-amyloidogenic, and insulin sensitising effects may account for the observed effects. Several clinical trials already revealed promising results using PPAR agonists, therefore PPARs represent an attractive therapeutic target for the treatment of AD

Peroxisome Proliferator-Activated Receptors (PPARs) as Potential Inducers of Antineoplastic Effects in CNS Tumors

The peroxisome proliferator-activated receptors (PPARs) are ligand-inducible transcription factors which belong to the superfamily of nuclear hormone receptors. In recent years it turned out that natural as well as synthetic PPAR agonists exhibit profound antineoplastic as well as redifferentiation effects in tumors of the central nervous system (CNS). The molecular understanding of the underlying mechanisms is still emerging, with partially controverse findings reported by a number of studies dealing with the influence of PPARs on treatment of tumor cells in vitro. Remarkably, studies examining the effects of these drugs in vivo are just beginning to emerge. However, the agonists of PPARs, in particular the thiazolidinediones, seem to be promising candidates for new approaches in human CNS tumor therapy

Impact and Therapeutic Potential of PPARs in Alzheimer's Disease

Peroxisome proliferator activated receptors (PPARs) are well studied for their role of peripheral metabolism, but they also may be involved in the pathogenesis of various disorders of the central nervous system (CNS) including multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's and, Parkinson's disease. The observation that PPARs are able to suppress the inflammatory response in peripheral macrophages and in several models of human autoimmune diseases, lead to the idea that PPARs might be beneficial for CNS disorders possessing an inflammatory component. The neuroinflammatory response during the course of Alzheimer's disease (AD) is triggered by the deposition of the β-amyloid peptide in extracellular plaques and ongoing neurodegeneration. Non-steroidal anti-inflammatory drugs (NSAIDs) have been considered to delay the onset and reduce the risk to develop Alzheimer’s disease, while they also directly activate PPARγ. This led to the hypothesis that NSAID protection in AD may be partly mediated by PPARγ. Several lines of evidence have supported this hypothesis, using AD related transgenic cellular and animal models. Stimulation of PPARγ by synthetic agonist (thiazolidinediones) inducing anti-inflammatory, anti-amyloidogenic and insulin sensitizing effects may account for the observed effects. Several clinical trials already revealed promising results using PPARγ agonists, therefore PPARγ represents an attractive therapeutic target for the treatment of AD

The Contribution of the Locus Coeruleus-Noradrenaline System Degeneration during the Progression of Alzheimer's Disease.

Alzheimer's disease (AD), which is characterized by extracellular accumulation of amyloid-beta peptide and intracellular aggregation of hyperphosphorylated tau, is the most common form of dementia. Memory loss, cognitive decline and disorientation are the ultimate consequences of neuronal death, synapse loss and neuroinflammation in AD. In general, there are many brain regions affected but neuronal loss in the locus coeruleus (LC) is one of the earliest indicators of neurodegeneration in AD. Since the LC is the main source of noradrenaline (NA) in the brain, degeneration of the LC in AD leads to decreased NA levels, causing increased neuroinflammation, enhanced amyloid and tau burden, decreased phagocytosis and impairment in cognition and long-term synaptic plasticity. In this review, we summarized current findings on the locus coeruleus-noradrenaline system and consequences of its dysfunction which is now recognized as an important contributor to AD progression

Long-term neuromuscular sequelae of critical illness

In this observational study, we analyzed the long-term neuromuscular deficits of survivors of critical illness. Intensive care unit-acquired muscular weakness (ICU-AW) is a very common complication of critical illness. Critical illness polyneuropathy (CIP) and critical illness myopathy (CIM) are two main contributors to ICU-AW. ICU-AW is associated with an increased mortality and leads to rehabilitation problems. However, the long-term outcome of ICU-AW and factors influencing it are not well known. We analyzed the medical records of 490 survivors of critical illness, aged 18-75years and located in the area of the study center. Intensive care unit (ICU) survivors with comorbidities that might influence neuromuscular follow-up examinations, muscle strength, or results of nerve conduction studies, such as renal or hepatic insufficiency, diabetes mellitus, or vitamin deficiency were excluded. A total of 51 patients were finally included in the study. Six to 24months after discharge from the ICU, we measured the Medical Research Council (MRC) sum score, the Overall Disability Sum score (ODSS), and also performed nerve conduction studies and EMG. For all ICU survivors, the median MRC sum score was 60 (range 47-60) and the median ODSS score was 0 (range 0-8). CIP was diagnosed in 21 patients (41%). No patient was diagnosed with CIM. Patients with diagnosis of CIP showed a higher median ODSS scores 1 (range 0-8) versus 0 (range 0-5); p<0.001 and lower median MRC sum scores 56 (range 47-60) versus 60 (range 58-60); p<0.001. The three main outcome variables MRC sum score, ODSS score and diagnosis of CIP were not related to age, gender, or diagnosis of sepsis. The MRC sum score (r=−0.33; p=0.02) and the ODSS score (r=0.31; p=0.029) were correlated with the APACHE score. There was a trend for an increased APACHE score in patients with diagnosis of CIP 19 (range 6-33) versus 16.5 (range 6-28); p=0.065. Patients with the diagnosis of CIP had more days of ICU treatment 11days (range 2-74) versus 4days (range 1-61); p=0.015, and had more days of ventilator support 8days (range 1-59) versus 2days (range 1-46); p=0.006. The MRC sum score and the ODSS score were correlated with the days of ICU treatment and with the days of ventilator support. The neuromuscular long-term consequences of critical illness were not severe in our study population. As patients with concomitant diseases and old patients were excluded from this study the result of an overall favorable prognosis of ICU-acquired weakness may not be true for other patient's case-mix. Risk factors for the development of long-term critical illness neuropathy are duration of ICU treatment, duration of ventilator support, and a high APACHE score, but not diagnosis of sepsis. Although ICU-AW can be serious complication of ICU treatment, this should not influence therapeutic decisions, given its favorable long-term prognosis, at least in relatively young patients with no concomitant disease

Microglia heterogeneity in health and disease

peer reviewedMicroglia, the resident immune cells of the central nervous system (CNS), have received significant attention due to their critical roles in maintaining brain homeostasis and mediating cerebral immune responses. Understanding the origin of microglia has been a subject of great interest, and emerging evidence suggests that microglia consist of multiple subpopulations with unique molecular and functional characteristics. These subpopulations of microglia may exhibit specialized roles in response to different environmental cues as in disease conditions. The newfound understanding of microglial heterogeneity has significant implications for elucidating their roles in both physiological and pathological conditions. In the context of disease, microglia have been studied rigorously as they play a very important role in neuroinflammation. Dysregulated microglial activation and function contribute to chronic inflammation. Further exploration of microglial heterogeneity and their interactions with other cell types in the CNS will undoubtedly pave the way to novel therapeutic strategies targeting microglia‐mediated pathologies. In this review, we discuss the latest advances in the field of microglia research, focusing specifically on the origin and subpopulations of microglia, the populations of microglia types in the brains of patients with neurodegenerative diseases, and how microglia are regulated in the healthy CNS

Immediate and long-term consequences of COVID-19 infections for the development of neurological disease

Increasing evidence suggests that infection with Sars-CoV-2 causes neurological deficits in a substantial proportion of affected patients. While these symptoms arise acutely during the course of infection, less is known about the possible long-term consequences for the brain. Severely affected COVID-19 cases experience high levels of proinflammatory cytokines and acute respiratory dysfunction and often require assisted ventilation. All these factors have been suggested to cause cognitive decline. Pathogenetically, this may result from direct negative effects of the immune reaction, acceleration or aggravation of pre-existing cognitive deficits, or de novo induction of a neurodegenerative disease. This article summarizes the current understanding of neurological symptoms of COVID-19 and hypothesizes that affected patients may be at higher risk of developing cognitive decline after overcoming the primary COVID-19 infection. A structured prospective evaluation should analyze the likelihood, time course, and severity of cognitive impairment following the COVID-19 pandemic

Effect of anti-inflammatory agents on transforming growth factor beta over-expressing mouse brains: a model revised.

BACKGROUND: The over-expression of transforming growth factor beta-1(TGF-beta1) has been reported to cause hydrocephalus, glia activation, and vascular amyloidbeta (Abeta) deposition in mouse brains. Since these phenomena partially mimic the cerebral amyloid angiopathy (CAA) concomitant to Alzheimer's disease, the findings in TGF-beta1 over-expressing mice prompted the hypothesis that CAA could be caused or enhanced by the abnormal production of TGF-beta1. This idea was in accordance with the view that chronic inflammation contributes to Alzheimer's disease, and drew attention to the therapeutic potential of anti-inflammatory drugs for the treatment of Abeta-elicited CAA. We thus studied the effect of anti-inflammatory drug administration in TGF-beta1-induced pathology. METHODS: Two-month-old TGF-beta1 mice and littermate controls were orally administered pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, or ibuprofen, a non steroidal anti-inflammatory agent, for two months. Glia activation was assessed by immunohistochemistry and western blot analysis; Abeta precursor protein (APP) by western blot analysis; Abeta deposition by immunohistochemistry, thioflavin-S staining and ELISA; and hydrocephalus by measurements of ventricle size on autoradiographies of brain sections. Results are expressed as means +/- SD. Data comparisons were carried with the Student's T test when two groups were compared, or ANOVA analysis when more than three groups were analyzed. RESULTS: Animals displayed glia activation, hydrocephalus and a robust thioflavin-S-positive vascular deposition. Unexpectedly, these deposits contained no Abeta or serum amyloid P component, a common constituent of amyloid deposits. The thioflavin-S-positive material thus remains to be identified. Pioglitazone decreased glia activation and basal levels of Abeta42- with no change in APP contents - while it increased hydrocephalus, and had no effect on the thioflavin-S deposits. Ibuprofen mimicked the reduction of glia activation caused by pioglitazone and the lack of effect on the thioflavin-S-labeled deposits. CONCLUSIONS: i) TGF-beta1 over-expressing mice may not be an appropriate model of Abeta-elicited CAA; and ii) pioglitazone has paradoxical effects on TGF-beta1-induced pathology suggesting that anti-inflammatory therapy may reduce the damage resulting from active glia, but not from vascular alterations or hydrocephalus. Identification of the thioflavin-S-positive material will facilitate the full appraisal of the clinical implication of the effects of anti-inflammatory drugs, and provide a more thorough understanding of TGF-beta1 actions in brain

Norepinephrine enhances the LPS-induced expression of COX-2 and secretion of PGE2 in primary rat microglia

<p>Abstract</p> <p>Background</p> <p>Recent studies suggest an important role for neurotransmitters as modulators of inflammation. Neuroinflammatory mediators such as cytokines and molecules of the arachidonic acid pathway are generated and released by microglia. The monoamine norepinephrine reduces the production of cytokines by activated microglia <it>in vitro</it>. However, little is known about the effects of norepinephrine on prostanoid synthesis. In the present study, we investigate the role of norepinephrine on cyclooxygenase- (COX-)2 expression/synthesis and prostaglandin (PG)E₂production in rat primary microglia.</p> <p>Results</p> <p>Interestingly, norepinephrine increased COX-2 mRNA, but not protein expression. Norepinephrine strongly enhanced COX-2 expression and PGE₂production induced by lipopolysaccharide (LPS). This effect is likely to be mediated by β-adrenoreceptors, since β-, but not α-adrenoreceptor agonists produced similar results. Furthermore, β-adrenoreceptor antagonists blocked the enhancement of COX-2 levels induced by norepinephrine and β-adrenoreceptor agonists.</p> <p>Conclusions</p> <p>Considering that PGE₂displays different roles in neuroinflammatory and neurodegenerative disorders, norepinephrine may play an important function in the modulation of these processes in pathophysiological conditions.</p