Sustained hippocampal IL-1β overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology

Solomon S. Shaftel; Stephanos Kyrkanides; John A. Olschowka; Jen Nie H. Miller; Renee E. Johnson; M. Kerry O'Banion

doi:10.1172/JCI31450

Sustained hippocampal IL-1β overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology

Solomon S. Shaftel, Stephanos Kyrkanides, John A. Olschowka, Jen Nie H. Miller, Renee E. Johnson, M. Kerry O'Banion

Oral Health Science

Research output: Contribution to journal › Article › peer-review

369 Scopus citations

Abstract

Neuroinflammation is a conspicuous feature of Alzheimer disease (AD) pathology and is thought to contribute to the ultimate neurodegeneration that ensues. IL-1β has emerged as a prime candidate underlying this response. Here we describe a transgenic mouse model of sustained IL-1β 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-1β overexpression led to a reduction in amyloid pathology. Congophilic plaque area fraction and frequency as well as insoluble amyloid beta 40 (Aβ40) and Aβ42 decreased significantly. These results demonstrate a possible adaptive role for IL-1β-driven neuroinflammation in AD and may help explain recent failures of antiinflammatory therapeutics for this disease.

Original language	English
Pages (from-to)	1595-1604
Number of pages	10
Journal	Journal of Clinical Investigation
Volume	117
Issue number	6
DOIs	https://doi.org/10.1172/JCI31450
State	Published - Jun 1 2007

ASJC Scopus subject areas

General Medicine

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title = "Sustained hippocampal IL-1β overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology",

abstract = "Neuroinflammation is a conspicuous feature of Alzheimer disease (AD) pathology and is thought to contribute to the ultimate neurodegeneration that ensues. IL-1β has emerged as a prime candidate underlying this response. Here we describe a transgenic mouse model of sustained IL-1β 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-1β overexpression led to a reduction in amyloid pathology. Congophilic plaque area fraction and frequency as well as insoluble amyloid beta 40 (Aβ40) and Aβ42 decreased significantly. These results demonstrate a possible adaptive role for IL-1β-driven neuroinflammation in AD and may help explain recent failures of antiinflammatory therapeutics for this disease.",

author = "Shaftel, {Solomon S.} and Stephanos Kyrkanides and Olschowka, {John A.} and Miller, {Jen Nie H.} and Johnson, {Renee E.} and O'Banion, {M. Kerry}",

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AU - Shaftel, Solomon S.

AU - Kyrkanides, Stephanos

AU - Olschowka, John A.

AU - Miller, Jen Nie H.

AU - Johnson, Renee E.

AU - O'Banion, M. Kerry

PY - 2007/6/1

Y1 - 2007/6/1

N2 - Neuroinflammation is a conspicuous feature of Alzheimer disease (AD) pathology and is thought to contribute to the ultimate neurodegeneration that ensues. IL-1β has emerged as a prime candidate underlying this response. Here we describe a transgenic mouse model of sustained IL-1β 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-1β overexpression led to a reduction in amyloid pathology. Congophilic plaque area fraction and frequency as well as insoluble amyloid beta 40 (Aβ40) and Aβ42 decreased significantly. These results demonstrate a possible adaptive role for IL-1β-driven neuroinflammation in AD and may help explain recent failures of antiinflammatory therapeutics for this disease.

AB - Neuroinflammation is a conspicuous feature of Alzheimer disease (AD) pathology and is thought to contribute to the ultimate neurodegeneration that ensues. IL-1β has emerged as a prime candidate underlying this response. Here we describe a transgenic mouse model of sustained IL-1β 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-1β overexpression led to a reduction in amyloid pathology. Congophilic plaque area fraction and frequency as well as insoluble amyloid beta 40 (Aβ40) and Aβ42 decreased significantly. These results demonstrate a possible adaptive role for IL-1β-driven neuroinflammation in AD and may help explain recent failures of antiinflammatory therapeutics for this disease.

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Sustained hippocampal IL-1β overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology

Abstract

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