Our laboratory has been interested in vaccination strategies for non-infectious diseases using the mucosal immune system, an approach which is less invasive and more physiological than parenteral administration and which is clinically applicable. In addition, we have begun a series of studies to investigate immune mechanisms of Alzheimer's disease both in animal models and in humans. Immunizing transgenic APP mice which develop beta-amyloid (Abeta) deposition resembling plaques in Alzheimer's disease (AD) results in a decrease of amyloid burden. In a clinical trial using this approach, some patients developed a neurological complication consistent with meningoencephalitis. A case report in humans showed the presence of microglia immunoreactive for Abeta in the regions lacking Abeta deposits and investigators have reported a local reduction of senile plaques in a neocortical region affected by incomplete ischemia in a case of AD with stroke. In studies in which we investigated the ability to induce experimental allergic encephalomyelitis (EAE) in PDAPP mice we unexpectedly discovered that animals with EAE had clearance of amyloid from the brain. Furthermore, this was independent of antibody as we observed it in B-cell deficient animals and appeared related to the induction of activated microglia that led to the amyloid clearance. This led to a series of experiments in which we were able to demonstrate clearance of amyloid by nasal vaccination with glatiramer acetate (a drug approved by the FDA for the treatment of relapsing forms of multiple sclerosis) combined with a proteosome based adjuvant that has been shown to be safe in humans as part of a flu vaccine. Thus, we have discovered in animals a novel immune mechanism to clear amyloid in an antibody independent fashion using two drugs shown to be safe in humans. In the present grant proposal we will investigate the mechanism by which this occurs and the ability to use this treatment in a preventative paradigm.
The specific aims of the proposal are: 1. What is the role of microglia in clearance of beta-amyloid in vivo. In this aim, we will investigate mechanisms by which our vaccination strategy activates endogenous microglia that in turn lead to efficient amyloid clearance. We will employ both in vitro and in vivo systems to isolate cell population. 2. What is the role of T-cells in beta-amyloid's clearance in APP Tg mouse model? In this aim, we will investigate the role of different T-cells subsets in activation of microglia towards amyloid clearance. 3. Immune approaches for long term mucosal immunotherapy to reduce Abeta deposition. In this aim, we will investigate long term mucosal strategy to prevent and treat APP Tg mice using unique mucosal adjuvant combination given nasally and their ability to enhance amyloid clearance.
|Butovsky, Oleg; Jedrychowski, Mark P; Moore, Craig S et al. (2014) Identification of a unique TGF-?-dependent molecular and functional signature in microglia. Nat Neurosci 17:131-43|
|Lifshitz, Veronica; Weiss, Ronen; Benromano, Tali et al. (2012) Immunotherapy of cerebrovascular amyloidosis in a transgenic mouse model. Neurobiol Aging 33:432.e1-432.e13|
|Butovsky, Oleg; Siddiqui, Shafiuddin; Gabriely, Galina et al. (2012) Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J Clin Invest 122:3063-87|
|Healy, B C; Liguori, M; Tran, D et al. (2010) HLA B*44: protective effects in MS susceptibility and MRI outcome measures. Neurology 75:634-40|
|Meier, D S; Balashov, K E; Healy, B et al. (2010) Seasonal prevalence of MS disease activity. Neurology 75:799-806|
|Frenkel, Dan; Puckett, Lindsay; Petrovic, Sanja et al. (2008) A nasal proteosome adjuvant activates microglia and prevents amyloid deposition. Ann Neurol 63:591-601|