Jonas J Neher

Jonas J Neher
German Center for Neurodegenerative Diseases (DZNE), Tübingen · Experimental Neuroimmunology

PhD

About

56
Publications
13,173
Reads
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4,634
Citations
Introduction
My primary research interest is the contribution of microglia to neurological disease, with a particular focus on the role of microglia in Alzheimer's disease and aging as well as their capacity to develop immune memory and its consequences for neuropathology.
Additional affiliations
June 2017 - present
Deutsches Zentrum für Neurodegenerative Erkrankungen
Position
  • Group Leader
March 2015 - present
Hertie-Institute for Clinical Brain Research
Position
  • Group Leader
December 2011 - February 2015
Hertie-Institute for Clinical Brain Research
Position
  • PostDoc Position

Publications

Publications (56)
Article
Full-text available
Significance Single-cell transcriptomics has revealed specific glial activation states associated with the pathogenesis of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease (AD and PD). What is still needed are clinically relevant biomarkers for deciphering such glial states in AD and PD patients. To this end, we applied prote...
Article
Although consistently implicated, the exact role of interferon (IFN) signaling in Alzheimer's disease remains largely unexplored. Roy et al. now demonstrate that type I IFNs may drive cognitive dysfunction through acting not only on microglia but, surprisingly, also on neurons.
Article
Background: Septic encephalopathy represents an acute cerebral dysfunction following systemic inflammation by pathogens. Notably, more than 70% of sepsis survivors present this disorder years after the hospital discharge (Widmann and Heneka, 2014). In rodents, septic shock can be modelled by an intraperitoneal injection of lipopolysaccharide (LPS)...
Article
Sepsis-associated encephalopathy (SAE) represents diverse cerebral dysfunctions in response to pathogen-induced systemic inflammation. Peripheral exposure to lipopolysaccharide (LPS), a component of the gram-negative bacterial cell wall, has been extensively used to model systemic inflammation. Our previous studies suggested that LPS led to hippoca...
Preprint
Full-text available
The integration of adult-born neurons in the existent neural circuitry is known to be activity-dependent. To decipher the underlying mechanisms, we genetically manipulated excitability of adult-born cells (via cell-specific overexpression of either Kv1.2 or Kir2.1 K + channels). Longitudinal in vivo Ca 2+ imaging and transcriptome analyses revealed...
Article
In neurodegenerative diseases, certain types of neurons perish first, but the mechanisms of this selective neuronal vulnerability remain unclear. A new study now highlights a crucial role for apolipoprotein E in driving neuronal death in both ageing and Alzheimer’s disease.
Article
Immune cells called macrophages have been found to shut down major metabolic pathways during ageing. Restoring metabolism in these cells is sufficient to alleviate age-associated cognitive decline in mice. Cognition restored by inhibiting EP2 receptor proteins in macrophages.
Article
The most common human amyloid is probably medin (AMed), which deposits in the aorta of nearly everyone above 50 years of age. Previous studies reported that medin amyloid may co‐aggregate and seed serum amyloid A. Because of this finding and its exceedingly high prevalence in the aging population, we studied whether medin aggregates form in the bra...
Article
Microglial cells play an important role in the pathogenesis of Alzheimer’s disease. We have previously shown that microglia activate the Hypoxia inducible factor‐1α (HIF‐1α) signalling pathway in response to cerebral β‐amyloidosis in a mouse model of Alzheimer’s pathology (Wendeln et al., Nature, 2018). Importantly, we also found that activation of...
Article
Full-text available
Background: Stem cells` (SC) functional heterogeneity and its poorly understood aetiology impedes clinical development of cell-based therapies in regenerative medicine and oncology. Recent studies suggest a strong correlation between the SC migration potential and their therapeutic efficacy in humans. Designating SC migration as a denominator of f...
Article
Medin is the most common amyloid known in humans, as it can be found in blood vessels of the upper body in virtually everybody over 50 years of age. However, it remains unknownwhether deposition of Medin plays a causal role in age-related vascular dysfunction. We now report that aggregates of Medin also develop in the aorta and brain vasculature of...
Chapter
During insults and disease blood-borne monocytes can invade brain and spinal cord, contributing to the neuroimmune response together with brain-resident microglia. The specific function of brain-infiltrating monocytes has been difficult to ascertain because of shared marker expression and morphology of these two immune cell types. Here we describe...
Chapter
Microglia are morphologically dynamic cells, neatly arranged in an interconnected three-dimensional lattice throughout the brain, constantly surveying the parenchyma, and swiftly responding to a variety of external stimuli. Capturing the dynamics of their morphology, reaction to trauma, pathogens, or endogenous stimuli, and studying changes in thei...
Article
Microglia, the resident macrophages of the brain, are highly plastic and well known to be pre-activated or ‘primed’ by active inflammatory processes, resulting in amplified responses to a second inflammatory insult. Furthermore, the capacity of microglia to develop ‘innate immune memory’ (IIM), that is, long-lasting molecular reprogramming, has rec...
Article
Full-text available
Coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with late-onset Alzheimer’s disease (AD). We demonstrate that amyloid plaque seeding is increased in the absence of functional Trem2. Increased seeding is accompanied by decreased microglial clustering around newly seeded plaques and reduced plaque-associ...
Article
This review discusses the profound connection between microglia, neuroinflammation, and Alzheimer's disease (AD)¹. Theories have been postulated, tested, and modified over several decades. The findings have further bolstered the belief that microglia‐mediated inflammation is both a product and contributor to AD pathology and progression. Distinct m...
Article
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The flagellated parasite Trypanosoma brucei is the causative agent of Human African Trypanosomiasis (HAT). By a mechanism not well understood yet, trypanosomes enter the central nervous system (CNS), invade the brain parenchyma, and cause a fatal encephalopathy if is not treated. Trypanosomes are fast dividing organisms that, without any immune res...
Article
Full-text available
Stroke is a major cause of death and disability worldwide. In addition to neuronal death resulting directly from energy depletion due to lack of blood supply, inflammation and microglial activation following ischemic brain injury has been increasingly recognized to be a key contributor to the pathophysiology of cerebrovascular disease. However, our...
Article
Full-text available
Innate immune memory is a vital mechanism of myeloid cell plasticity that occurs in response to environmental stimuli and alters subsequent immune responses. Two types of immunological imprinting can be distinguished-training and tolerance. These are epigenetically mediated and enhance or suppress subsequent inflammation, respectively. Whether immu...
Article
Full-text available
Stroke is a major cause of death and disability worldwide. In addition to neuronal death resulting directly from energy depletion due to lack of blood supply, inflammation and microglial activation following ischemic brain injury has been increasingly recognized to be a key contributor to the pathophysiology of cerebrovascular disease. However, our...
Article
Full-text available
Stroke is a major cause of death and disability worldwide. In addition to neuronal death resulting directly from energy depletion due to lack of blood supply, inflammation and microglial activation following ischemic brain injury has been increasingly recognized to be a key contributor to the pathophysiology of cerebrovascular disease. However, our...
Article
Full-text available
To clarify the role of microglia in brain homeostasis and disease, an understanding of their maintenance, proliferation and turnover is essential. The lifespan of brain microglia, however, remains uncertain, and reflects confounding factors in earlier assessments that were largely indirect. We genetically labeled single resident microglia in living...
Article
Full-text available
Alzheimer’s disease is the most common form of dementia in the western world, however there is no cure available for this devastating neurodegenerative disorder. Despite clinical and experimental evidence implicating the intestinal microbiota in a number of brain disorders, its impact on Alzheimer’s disease is not known. To this end we sequenced ba...
Article
Full-text available
The generalized seizures of status epilepticus (SE) trigger a series of molecular and cellular events that produce cognitive deficits and can culminate in the development of epilepsy. Known early events include opening of the blood-brain barrier (BBB) and astrocytosis accompanied by activation of brain microglia. Whereas circulating monocytes do no...
Article
Unlabelled: The aggregation of amyloid-β peptide (Aβ) in brain is an early event and hallmark of Alzheimer's disease (AD). We combined the advantages of in vitro and in vivo approaches to study cerebral β-amyloidosis by establishing a long-term hippocampal slice culture (HSC) model. While no Aβ deposition was noted in untreated HSCs of postnatal A...
Article
Immune cells of myeloid lineage are encountered in the Alzheimer's disease (AD) brain, where they cluster around amyloid-β plaques. However, assigning functional roles to myeloid cell subtypes has been problematic, and the potential for peripheral myeloid cells to alleviate AD pathology remains unclear. Therefore, we asked whether replacement of br...
Article
Full-text available
Alzheimer's disease is the most common form of dementia in the western world, however there is no cure available for this devastating neurodegenerative disorder. Despite clinical and experimental evidence implicating the intestinal microbiota in a number of brain disorders, its impact on Alzheimer's disease is not known. We generated a germ-free mo...
Article
Full-text available
Identification of fluorescent dyes that label filamentous protein aggregates characteristic of neurodegenerative disease, such as β-amyloid and tau in Alzheimer’s disease (AD), in a live cell culture system has previously been a major hurdle. Here we show that pentameric formyl thiophene acetic acid (pFTAA) fulfils this function in living neurons c...
Article
Histopathologic assessment in transient middle cerebral artery occlusion (MCAo) rodent models generally lacks comprehensiveness and exposes to interobserver bias. Here we compared a novel quantitative assessment of regional infarction, selective neuronal loss (SNL) and microglial activation (MA) across the MCA territory to a previously published se...
Article
Full-text available
Microglia activated through Toll-like receptor (TLR)-2 or -4 can cause neuronal death by phagocytosing otherwise-viable neurons—a form of cell death called “phagoptosis.” UDP release from neurons has been shown to provoke microglial phagocytosis of neurons via microglial P2Y6 receptors, but whether inhibition of this process affects neuronal surviv...
Article
Microglia, the brain's professional phagocytes, can remove dead and dying neurons as well as synapses and the processes of live neurons. However, we and others have recently shown that microglia can also execute neuronal death by phagocytosing stressed-but-viable neurons - a process that we have termed phagoptosis. In this Progress article, we disc...
Article
Full-text available
Delayed neuronal loss and brain atrophy after cerebral ischemia contribute to stroke and dementia pathology, but the mechanisms are poorly understood. Phagocytic removal of neurons is generally assumed to be beneficial and to occur only after neuronal death. However, we report herein that inhibition of phagocytosis can prevent delayed loss and deat...
Article
Microglia cells are essential for brain homeostasis and have essential roles in neurodegenerative diseases. Aging is the main risk factor for most neurodegenerative diseases and age-related changes in microglia may contribute to the susceptibility of the aging brain to dysfunction and neurodegeneration. We have analyzed morphology and dynamic behav...
Article
Rotenone, a common pesticide and inhibitor of mitochondrial complex I, induces microglial activation and loss of dopaminergic neurons in models of Parkinson's disease. However, the mechanisms of rotenone neurotoxicity are still poorly defined. Here, we used primary neuronal/glial cultures prepared from rat cerebella to investigate the contribution...
Article
Phagoptosis, also called primary phagocytosis, is a recently recognised form of cell death caused by phagocytosis of viable cells, resulting in their destruction. It is provoked by exposure of 'eat-me' signals and/or loss of 'don't-eat-me' signals by viable cells, causing their phagocytosis by phagocytes. Phagoptosis mediates turnover of erythrocyt...
Article
Full-text available
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 resul...
Article
Full-text available
Milk-fat globule EGF factor-8 (MFG-E8, SED1, lactadherin) is known to mediate the phagocytic removal of apoptotic cells by bridging phosphatidylserine (PS)-exposing cells and the vitronectin receptor (VR) on phagocytes. However, we show here that MFG-E8 can mediate phagocytosis of viable neurons during neuroinflammation induced by lipopolysaccharid...
Article
Full-text available
Alzheimer disease is characterized by neuronal loss and brain plaques of extracellular amyloid β (Aβ), but the means by which Aβ may induce neuronal loss is not entirely clear. Although high concentrations of Aβ (μM) can induce direct toxicity to neurons, we find that low concentration (nM) induce neuronal loss through a microglia-mediated mechanis...
Article
Full-text available
It is well-known that dead and dying neurons are quickly removed through phagocytosis by the brain's macrophages, the microglia. Therefore, neuronal loss during brain inflammation has always been assumed to be due to phagocytosis of neurons subsequent to their apoptotic or necrotic death. However, we report in this article that under inflammatory c...
Article
Inflammation contributes to a wide variety of brain pathologies. In this chapter methods are described for using microglia and astrocytes in culture to investigate inflammatory processes and inflammatory neurodegeneration, including the use of neuronal/glial co-cultures and transwells. Methods for detecting and characterising inflammatory activatio...
Article
Full-text available
Inflammatory neurodegeneration contributes to a wide variety of brain pathologies. A number of mechanisms by which inflammatory-activated microglia and astrocytes kill neurons have been identified in culture. These include: (1) acute activation of the phagocyte NADPH oxidase (PHOX) found in microglia, (2) expression of the inducible nitric oxide sy...
Article
Full-text available
Gram-positive bacterial infections of the central nervous system, such as meningitis, induce an extensive inflammatory response, which in turn may damage neurons. LTA (lipoteichoic acid) is a component of the Gram-positive bacterial cell wall that induces glial inflammatory activation in vitro and in vivo. It does so by binding to Toll-like recepto...
Article
Hypoxia/ischaemia is known to trigger neuronal death, but the role of neuronal nitric oxide synthase (nNOS) in this process is controversial. Nitric oxide (NO) inhibits cytochrome oxidase in competition with oxygen. We tested whether NO derived from nNOS synergises with hypoxia to induce neuronal death by inhibiting mitochondrial cytochrome oxidase...