Combination of Aβ Suppression and Innate Immune Activation in the Brain Significantly Attenuates Amyloid Plaque Deposition

Christophe Verbeeck, Anna Carrano, Paramita Chakrabarty, Joanna L. Jankowsky, Pritam Das

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Anti-Aβ clinical trials are currently under way to determine whether preventing amyloid deposition will be beneficial in arresting progression of Alzheimer disease. Both clinical and preclinical studies suggest that antiamyloid strategies are only effective if started at early stages of the disease process in a primary prevention strategy. Because this approach will be difficult to deploy, strategies for secondary prevention aimed at later stages of disease are also needed. In this study, we asked whether combining innate immune activation in the brain with concurrent Aβ suppression could enhance plaque clearance and could improve pathologic outcomes in mice with moderate amyloid pathologic disorder. Starting at 5 months of age, tet-off amyloid precursor protein transgenic mice were treated with doxycycline (dox) to suppress further amyloid precursor protein/Aβ production, and at the same time mice were intracranially injected with adeno-associated virus 1 expressing murine IL-6 (AAV1-mIL-6). Three months later, mice treated with the combination of Aβ suppression and AAV1-mIL-6 showed significantly less plaque pathologic disorder than dox or AAV1-mIL-6 only groups. The combination of AAV1-mIL-6 + dox treatment lowered total plaque burden by >60% versus untreated controls. Treatment with either dox or AAV1-mIL-6 alone was less effective than the combination. Our results suggest a synergistic mechanism by which the up-regulation of mIL-6 was able to improve plaque clearance in the setting of Aβ suppression.

Original languageEnglish (US)
Pages (from-to)2886-2894
Number of pages9
JournalAmerican Journal of Pathology
Volume187
Issue number12
DOIs
StatePublished - Dec 1 2017

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Dependovirus
Amyloid Plaques
Doxycycline
Interleukin-6
Brain
Serum Amyloid A Protein
Amyloid beta-Protein Precursor
Amyloid
Primary Prevention
Secondary Prevention
Transgenic Mice
Alzheimer Disease
Up-Regulation
Clinical Trials
Therapeutics

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Combination of Aβ Suppression and Innate Immune Activation in the Brain Significantly Attenuates Amyloid Plaque Deposition. / Verbeeck, Christophe; Carrano, Anna; Chakrabarty, Paramita; Jankowsky, Joanna L.; Das, Pritam.

In: American Journal of Pathology, Vol. 187, No. 12, 01.12.2017, p. 2886-2894.

Research output: Contribution to journalArticle

Verbeeck, Christophe ; Carrano, Anna ; Chakrabarty, Paramita ; Jankowsky, Joanna L. ; Das, Pritam. / Combination of Aβ Suppression and Innate Immune Activation in the Brain Significantly Attenuates Amyloid Plaque Deposition. In: American Journal of Pathology. 2017 ; Vol. 187, No. 12. pp. 2886-2894.
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