Primary Phagocytosis of Neurons by Inflamed Microglia: Potential Roles in Neurodegeneration

Microglial phagocytosis of dead or dying neurons can be beneficial by preventing the release of damaging and/or pro-inflammatory intracellular components. However, there is now evidence that under certain conditions, such as inflammation, microglia can also phagocytose viable neurons, thus executing their death. Such phagocytic cell death may result from exposure of phosphatidylserine (PS) or other eat-me signals on otherwise viable neurons as a result of physiological activation or sub-toxic insult, and neuronal phagocytosis by activated microglia. In this review, we discuss the mechanisms of phagocytic cell death and its potential roles in Alzheimer’s Disease, Parkinson’s Disease, and Frontotemporal Dementia

Amyloid β induces microglia to phagocytose neurons via activation of protein kinase Cs and NADPH oxidase.

Alzheimer's disease is characterized by brain plaques of amyloid beta and by neuronal loss, but it is unclear how amyloid beta causes neuronal loss and how to prevent this loss. We have previously shown that amyloid beta causes neuronal loss by inducing microglia to phagocytose neurons, and here we investigated whether protein kinase Cs and NADPH oxidase were involved in this. The loss of neurons induced by amyloid beta in co-cultures of primary glia and neurons was completely prevented by inhibiting protein kinase Cs with Gö6976 or Gö6983. Directly activating protein kinase Cs with phorbol myristate acetate stimulated microglial phagocytosis, and induced neuronal loss mediated by MFG-E8/vitronectin receptor pathway of microglial phagocytosis. Blocking phagocytosis by MFG-E8 knockout or receptor inhibition left live neurons, indicating microglial phagocytosis was the cause of neuronal death. Phorbol myristate acetate stimulated the microglial NADPH oxidase, and inhibiting the oxidase prevented neuronal loss. A physiological activator of NADPH oxidase, fMLP, also induced neuronal loss dependent on microglia. Amyloid beta-induced neuronal loss was blocked by NADPH oxidase inhibitors, superoxide dismutase or Toll-like receptor function-blocking antibodies. The results indicate that amyloid beta induces microglial phagocytosis of neurons via activating protein kinase Cs and NADPH oxidase, and that activating the kinases or oxidase is sufficient to induce neuronal loss by microglial phagocytosis. Thus inhibiting protein kinase Cs or NADPH oxidase might be beneficial in Alzheimer's disease or other brain pathologies involving inflammatory neuronal loss mediated by microglia.This work was partially supported by the Medical Research Council UK (MR/L010593). UN was supported by St John’s College (University of Cambridge), Department of Biochemistry (University of Cambridge) and the Cambridge Trust.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.biocel.2016.06.00

The impact of maternal high-fat diet on offspring neurodevelopment

A maternal high-fat diet affects offspring neurodevelopment with long-term consequences on their brain health and behavior. During the past three decades, obesity has rapidly increased in the whole human population worldwide, including women of reproductive age. It is known that maternal obesity caused by a high-fat diet may lead to neurodevelopmental disorders in their offspring, such as autism spectrum disorder, attention deficit hyperactivity disorder, anxiety, depression, and schizophrenia. A maternal high-fat diet can affect offspring neurodevelopment due to inflammatory activation of the maternal gut, adipose tissue, and placenta, mirrored by increased levels of pro-inflammatory cytokines in both maternal and fetal circulation. Furthermore, a maternal high fat diet causes gut microbial dysbiosis further contributing to increased inflammatory milieu during pregnancy and lactation, thus disturbing both prenatal and postnatal neurodevelopment of the offspring. In addition, global molecular and cellular changes in the offspring’s brain may occur due to epigenetic modifications including the downregulation of brain-derived neurotrophic factor (BDNF) expression and the activation of the endocannabinoid system. These neurodevelopmental aberrations are reflected in behavioral deficits observed in animals, corresponding to behavioral phenotypes of certain neurodevelopmental disorders in humans. Here we reviewed recent findings from rodent models and from human studies to reveal potential mechanisms by which a maternal high-fat diet interferes with the neurodevelopment of the offspring

Tumour necrosis factor alpha-induced neuronal loss is mediated by microglial phagocytosis

This is the final published version of the article. It originally appeared in FEBS Letters at http://www.sciencedirect.com/science/article/pii/S0014579314004360.Tumour necrosis factor-α (TNF-α) is a pro-inflammatory cytokine, expressed in many brain pathologies and associated with neuronal loss. We show here that addition of TNF-α to neuronal–glial co-cultures increases microglial proliferation and phagocytosis, and results in neuronal loss that is prevented by eliminating microglia. Blocking microglial phagocytosis by inhibiting phagocytic vitronectin and P2Y6 receptors, or genetically removing opsonin MFG-E8, prevented TNF-α induced loss of live neurons. Thus TNF-α appears to induce neuronal loss via microglial activation and phagocytosis of neurons, causing neuronal death by phagoptosis.This work was supported by the Wellcome Trust [084645/Z/08/Z]. UN was supported by St John’s College (University of Cambridge), Department of Biochemistry (University of Cambridge) and the Cambridge Trust

Peptidylarginine deiminases as drug targets in neonatal hypoxic-ischemic encephalopathy

Oxygen deprivation and infection are major causes of perinatal brain injury leading to cerebral palsy and other neurological disabilities. The identification of novel key factors mediating white and grey matter damage are crucial to allow better understanding of the specific contribution of different cell types to the injury processes and pathways for clinical intervention. Recent studies in the Rice-Vannucci mouse model of neonatal hypoxic ischaemia (HI) have highlighted novel roles for calcium-regulated peptidylarginine deiminases (PADs) and demonstrated neuro-protective effects of pharmacological PAD inhibition following HI and synergistic infection mimicked by LPS stimulation

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

Objective: Frontotemporal lobar degeneration (FTLD) is the second most prevalent dementia in young patients and is characterized by the presence of two main protein aggregates in the brain, tau (FTLD-Tau) or TDP43 (FTLD-TDP), which likely require distinct pharmacological therapy. However, specific diagnosis of FTLD and its subtypes remains challenging due to largely overlapping clinical phenotypes. Here, we aimed to assess the clinical performance of novel cerebrospinal fluid (CSF) biomarkers for discrimination of FTLD and its pathological subtypes. Methods: YKL40, FABP4, MFG-E8, and the activities of catalase and specific lysosomal enzymes were analyzed in patients with FTLD-TDP (n\ua0=\ua030), FTLD-Tau (n\ua0=\ua020), AD (n\ua0=\ua030), DLB (n\ua0=\ua029), and nondemented controls (n\ua0=\ua029) obtained from two different centers. Models were validated in an independent CSF cohort (n\ua0=\ua0188). Results: YKL40 and catalase activity were increased in FTLD-TDP cases compared to controls. YKL40 levels were also higher in FTLD-TDP compared to FTLD-Tau. We identified biomarker models able to discriminate FTLD from nondemented controls (MFG-E8, tTau, and A\u3b242; 78% sensitivity and 83% specificity) and non-FTLD dementia (YKL40, pTau, p/tTau ratio, and age; 90% sensitivity, 78% specificity), which were validated in an independent cohort. In addition, we identified a biomarker model differentiating FTLD-TDP from FTLD-Tau (YKL40, MFGE-8, \u3b2HexA together with \u3b2HexA/tHex and p/tTau ratios and age) with 80% sensitivity and 82% specificity. Interpretation: This study identifies CSF protein signatures distinguishing FTLD and the two main pathological subtypes with optimal accuracy (specificity/sensitivity\ua0>\ua080%). Validation of these models may allow appropriate selection of cases for clinical trials targeting the accumulation of Tau or TDP43, thereby increasing their efficiency and facilitating the development of successful therapies