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

5 years ago

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

Anti-Aβ clinical trials are currently underway to determine whether preventing amyloid deposition will be beneficial in arresting progression of Alzheimer disease. Both clinical and pre-clinical studies suggest that anti-amyloid strategies are only effective if started at very 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 improve pathological outcomes in mice with moderate amyloid pathology. Starting at 5 months of age, tet-off APP transgenic mice were treated with doxycycline to suppress further APP/Aβ production and at the same time, mice were intracranially injected with adeno associated virus 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 pathology than dox or AAV1-mIL-6 only groups. The combination of AAV1-mIL-6 + dox treatment lowered total plaque burden by >60% compared to 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.

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DOI: S0002944017304935