Brain aggregates are often accompanied by astrogliosis, characterized by an altered astrocyte morphology and an induction of the protein GFAP in these cells.
Recently, astrocytes have been identified as the neural progenitors in the adult brain, even in non-neurogenic regions. This finding has important implications for neurodegenerative diseases, since astrocytes are present throughout the brain and thus also in areas with pathology or damage. A prolonged accumulation of aggregated proteins, caused by, e.g., a deficient ubiquitin proteasome system, will lead to neuronal dysfunction, and eventually neuronal loss, in specific brain areas. Therefore astrocytes may be an invaluable pool of progenitors that may be stimulated to replace degenerating neurons in these brain areas. Our group aims at understanding the role of the ubiquitin proteasome system in Alzheimer’s and Parkinson’s disease, the interaction between aggregate formation and astrocyte activation, and the potential of the astrocytes to facilitate neural repair in neurodegenerative diseases.
Acute isolation and transcriptome characterization of cortical astrocytes and microglia from young and aged mice
Astrocyte Biology and Neurodegeneration, Netherlands Institute for Neuroscience (NIN), an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands.
Astrocytes and microglia become reactive in many neurological disorders resulting in phenotypic and functional alterations. Both cell types might also display functional changes during normal aging. To identify gene signatures and changes in basal cellular functions of astrocytes and microglia in relation to aging, we isolated viable astrocytes and microglia from young adult and aged mouse cortices and determined their gene expression profile. Aged astrocytes, compared with young astrocytes, showed an increased inflammatory phenotype and increased 'zinc ion binding.' Young astrocytes showed higher expression of genes involved in 'neuronal differentiation' and hemoglobin synthesis. Astrocyte expression of genes involved in neuronal signaling remains high throughout age. Aged microglia had higher expression of genes involved in 'vesicle release,' 'zinc ion binding,' and genes within the tumor necrosis factor-ligand family and young microglia had increased transcript levels of C-C motif chemokines. These data provide a transcriptome database of cell-type enriched genes of astrocytes and microglia from adult mice and give insight into the differential gene signature of astrocytes and microglia in relation to normal aging. Orre et a. Neurobiology of Aging 2014 35:1-14.
Reactive glia show increased immunoproteasome activity in Alzheimer's disease
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.
Differential cell proliferation in the cortex of the APPswePS1dE9 Alzheimer's disease mouse model
Plaque deposition in Alzheimer's disease (AD) is known to decrease proliferation in neurogenic niches in AD mouse models, but the effects on cell proliferation and differentiation in other brain areas have not been studied in detail. We analyzed cell proliferation in the cortex of wild type (WT) and APPswePS1dE9 transgenic (AD) mice at different ages. Mice were studied shortly after the last BrdU injection (BrdU[ST]). In AD mice, the number of proliferating cells increased fourfold, coinciding with plaque appearance and its associated reactive gliosis and activation of microglia. An increase in the number of BrdU[ST]-cells expressing markers for activated microglia is underlying the enhanced proliferation. Cortical reactive astrocytes did not become proliferative since BrdU[ST]-cells were negative for different astrocyte-specific markers. The number of Olig2-positive oligodendrocyte precursor cells was unchanged. Four weeks after the last BrdU application, the number of BrdU[LT]-cells with an activated microglia signature was still enhanced in AD mice. None of the newborn cells had differentiated into oligodendrocytes, astrocytes, or neurons. On the basis of these observations, 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. The proliferation of microglia contributes to the rapid accumulation of microglia around plaques and may play a role in limitating plaque expansion. Kamphuis et al. Glia 2012 60:615-629.