This FIRCA grant focuses on the neuroimmune response and microglial/glial activation associated with immunotherapy against A2, a promising therapy for Alzheimer's disease (AD) presently under clinical trial by several research groups. This application is collaboration between the Neuropathology Core of the Johns Hopkins Medical Institutions (JHMI) Alzheimer's disease Research Center (ADRC) and the Neuroscience Laboratory at the Pontificia Universidad Catslica de Chile (PUC).
The specific aims of the ADRC Neuropathology Core include the support of animal studies relevant to AD and investigators of this Core have been engaged and are experienced in studies of immunotherapy against A2. The studies proposed in this FIRCA application entail assessments of biochemical and morphological changes in a transgenic mouse model of AD receiving passive immunization with antibodies against A2. These changes will be correlated with cognitive and behavioral parameters. The PUC Neuroscience Laboratory focuses on the study of neuroinflammation and the role of microglial and glial cells in the pathogenesis of AD. It has been widely proposed that accumulation of A2 is one of the major causes of AD. We believe that in addition to A2-related toxicity, microglial cell impairment derived from chronic inflammatory activation is responsible for both A2 accumulation and neuronal dysfunction. Based on these concepts, this FIRCA application proposes to characterize the neuroimmune response to passive immunotherapy against A2 and its effects in a transgenic model of A2 deposition. Immunotherapy greatly induces A2-uptake by microglial cells. On the other hand, scavenger receptors (SR) are involved in the binding of A2 and mediating the inflammatory response of glial cells. Furthermore, this response is modulated by pro- and anti- inflammatory cytokines, i.e. TGF2. Moreover, the expression of both pro- and anti-inflammatory cytokines and some of their signaling pathways are modified in aging and potentially could result in the impairment of glial cell regulation. Our hypothesis is that "changes on the expression of scavenger receptors and TGF2 are responsible for immunotherapy-dependent A2 clearance and cognitive improvement on a transgenic model of A2 deposition." In order to assess this hypothesis, we will use APPswe/PS1dE9 transgenic mice, a model of A2 brain deposition. The mice will be exposed to a chronic pro-inflammatory stimulus (LPS) and passive immunotherapy against A2. We will evaluate the expression of the inflammation modulator TGF2 and its signaling pathway as well as the expression and functional levels of scavenger receptors known to bind A2. Those markers will be correlated with phagocytic activity and cognitive performance. This study addresses neuroimmune mechanisms relevant to the pathogenesis of AD and also to the development of therapeutic strategies for this disease.
Alzheimer's disease is a significant health problem worldwide and its impact will increase as the population ages. It is countries on their way to development which will have most of the Alzheimer's patients in the next few decades (Ferri et al., 2005). This is the situation that Chile will soon face since the prevalence of the disease is sharply increasing, but the resources to care for these patients are and will be very scarce. Currently, there is no effective way to prevent or cure Alzheimer's Disease. Therefore, the development of treatments like Immunotherapy that could be relevant for both prevention and arresting the progression of Alzheimer's disease is critical for improving its management at the public health level. This application addresses issues directly relevant to the development of immunotherapy or a vaccine for Alzheimer's.
|Tichauer, Juan E; Flores, Betsi; Soler, Bernardita et al. (2014) Age-dependent changes on TGF?1 Smad3 pathway modify the pattern of microglial cell activation. Brain Behav Immun 37:187-96|
|Savonenko, Alena V; Melnikova, Tatiana; Hiatt, Andrew et al. (2012) Alzheimer's therapeutics: translation of preclinical science to clinical drug development. Neuropsychopharmacology 37:261-77|