Chronic glial activation, neurodegeneration, and APP immunoreactive deposits following acute administration of double-stranded RNA.
Several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, are associated with immunocompetent microglia, leading to the suggestion that chronic glial-mediated inflammation contributes to the neurodegeneration seen in these diseases. Little direct evidence supports this hypothesis, and no suitable rodent models exist that do not involve the use of blunt trauma or ischaemia, events that are infrequently encountered in the human disease state. In the present study, we report that administration of double-stranded RNA, a classical inducer of interferon-gamma (IFN-gamma), causes rapid and persistent activation of microglia and astrocytes, as well as induction of interleukin-1beta (IL-beta) and nitric oxide synthase. In close temporal succession to glial activation, there is neurodegeneration, with neuron loss involving apoptosis in selected brain regions including the septal nucleus, hippocampus, cortex and thalamus, along with hippocampal atrophy. This neuronal loss is accompanied by punctate deposits of material that are immunoreactive for amyloid precursor protein, beta-amyloid peptide (Abeta), and apolipoprotein E. The findings may have clinical relevance, since the administration of the nonsteroidal antiinflammatory agent (NSAID) ibuprofen markedly reduces the neurodegeneration observed in the absence of significant glial inhibition. These findings may be relevant to the pathogenesis of Alzheimer's disease in particular, and to other neurodegenerative diseases involving inflammation.
Melton
Lisa M
LM
MRC-Newcastle University Centre Development for Clinical Brain Ageing, Newcastle General Hospital, Newcastle upon Tyne, United Kingdom.
Keith
Alexander B
AB
Davis
Sue
S
Oakley
Arthur E
AE
Edwardson
James A
JA
Morris
Christopher M
CM
D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001057:Apolipoproteins E / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002908:Chronic Disease; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004660:Encephalitis / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology; D005911:Gliosis / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology; D009457:Neuroglia / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics / Q000276:immunology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001057:Apolipoproteins E; D007375:Interleukin-1; D012330:RNA, Double-Stranded; D019001:Nitric Oxide Synthase