Patients with Alzheimer's disease (AD) develop deposits of aggregated amyloid ?-protein (A?) in the brain. A? accumulation is thought to be a causal event in the etiology of AD. Fibrillar A2 deposits in AD brain are accompanied by innate immune responses such as activated microglia and increased levels of cytokines. Accumulating evidence supports the hypothesis that activated microglia, innate immune cells in the central nervous system, play a pivotal role in the AD progression: either clearing A? deposits by phagocytic activity or releasing cytotoxic substances. Toll-like receptors (TLRs) are a class of pattern-recognition receptors in the innate immune system. One of the important roles of TLRs is to activate phagocytes/microglia to respond to insults including pathogens and damaged host cells, leading to clearance of pathogens, damaged tissues and accumulated wastes. We hypothesize that these protective functions are mediated by MyD88-dependent pathways and that A? load in the brain can be modulated by TLR4 signaling. We will determine the roles of MyD88-dependent pathways and TLR4 signaling in A? clearance by completing the Specific Aim 1 and 2. We further hypothesize that A? load in the brain and cognitive functions are modulated by TLR4 effector cytokines/chemokines, which will be tested by performing Aim 3.
In Aim 4, we will test the hypothesis that accumulation of A? in the brain induces dysfunction of TLR4 signaling in microglia resulting in exacerbation of A? deposition in AD patients and AD mouse models.
Specific Aims are (Aim 1) to determine cerebral A? load, inflammation and behavioral deficits in AD mouse models on a MyD88-deficient genetic background, (Aim 2) to determine cerebral A? load, inflammation and behavioral deficits in AD mouse models that overexpress TLR4, (Aim 3a) to compare cerebral cytokine and chemokine expression profiles between TLR4 wild-type and mutant AD mouse models, (Aim 3b) to overexpress TLR4 effector cytokines and/or chemokines in the brain via adeno-associated virus gene delivery and determine cerebral A? load, inflammation and behavioral deficits in the AD mouse models, and (Aim 4) to determine whether A? induces dysfunction of TLR signaling, using cultured microglia, AD mouse models and tissue samples from AD patients. The long term goal of this research is to determine the roles of TLR signaling and its effector cytokines/chemokines in the AD progression.

Public Health Relevance

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. To date, however, no satisfactory treatments are available for AD. Patients with AD develop deposits of aggregated amyloid 2 protein (A?) in the brain. A? accumulation is thought to be a causal event in the etiology of AD. This study will elucidate the mechanisms by which A? deposits are cleared and serve as a proof of principle to demonstrate if our novel cytokine/chemokine gene therapy modality is effective in treating an animal model of AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG030399-04
Application #
8306214
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Petanceska, Suzana
Project Start
2009-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$306,269
Indirect Cost
$111,193
Name
University of Illinois at Chicago
Department
Biology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
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Lim, Jeong-Eun; Kou, Jinghong; Song, Min et al. (2011) MyD88 deficiency ameliorates *-amyloidosis in an animal model of Alzheimer's disease. Am J Pathol 179:1095-103
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