There is compelling evidence that accumulation of A? aggregates plays a pivotal role in Alzheimer's disease (AD);thus, multiple strategies targeting A? are being developed as therapeutics. Numerous preclinical studies demonstrate the therapeutic potential of targeting A? by active or passive immunization paradigms. Although anti-A? immunotherapies remain mainstays of disease modifying therapies being tested in humans, it is our general premise that current agents represent first generation therapeutics with suboptimal properties and that the therapeutic potential of immunotherapy can be dramatically improved by both enhancing the understanding of how immunotherapies work and by developing alternative biological immunotherapies. Indeed, there remain a number of unanswered questions regarding both mechanism of action and pharmacokinetics of A? immunotherapies that are critical to address in order to optimize the approach. Herein, we propose three distinct, but interrelated, aims that will further explore aspects of A? immunotherapy. The experiments in Aim 1 represent a shift from previous studies in the area of AD immunotherapy. As opposed to using antigen specific antibodies targeting A? we will harness soluble Toll Like Receptors (sTLRs) as decoy innate immune pattern recognition receptors to therapeutically target amyloid and amyloid-like aggregates. The studies in Aim 2 stem from data showing that pro-inflammatory stimuli attenuate and anti-inflammatory stimuli promote A? deposition. We, therefore, propose that preexisting alterations in the innate immune activation state that are present in the aged human brain, but not as much in APP mice, might dramatically alter the efficacy of anti-A? immunotherapy. We will evaluate this hypothesis by exploring how pro- or anti-inflammatory "preconditioning" of the brain alters efficacy of anti-A? immunotherapy.
In Aim 3 we will determine the cycling time of anti-A? antibodies between the brain and periphery and identify parameters that regulate this process. Establishing the cycling time is critical to understand the pharmacokinetics that regulate antibody exposure in the brain and has major conceptual ramifications regarding development of immunotherapies for A? and other CNS targets.
Finding effective therapy for Alzheimer's disease is a huge unmet medical need. The proposed studies will provide key information that will help guide development and optimization of current immunotherapies and provide the rationale for further development of novel therapies harnessing innate immune receptors that could target multiple pathologies relevant to Alzheimer's disease.
|Rosario, Awilda M; Cruz, Pedro E; Ceballos-Diaz, Carolina et al. (2016) Microglia-specific targeting by novel capsid-modified AAV6 vectors. Mol Ther Methods Clin Dev 3:16026|
|Levites, Yona; O'Nuallain, Brian; Puligedda, Rama Devudu et al. (2015) A human monoclonal IgG that binds aÎ² assemblies and diverse amyloids exhibits anti-amyloid activities in vitro and in vivo. J Neurosci 35:6265-76|
|Fernandez-Funez, Pedro; Zhang, Yan; Sanchez-Garcia, Jonatan et al. (2015) Anti-AÎ² single-chain variable fragment antibodies exert synergistic neuroprotective activities in Drosophila models of Alzheimer's disease. Hum Mol Genet 24:6093-105|
|Chakrabarty, Paramita; Li, Andrew; Ceballos-Diaz, Carolina et al. (2015) IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron 85:519-33|
|Ayers, Jacob I; Fromholt, Susan; Sinyavskaya, Olga et al. (2015) Widespread and efficient transduction of spinal cord and brain following neonatal AAV injection and potential disease modifying effect in ALS mice. Mol Ther 23:53-62|
|Li, Andrew; Ceballos-Diaz, Carolina; DiNunno, Nadia et al. (2015) IFN-Î³ promotes Ï„ phosphorylation without affecting mature tangles. FASEB J 29:4384-98|
|Chu, Jin; Li, Jian-Guo; Ceballos-Diaz, Carolina et al. (2013) The influence of 5-lipoxygenase on Alzheimer's disease-related tau pathology: in vivo and in vitro evidence. Biol Psychiatry 74:321-8|
|Chu, Jin; Giannopoulos, Phillip F; Ceballos-Diaz, Carolina et al. (2012) 5-Lipoxygenase gene transfer worsens memory, amyloid, and tau brain pathologies in a mouse model of Alzheimer disease. Ann Neurol 72:442-54|
|Chu, Jin; Giannopoulos, Phillip F; Ceballos-Diaz, Carolina et al. (2012) Adeno-associated virus-mediated brain delivery of 5-lipoxygenase modulates the AD-like phenotype of APP mice. Mol Neurodegener 7:1|
|Cai, Jun; Qi, Xiaoping; Kociok, Norbert et al. (2012) Î²-Secretase (BACE1) inhibition causes retinal pathology by vascular dysregulation and accumulation of age pigment. EMBO Mol Med 4:980-91|
Showing the most recent 10 out of 24 publications