Evidence That Nucleocytoplasmic Olig2 Translocation Mediates Brain-Injury -Induced Differentiation of Glial Precursors to Astrocytes

The mechanisms by which neural and glial progenitor cells in the adult brain respond to tissue injury are unknown. We studied the responses of these cells to stab wound injury in rats and in two transgenic mouse models in which Y/GFP is driven either by Sox2 (a neural stem cell marker) or by T alpha-1 (which marks newly born neurons). The response of neural progenitors was low in all nonneurogenic regions, and no neurogenesis occurred at the injury site. Glial progenitors expressing Olig2 and NG2 showed the greatest response. The appearance of these progenitors preceded the appearance of reactive astrocytes. Surprisingly, we found evidence of the translocation of the transcription factor Olig2 into cytoplasm in the first week after injury, a mechanism that is known to mediate the differentiation of astrocytes during brain development. Translocation of Olig2, down-regulation of NG2, and increased glial fibrillary acidic protein expression were recapitulated in vitro after exposure of glial progenitors to serum components or bone morphogentic protein by up- regulation of Notch-1. The glial differentiation and Olig2 translocation could be blocked by inhibition of Notch-1 with the gamma-secretase inhibitor DAPT. Together, these data indicate that the prompt maturation of numerous Olig2(+) glial progenitors to astrocytes underlies the repair process after a traumatic injury. In contrast, neural stem cells and neuronal progenitor cells appear to play only a minor role in the injured adult CNS. (c) 2007 Wiley-Liss, Inc

Telomere Protection Mechanisms Change during Neurogenesis and Neuronal Maturation: Newly Generated Neurons Are Hypersensitive to Telomere and DNA Damage

Telomeres are DNA-protein complexes at the ends of eukaryotic chromosomes that play an important role in maintaining the integrity of the genome. In proliferative stem cells and cancer cells, telomere length is maintained by telomerase, and telomere structure and functions are regulated by telomere-associated proteins. We find that telomerase levels are high in embryonic cortical neural progenitor cells (NPCs) and low in newly generated neurons ( NGNs) and mature neurons (MNs). In contrast, telomere repeat-binding factor 2 (TRF2) expression is undetectable in early brain development in vivo and in cultured NPCs and is expressed at progressively higher levels as NPCs cease proliferation and differentiate into postmitotic neurons. The telomere-disrupting agent telomestatin induces a DNA damage response and apoptosis in NGNs (which have low levels of TRF2 and telomerase), whereas NPCs (which have high levels of telomerase) and MNs (which have high levels of TRF 2) are resistant to telomere damage. Overexpression of TRF2 in NGNs protects them against death induced by telomestatin and other DNA-damaging agents. Knockdown of TRF2 expression in MNs and knock-out of telomerase reverse transcriptase in NPCs increased their sensitivity to telomere-and DNA- damaging agents but did not affect the vulnerability of NGNs . These findings suggest that TRF2 and telomerase function as distinct telomere protection mechanisms during the processes of neurogenesis and neuronal maturation and that hypersensitivity of NGNs to telomere damage results from relative deficiencies of both telomerase and TRF2

Soluble Neuroprotective Antioxidant Uric Acid Analogs Ameliorate Ischemic Brain Injury in Mice

Uric acid is a major antioxidant in the blood of humans that can protect cultured neurons against oxidative and metabolic insults. However, uric acid has a very low solubility which compromises its potential clinical use for neurodegenerative disorders. Here we describe the synthesis, characterization and preclinical development of neuroprotective methyl- and sulfur-containing analogs of uric acid with increased solubility. In vitro and cell culture screening identified 1,7-dimethyluric acid (mUA2) and 6,8-dithiouric acid (sUA2) as two analogs with high antioxidant and neuroprotective activities. When administered intravenously in mice, uric acid analogs mUA2 and sUA2 lessened damage to the brain and improved functional outcome in an ischemia-reperfusion mouse model of stroke. Analogs sUA2 and mUA2 were also effective in reducing damage to the cerebral cortex when administered up to 4 h after stroke onset in a permanent middle cerebral artery occlusion mouse model. These findings suggest a therapeutic potential for soluble analogs of uric acid in the treatment of stroke and related neurodegenerative conditions

Toll-Like Receptor-4 Mediates Neuronal Apoptosis Induced by Amyloid Beta- Peptide and the Membrane Lipid Peroxidation Product 4-Hydroxynonenal

The innate immune system senses the invasion of pathogenic microorganisms and tissue injury through Toll-like receptors (TLR), a mechanism thought to be limited to immune cells. We recently found that neurons express several TLRs, and that the levels of TLR2 and TLR4 are increased in neurons in response to energy deprivation. Here we report that TLR4 expression increases in neurons when exposed to amyloid beta -peptide (A beta 1-42) or the lipid pet-oxidation product 4- hydroxynonenal (HNE). Neuronal apoptosis triggered by A beta and HNE was mediated by jun N- terminal kinase (JNK); neurons from TLR4 mutant mice exhibited reduced JNK and caspase-3 activation and were protected against apoptosis induced by A beta and HNE. Levels of TLR4 were decreased in inferior parietal cortex tissue specimens from end-stage AD patients compared to aged-matched Control Subjects, possibly as the result of loss of neurons expressing TLR 4. Our findings Suggest that TLR4 signaling increases the vulnerability of neurons to A beta and oxidative stress in AD, and identify TLR4 as a potential therapeutic target for AD

Diffuse Capillary Telangiectasia of the Brain Manifested as a Slowly Progressive Course

Brain capillary telangiectasia (BCT) are usually small, solitary, benign in clinical manifestation, or found incidentally at autopsy. However, diffuse BCT are rarely reported. A 39-year-old woman had the first generalized seizure 10 years previously. Thereafter, she had sustained progressive spastic paraparesis and blurred vision. Computed tomography ( CT) showed diffuse brain atrophy with numerous calcified spots. Contrast T 1-weighted magnetic resonance images showed diffuse faintly enhancing lesions with stippled appearance in the whole brain. Cerebral angiography revealed multiple small nets of dilated capillaries and Xenon CT showed diffuse low cerebral blood flow in the resting and good cerebral reserve capacity in the acetazolamide challenge test. Therefore, diffuse BCT was diagnosed clinically. Although BCT are not rare, diffuse BCT with slowly progressive neurological symptoms had never been reported before. It causes global cerebral ischemia that lead to brain atrophy and a degenerative course. Copyright 2003 S. Karger AG, Base