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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01AG018454-12A1
Application #
8696053
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Petanceska, Suzana
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Florida
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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
Wang, Allan; Das, Pritam; Switzer 3rd, Robert C et al. (2011) Robust amyloid clearance in a mouse model of Alzheimer's disease provides novel insights into the mechanism of amyloid-beta immunotherapy. J Neurosci 31:4124-36
Golde, Todd E; Schneider, Lon S; Koo, Edward H (2011) Anti-a? therapeutics in Alzheimer's disease: the need for a paradigm shift. Neuron 69:203-13
Chakrabarty, Paramita; Jansen-West, Karen; Beccard, Amanda et al. (2010) Massive gliosis induced by interleukin-6 suppresses Abeta deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB J 24:548-59
Golde, Todd E; Petrucelli, Leonard; Lewis, Jada (2010) Targeting Abeta and tau in Alzheimer's disease, an early interim report. Exp Neurol 223:252-66
Chakrabarty, Paramita; Ceballos-Diaz, Carolina; Beccard, Amanda et al. (2010) IFN-gamma promotes complement expression and attenuates amyloid plaque deposition in amyloid beta precursor protein transgenic mice. J Immunol 184:5333-43
Kim, Jungsu; Miller, Victor M; Levites, Yona et al. (2008) BRI2 (ITM2b) inhibits Abeta deposition in vivo. J Neurosci 28:6030-6
Levites, Yona; Jansen, Karen; Smithson, Lisa A et al. (2006) Intracranial adeno-associated virus-mediated delivery of anti-pan amyloid beta, amyloid beta40, and amyloid beta42 single-chain variable fragments attenuates plaque pathology in amyloid precursor protein mice. J Neurosci 26:11923-8
Levites, Yona; Smithson, Lisa A; Price, Robert W et al. (2006) Insights into the mechanisms of action of anti-Abeta antibodies in Alzheimer's disease mouse models. FASEB J 20:2576-8
Levites, Yona; Das, Pritam; Price, Robert W et al. (2006) Anti-Abeta42- and anti-Abeta40-specific mAbs attenuate amyloid deposition in an Alzheimer disease mouse model. J Clin Invest 116:193-201

Showing the most recent 10 out of 13 publications