Sustained hippocampal IL-1 beta overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology.
Neuroinflammation is a conspicuous feature of Alzheimer disease (AD) pathology and is thought to contribute to the ultimate neurodegeneration that ensues. IL-1 beta has emerged as a prime candidate underlying this response. Here we describe a transgenic mouse model of sustained IL-1 beta overexpression that was capable of driving robust neuroinflammation lasting months after transgene activation. This response was characterized by astrocytic and microglial activation in addition to induction of proinflammatory cytokines. Surprisingly, when triggered in the hippocampus of the APPswe/PS1dE9 mouse model of AD, 4 weeks of IL-1 beta overexpression led to a reduction in amyloid pathology. Congophilic plaque area fraction and frequency as well as insoluble amyloid beta 40 (A beta 40) and A beta 42 decreased significantly. These results demonstrate a possible adaptive role for IL-1 beta-driven neuroinflammation in AD and may help explain recent failures of antiinflammatory therapeutics for this disease.
Shaftel
Solomon S
SS
Department of Neurobiology and Anatomy, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
Kyrkanides
Stephanos
S
Olschowka
John A
JA
Miller
Jen-nie H
JN
Johnson
Renee E
RE
O'Banion
M Kerry
MK
D000544:Alzheimer Disease / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D006624:Hippocampus / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D053583:Interleukin-1beta / Q000235:genetics* / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000276:immunology; D058225:Plaque, Amyloid / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000627:therapeutic use
D016564:Amyloid beta-Protein Precursor; D017931:DNA Primers; D053583:Interleukin-1beta; D053764:Presenilin-1; D011994:Recombinant Proteins