Diet-induced weight loss in obese/diabetic mice normalizes glucose metabolism and promotes functional recovery after stroke.

Background: Post-stroke functional recovery is severely impaired by type 2 diabetes (T2D). This is an important clinical problem since T2D is one of the most common diseases. Because weight loss-based strategies have been shown to decrease stroke risk in people with T2D, we aimed to investigate whether diet-induced weight loss can also improve post-stroke functional recovery and identify some of the underlying mechanisms.

Neurofilament Light Chain (NfL) in Blood-A Biomarker Predicting Unfavourable Outcome in the Acute Phase and Improvement in the Late Phase after Stroke.

Increased sensitivity of methods assessing the levels of neurofilament light chain (NfL), a neuron-specific intermediate filament protein, in human plasma or serum, has in recent years led to a number of studies addressing the utility of monitoring NfL in the blood of stroke patients. In this review, we discuss that elevated blood NfL levels after stroke may reflect several different neurobiological processes. In the acute and post-acute phase after stroke, high blood levels of NfL are associated with poor clinical outcome, and later on, the blood levels of NfL positively correlate with secondary neurodegeneration as assessed by MRI.

Nestin affects fusion pore dynamics in mouse astrocytes.

Aim: Astrocytes play a homeostatic role in the central nervous system and influence numerous aspects of neurophysiology via intracellular trafficking of vesicles. Intermediate filaments (IFs), also known as nanofilaments, regulate a number of cellular processes including organelle trafficking and adult hippocampal neurogenesis. We have recently demonstrated that the IF protein nestin, a marker of neural stem cells and immature and reactive astrocytes, is also expressed in some astrocytes in the unchallenged hippocampus and regulates neurogenesis through Notch signalling from astrocytes to neural stem cells, possibly via altered trafficking of vesicles containing the Notch ligand Jagged-1.

Nestin Null Mice Show Improved Reversal Place Learning.

The intermediate filament protein nestin is expressed by neural stem cells, but also by some astrocytes in the neurogenic niche of the hippocampus in the adult rodent brain. We recently reported that nestin-deficient (Nes) mice showed increased adult hippocampal neurogenesis, reduced Notch signaling from Nes astrocytes to the neural stem cells, and impaired long-term memory. Here we assessed learning and memory of Nes mice in a home cage set up using the IntelliCage system, in which the mice learn in which cage corner a nose poke earns access to drinking water.

Vimentin Phosphorylation Is Required for Normal Cell Division of Immature Astrocytes.

Vimentin (VIM) is an intermediate filament (nanofilament) protein expressed in multiple cell types, including astrocytes. Mice with mutations of serine sites phosphorylated during mitosis (VIM) show cytokinetic failure in fibroblasts and lens epithelial cells, chromosomal instability, facilitated cell senescence, and increased neuronal differentiation of neural progenitor cells. Here we report that in vitro immature VIM astrocytes exhibit cytokinetic failure and contain vimentin accumulations that co-localize with mitochondria.

The role of GFAP and vimentin in learning and memory.

Intermediate filaments (also termed nanofilaments) are involved in many cellular functions and play important roles in cellular responses to stress. The upregulation of glial fibrillary acidic protein (GFAP) and vimentin (Vim), intermediate filament proteins of astrocytes, is the hallmark of astrocyte activation and reactive gliosis in response to injury, ischemia or neurodegeneration. Reactive gliosis is essential for the protective role of astrocytes at acute stages of neurotrauma or ischemic stroke.

Vimentin is required for normal accumulation of body fat.

Intermediate filaments (nanofilaments) have many functions, especially in response to cellular stress. Mice lacking vimentin (Vim-/-) display phenotypes reflecting reduced levels of cell activation and ability to counteract stress, for example, decreased reactivity of astrocytes after neurotrauma, decreased migration of astrocytes and fibroblasts, attenuated inflammation and fibrosis in lung injury, delayed wound healing, impaired vascular adaptation to nephrectomy, impaired transendothelial migration of lymphocytes and attenuated atherosclerosis. To address the role of vimentin in fat accumulation, we assessed the body weight and fat by dual-energy X-ray absorptiometry (DEXA) in Vim-/- and matched wildtype (WT) mice.

Nestin Regulates Neurogenesis in Mice Through Notch Signaling From Astrocytes to Neural Stem Cells.

The intermediate filament (nanofilament) protein nestin is a marker of neural stem cells, but its role in neurogenesis, including adult neurogenesis, remains unclear. Here, we investigated the role of nestin in neurogenesis in adult nestin-deficient (Nes-/-) mice. We found that the proliferation of Nes-/- neural stem cells was not altered, but neurogenesis in the hippocampal dentate gyrus of Nes-/- mice was increased.

Vimentin deficiency in macrophages induces increased oxidative stress and vascular inflammation but attenuates atherosclerosis in mice.

The aim was to clarify the role of vimentin, an intermediate filament protein abundantly expressed in activated macrophages and foam cells, in macrophages during atherogenesis. Global gene expression, lipid uptake, ROS, and inflammation were analyzed in bone-marrow derived macrophages from vimentin-deficient (Vim) and wild-type (Vim) mice. Atherosclerosis was induced in Ldlr mice transplanted with Vim and Vim bone marrow, and in Vim and Vim mice injected with a PCSK9 gain-of-function virus.

Astrocyte activation and reactive gliosis-A new target in stroke?

Stroke is an acute insult to the central nervous system (CNS) that triggers a sequence of responses in the acute, subacute as well as later stages, with prominent involvement of astrocytes. Astrocyte activation and reactive gliosis in the acute stage of stroke limit the tissue damage and contribute to the restoration of homeostasis. Astrocytes also control many aspects of neural plasticity that is the basis for functional recovery.

Attenuation of reactive gliosis in stroke-injured mouse brain does not affect neurogenesis from grafted human iPSC-derived neural progenitors.

Induced pluripotent stem cells (iPSCs) or their progeny, derived from human somatic cells, can give rise to functional improvements after intracerebral transplantation in animal models of stroke. Previous studies have indicated that reactive gliosis, which is associated with stroke, inhibits neurogenesis from both endogenous and grafted neural stem/progenitor cells (NSPCs) of rodent origin. Here we have assessed whether reactive astrocytes affect the fate of human iPSC-derived NSPCs transplanted into stroke-injured brain.

Increased Neuronal Differentiation of Neural Progenitor Cells Derived from Phosphovimentin-Deficient Mice.

Vimentin is an intermediate filament (also known as nanofilament) protein expressed in several cell types of the central nervous system, including astrocytes and neural stem/progenitor cells. Mutation of the vimentin serine sites that are phosphorylated during mitosis (VIM ) leads to cytokinetic failures in fibroblasts and lens epithelial cells, resulting in chromosomal instability and increased expression of cell senescence markers. In this study, we investigated morphology, proliferative capacity, and motility of VIM astrocytes, and their effect on the differentiation of neural stem/progenitor cells.

Injury Leads to the Appearance of Cells with Characteristics of Both Microglia and Astrocytes in Mouse and Human Brain.

Microglia and astrocytes have been considered until now as cells with very distinct identities. Here, we assessed the heterogeneity within microglia/monocyte cell population in mouse hippocampus and determined their response to injury, by using single-cell gene expression profiling of cells isolated from uninjured and deafferented hippocampus. We found that in individual cells, microglial markers Cx3cr1, Aif1, Itgam, and Cd68 were co-expressed.

Neural Progenitor Cells in Cerebral Cortex of Epilepsy Patients do not Originate from Astrocytes Expressing GLAST.

Adult neurogenesis in human brain is known to occur in the hippocampus, the subventricular zone, and the striatum. Neural progenitor cells (NPCs) were reported in the cortex of epilepsy patients; however, their identity is not known. Since astrocytes were proposed as the source of neural progenitors in both healthy and diseased brain, we tested the hypothesis that NPCs in the epileptic cortex originate from reactive, alternatively, de-differentiated astrocytes that express glutamate aspartate transporter (GLAST).

Heterogeneity of Notch signaling in astrocytes and the effects of GFAP and vimentin deficiency.

Astrocytes have multiple roles in the CNS including control of adult neurogenesis. We recently showed that astrocyte inhibition of neurogenesis through Notch signaling depends on the intermediate filament proteins glial fibrillary acidic protein (GFAP) and vimentin. Here, we used real-time quantitative PCR to analyze gene expression in individual mouse astrocytes in primary cultures and in GFAP(POS) or Aldh1L1(POS) astrocytes freshly isolated from uninjured, contralesional and lesioned hippocampus 4 days after entorhinal cortex lesion.

Classification of subpopulations of cells within human primary brain tumors by single cell gene expression profiling.

Brain tumors are heterogeneous with respect to genetic and histological properties of cells within the tumor tissue. To study subpopulations of cells, we developed a protocol for obtaining viable single cells from freshly isolated human brain tissue for single cell gene expression profiling. We evaluated this technique for characterization of cell populations within brain tumor and tumor penumbra.

Beneficial effects of gfap/vimentin reactive astrocytes for axonal remodeling and motor behavioral recovery in mice after stroke.

The functional role of reactive astrocytes after stroke is controversial. To elucidate whether reactive astrocytes contribute to neurological recovery, we compared behavioral outcome, axonal remodeling of the corticospinal tract (CST), and the spatio-temporal change of chondroitin sulfate proteoglycan (CSPG) expression between wild-type (WT) and glial fibrillary acidic protein/vimentin double knockout (GFAP(-/-) Vim(-/-) ) mice subjected to Rose Bengal induced cerebral cortical photothrombotic stroke in the right forelimb motor area. A foot-fault test and a single pellet reaching test were performed prior to and on day 3 after stroke, and weekly thereafter to monitor functional deficit and recovery.

The dual role of astrocyte activation and reactive gliosis.

Astrocyte activation and reactive gliosis accompany most of the pathologies in the brain, spinal cord, and retina. Reactive gliosis has been described as constitutive, graded, multi-stage, and evolutionary conserved defensive astroglial reaction [Verkhratsky and Butt (2013) In: Glial Physiology and Pathophysiology]. A well- known feature of astrocyte activation and reactive gliosis are the increased production of intermediate filament proteins (also known as nanofilament proteins) and remodeling of the intermediate filament system of astrocytes.

Axonal regeneration after sciatic nerve lesion is delayed but complete in GFAP- and vimentin-deficient mice.

Peripheral axotomy of motoneurons triggers Wallerian degeneration of injured axons distal to the lesion, followed by axon regeneration. Centrally, axotomy induces loss of synapses (synaptic stripping) from the surface of lesioned motoneurons in the spinal cord. At the lesion site, reactive Schwann cells provide trophic support and guidance for outgrowing axons.

Plasticity response in the contralesional hemisphere after subtle neurotrauma: gene expression profiling after partial deafferentation of the hippocampus.

Neurotrauma or focal brain ischemia are known to trigger molecular and structural responses in the uninjured hemisphere. These responses may have implications for tissue repair processes as well as for the recovery of function. To determine whether the plasticity response in the uninjured hemisphere occurs even after a subtle trauma, we subjected mice to a partial unilateral deafferentation of the hippocampus induced by stereotactically performed entorhinal cortex lesion (ECL).

Versatile and simple approach to determine astrocyte territories in mouse neocortex and hippocampus.

Background: Besides their neuronal support functions, astrocytes are active partners in neuronal information processing. The typical territorial structure of astrocytes (the volume of neuropil occupied by a single astrocyte) is pivotal for many aspects of glia-neuron interactions.

Methods: Individual astrocyte territorial volumes are measured by Golgi impregnation, and astrocyte densities are determined by S100β immunolabeling.

Astrocytoma grade IV (glioblastoma multiforme) displays 3 subtypes with unique expression profiles of intermediate filament proteins.

Astrocytoma grade IV (glioblastoma multiforme) is the most common and most malignant tumor of the central nervous system and is currently noncurable. Here, we have examined a population-based cohort of 47 patients with grade IV astrocytoma, who underwent tumor surgery at Sahlgrenska University Hospital in Sweden and who survived after surgery for less than 200 days (short survivors, 28 patients) and more than 500 days (long survivors, 19 patients). For each tumor, we ascertained information on patient age, sex, tumor location, oncological treatment, and survival after surgery.

Synemin is expressed in reactive astrocytes and Rosenthal fibers in Alexander disease.

Alexander disease (AxD) is a neurodegenerative disorder with prominent white matter degeneration and the presence of Rosenthal fibers containing aggregates of glial fibrillary acidic protein (GFAP), and small stress proteins HSP27 and αB-crystallin, and widespread reactive gliosis. AxD is caused by mutations in GFAP, the main astrocyte intermediate filament protein. We previously showed that intermediate filament protein synemin is upregulated in reactive astrocytes after neurotrauma.

Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice.

The accumulation of aggregated amyloid-β (Aβ) in amyloid plaques is a neuropathological hallmark of Alzheimer's disease (AD). Reactive astrocytes are intimately associated with amyloid plaques; however, their role in AD pathogenesis is unclear. We deleted the genes encoding two intermediate filament proteins required for astrocyte activation-glial fibrillary acid protein (Gfap) and vimentin (Vim)-in transgenic mice expressing mutant human amyloid precursor protein and presenilin-1 (APP/PS1).