Biomedical subjects

Angela M Bodles

Publications and source records attributed to Angela M Bodles.

5 recordsLinked to original sources

PubMed2005

Secreted beta-amyloid precursor protein activates microglia via JNK and p38-MAPK.

Reactive microglia are thought to play a role in the pathogenesis of Alzheimer's disease (AD) and are localized to the senile plaques that are associated with cognitive decline. The beta-amyloid precursor protein (betaAPP) is over-expressed in the dystrophic neurites near such plaques, and secreted forms of betaAPP (sAPPalpha) activate inflammatory responses in microglia. To characterize the mechanisms by which sAPPalpha activates microglia, we assayed its effects on MAP kinases, including c-Jun N-terminal kinases (JNK), extracellular signal-regulated protein kinases (ERK), and p38-MAPK. sAPPalpha was found to rapidly activate JNKs, ERKs and p38-MAPK in a dose-dependent manner. The JNK inhibitor SP600125 and the p38 inhibitor SB203580 independently reduced both nitrite accumulation and induction of inflammatory nitric oxide synthase (iNOS). By contrast, inhibition of the ERK pathway with U0126 did not appreciably affect either outcome measure. These findings suggest that sAPP activates the ERK, JNK and p38 classes of MAP kinases but that only JNK and p38-MAPK are critical for activation of microglia by sAPPalpha, a process that compromises neuronal function and survival.

Amyloid beta-Protein Precursor↗

PubMed2004

Induction of serine racemase expression and D-serine release from microglia by amyloid beta-peptide.

BACKGROUND: Roles for excitotoxicity and inflammation in Alzheimer's disease have been hypothesized. Proinflammatory stimuli, including amyloid beta-peptide (Abeta), elicit a release of glutamate from microglia. We tested the possibility that a coagonist at the NMDA class of glutamate receptors, D-serine, could respond similarly. METHODS: Cultured microglial cells were exposed to Abeta. The culture medium was assayed for levels of D-serine by HPLC and for effects on calcium and survival on primary cultures of rat hippocampal neurons. Microglial cell lysates were examined for the levels of mRNA and protein for serine racemase, the enzyme that forms D-serine from L-serine. The racemase mRNA was also assayed in Alzheimer hippocampus and age-matched controls. A microglial cell line was transfected with a luciferase reporter construct driven by the putative regulatory region of human serine racemase. RESULTS: Conditioned medium from Abeta-treated microglia contained elevated levels of D-serine. Bioassays of hippocampal neurons with the microglia-conditioned medium indicated that Abeta elevated a NMDA receptor agonist that was sensitive to an antagonist of the D-serine/glycine site (5,7-dicholorokynurenic acid; DCKA) and to enzymatic degradation of D-amino acids by D-amino acid oxidase (DAAOx). In the microglia, Abeta elevated steady-state levels of dimeric serine racemase, the apparent active form of the enzyme. Promoter-reporter and mRNA analyses suggest that serine racemase is transcriptionally induced by Abeta. Finally, the levels of serine racemase mRNA were elevated in Alzheimer's disease hippocampus, relative to age-matched controls. CONCLUSIONS: These data suggest that Abeta could contribute to neurodegeneration through stimulating microglia to release cooperative excitatory amino acids, including D-serine.

Journal Article↗

PubMed2004

Inhibition of fibril formation and toxicity of a fragment of alpha-synuclein by an N-methylated peptide analogue.

Alpha-synuclein has been linked to amyloidogenesis in Parkinson's disease and other neurodegenerative disorders. We have previously shown that a peptide comprising residues 68-78 of alpha-synuclein is the minimum fragment that, like alpha-synuclein itself, forms amyloid fibrils and exhibits toxicity towards cells in culture. Hughes et al. [J. Biol. Chem. 275 (2000) 25109] showed that an N-methylated derivative of Abeta(25-35) inhibited the formation of fibrils by Abeta(25-35) and reduced its toxicity. We have now extended this concept to an amyloidogenic alpha-synuclein-based peptide. Alpha-synuclein(68-78), N-methylated at G1y73, was compared to non-methylated peptide. Whereas alpha-synuclein(68-78) formed fibrils and was toxic to cells, the N-methylated analogue had neither of these properties. Moreover, an equimolar mixture of the non-methylated and methylated peptides formed very few fibrils and toxicity was markedly reduced.

Amyloid beta-Peptides↗

PubMed2004

Cytokines and the aging brain - what we don't know might help us.

Cognitive aspects of aging represent a grave challenge for our societal circumstances as members of the baby-boom generation spiral toward a collective 'senior moment'. In addition, age-related changes in the CNS can contribute to motor deficits and other somatic aberrations. Inflammation and its regulation by cytokines have been connected to many aspects of aging, and mechanisms addressed here provide a rationale for this. Nevertheless, a role for cytokines in normal aging of the human brain has not been confirmed, and it seems to be possible to ameliorate both cognitive decline and cytokine elevation via lifestyle choices. So ignorance of the brain should not prohibit development of successful strategies for delaying or avoiding neurological deficits.

Adaptation, Physiological↗

PubMed2004

Alpha-synuclein aggregation.

Alpha-synuclein is a major component of Lewy bodies in Parkinson's disease and is found associated with several other forms of dementia. As with other neurodegenerative diseases, the ability of alpha-synuclein to aggregate and form fibrillar deposits seems central to its pathology. We have defined a sequence within the NAC region of alpha-synuclein that is necessary for aggregation. Exploitation of chemically modified analogues of this peptide may produce inhibitors of aggregation.

Amino Acid Sequence↗