Marie Orre and Willem Kamphuis publish in Brain about the proteasome activity in Alzheimer
The proteasome is the major protein degradation system within the cell, comprised of different proteolytic subunits; Amyloid-β is thought to impair its activity in Alzheimer’s disease. Neuroinflammation is a prominent hallmark of Alzheimer’s disease, which may implicate an activation of the immunoproteasome, a specific proteasome variant induced by immune signaling that holds slightly different proteolytic properties than the constitutive proteasome. Using a novel cell-permeable proteasome activity probe, we found that Amyloid-β enhances proteasome activity in glial and neuronal cultures. Additionally, using a subunit specific proteasome activity assay we showed that in the cortex of the APPswePS1dE9 plaque pathology mouse model, immunoproteasome activities were strongly increased together with increased mRNA and protein expression in reactive glia surrounding plaques. Importantly, this elevated activity was confirmed in human post mortem tissue from donors with Alzheimer’s disease. These findings are in contrast with earlier studies, which reported impairment of proteasome activity in human Alzheimer’s disease tissue and mouse models. Targeting the increased immunoproteasome activity with a specific inhibitor resulted in a decreased expression of inflammatory markers in ex-vivo microglia. This may serve as a potential novel approach to modulate sustained neuroinflammation and glial dysfunction associated with Alzheimer’s disease.
Orre et al. Brain 2013 136:1415-31.
Eloy Cuadrado publishes in Brain about an astrocyte model for Aicardi Goutières Syndrome.
This work is a collaborative effort between the Hol group at the NIN and the lab of Prof. Taco Kuijpers at the AMC.
Aicardi-Goutières syndrome (AGS) is a genetically determined infantile encephalopathy, manifesting as progressive microcephaly, psychomotor retardation, and, in approximately 25% of patients, death in early childhood. Our results support the idea of IFN-α as key factor in the pathogenesis of AGS relating to the observed leukodystrophy and microangiopathy. Due to the sustained IFN-α effect, even after IFN-α withdrawal, therapeutic targets for AGS may include downstream IFN-α signaling cascade effectors rather than IFN-α alone.
Cuadrado et al. Brain 2013 136:245-258.
Carlyn mamber publishes in PLoSONE on GFAP-delta in the mouse brain during development.
Our data suggest that all astroglia cells in the developing and adolescent mouse brain express GFAPδ, regardless of their neurogenic capabilities. GFAPδ may be an integral component of all mouse astrocytes, but it is not a specific neural stem cell marker in mice as it is in humans.
PLoS One. 2012;7(12):e52659
October 2012 - Our work on endogenous neural stem cells has been identified as a highlight of the ECNP meeting in Vienna (click picture for video : 11:40-14:45 min).
New astro-group publication in PLoS ONE on mouse GFAP-isoforms
GFAP isoforms in adult Mouse Brain with a focus on neurogenic astrocytes and reactive astrogliosis in mouse models of Alzheimer disease. We show that in mice brains, GFAPδ protein is present in SVZ, RMS, and neurogenic astrocytes of the SGZ, but also outside neurogenic niches. Furthermore, differential GFAP isoform expression is not linked with aging or reactive gliosis. Kamphuis and Mamber et al.PLoS ONE 2012; 7:e42823
Willem Kamphuis publishes in Glia on glia proliferation in Alzheimer mouse brains
Differential cell proliferation in the cortex of the APPswePS1de9 Alzheimer's disease mouse model. We conclude that amyloid plaque deposition increases proliferation of microglia around plaques but does not affect the proliferation of cortical oligodendrocyte precursor cells. No evidence was found for damage-induced proliferation of reactive astrocytes or for a redirected neurogenesis from the subventricular zone
Kamphuis et al Glia 2012 ; 60:615-629
Stem cell research of Hol group on Dutch television
On February 8th 2012, the VPRO boradcasted a program on our stem cell research in Parkinson patients (in Dutch).
Simone van den Berge publishes in Brain about adult stem cells in brain of Parkinson patients
The proliferative capacity of the subventricular zone is maintained in the parkinsonian brain. We show that the adult neural stem cell pool in the subventricular zone is not clearly affected in the human parkinsonian brain or a Parkinson's disease mouse model. This is in contrast with earlier published studies.
Simone A. van den Berge, et al. Brain 2011; 134:3249-3263
Deep brain stimulation - role of astrocytes
Deep brain stimulation (DBS) has emerged as a powerful surgical therapy for the management of treatment-resistant movement disorders, epilepsy and neuropsychiatric disorders. Although DBS may be clinically effective in many cases, its mode of action is still elusive. It is unclear which neural cell types are involved in the mechanism of DBS, and how high-frequency stimulation of these cells may lead to alleviation of the clinical symptoms. Neurons have commonly been a main focus in the many theories explaining the working mechanism of DBS. Recent data, however, demonstrates that astrocytes may be active players in the DBS mechanism of action. In this review article, we will discuss the potential role of reactive and neurogenic astrocytes (neural progenitors) in DBS.
Vedam-Mai, van Battum et al. Mol Psych 2011