Glatiramer acetate fights against Alzheimer’s disease by inducing dendritic-like microglia expressing insulin-like growth factor 1

Abstract

Alzheimer's disease (AD) is characterized by plaque formation, neuronal loss, and cognitive decline. The functions of the local and systemic immune response in this disease are still controversial. Using AD double-transgenic (APP͞PS1) mice, we show that a T cell-based vaccination with glatiramer acetate, given according to a specific regimen, resulted in decreased plaque formation and induction of neurogenesis. It also reduced cognitive decline, assessed by performance in a Morris water maze. The vaccination apparently exerted its effect by causing a phenotype switch in brain microglia to dendritic-like (CD11c) cells producing insulin-like growth factor 1. In vitro findings showed that microglia activated by aggregated ␤-amyloid, and characterized as CD11b ؉ ͞CD11c ؊ ͞ MHC class II ؊ ͞TNF-␣ ؉ cells, impeded neurogenesis from adult neural stem͞progenitor cells, whereas CD11b ؉ ͞CD11c ؉ ͞MHC class II ؉ ͞TNF-␣ ؊ microglia, a phenotype induced by IL-4, counteracted the adverse ␤-amyloid-induced effect. These results suggest that dendritic-like microglia, by facilitating the necessary adjustment, might contribute significantly to the brain's resistance to AD and argue against the use of antiinflammatory drugs.␤-amyloid ͉ CD11c ͉ T cell vaccination ͉ immunomodulation ͉ neurodegeneration

Continuous vaccinations of 4Aβ1-15 induces specific fluctuation of inflammatory factors accompany with pathologic alterations alleviation in APP/PS1 mice

“…15 Under normal conditions, microglia scavenge the CNS for plaques, damaged neurons and infectious agents constantly, but when they are activated too much, large numbers of inflammatory factors associated with serious pathologies are released, aggravating nerve injury and causing harm to normal organisms. 11,16 In other words, microglial cells activate the precursors of inflammation factors. With Ab plaques continuously cleared, the cognitive abilities were improved, and the inflammatory responses and microglia declined.…”

“…These results made us question how the microglial cell activation changes during the continuous vaccinations. 11 Ab plaques and activated microglia were double-labeled by immunohistochemical method. The confocal micrographs showed microglia cells in the APP/PS1 transgenic mice were activated and tended to surround Ab plaques.…”

“…The place navigation included the acquisition phase from the 1st to the 4th days and a reversal phase on the 6th and 7th days, whereas the spatial probe occurred on the 5th day. 11 On the first day, the mice were required to locate a visible platform located 1 cm above the water surface to test whether immunity influenced motility or vision in APP/PS1 mice. On the next 3 days, the mice were required to find a hidden platform located 1 cm below the water surface in each trial.…”

Immune Modulation in Glaucoma – Can Manipulation of Microglial Activation Help?

“…T-cell-based vaccination with GA resulted in decreased plaque formation, reduction of excitotoxicity and induction of neurogenesis in Alzheimer's disease (AD) mouse model (Butovsky et al, 2006a;2006b). This GA vaccination caused a phenotype switch in brain microglia to dendritic-like morphology, with the ability to produce insulin-like growth factor 1 (IGF-1) that counteracted the adverse Aβ-induced effects (Butovsky et al, 2006a;2006b;2007). Vaccination with GA significantly reduces loss of RGCs in rodent models of optic nerve crush injury, intraocular glutamate toxicity, glaucoma and macular degeneration (Schori et al, 2001).…”

“…GA is a synthetic oligopeptide of four naturally occurring amino acids, its activity derives from its ability to serve as a "universal antigen' that weakly activates a wide spectrum of self-reactive T-cells (Kipnis and Schwartz, 2002). T-cell-based vaccination with GA resulted in decreased plaque formation, reduction of excitotoxicity and induction of neurogenesis in Alzheimer's disease (AD) mouse model (Butovsky et al, 2006a;2006b). This GA vaccination caused a phenotype switch in brain microglia to dendritic-like morphology, with the ability to produce insulin-like growth factor 1 (IGF-1) that counteracted the adverse Aβ-induced effects (Butovsky et al, 2006a;2006b;2007).…”