Alzheimer's Disease (AD) is the most common cause of dementia after the age of 60. The pathological hallmarks of Alzheimer's disease include deposition of amyloid ?-peptide (A?) in neuritic plaques and cerebral blood vessels, neurofibrillary tangles, and loss of neurons. Increasing evidence supports the notion that A? and its precursor play important roles in the pathogenesis of Alzheimer's disease. Immunization of mouse models of Alzheimer's disease with synthetic A? reduces A? deposits and attenuates their memory and learning deficits. Recent clinical trials, however, were halted due to brain inflammation, presumably induced by T-cell mediated and/or Fc-mediated immune responses. Peripheral administration of antibodies against A? also induced clearance of preexisting amyloid plaques in AD mouse models, indicating that an active T-cell-mediated immune response is unnecessary. Topical application of the F(ab')2 without Fc of antibodies against A? led to clearance of amyloid deposits in an AD mouse model, indicating that non-Fc-mediated mechanisms are also involved in the clearance. We have demonstrated that human single chain antibody (scFv) against A? was also effective in reducing brain A? load in an AD mouse model. Although these passive immunization modalities may be effective in treating AD patients without inducing side effects such as inflammatory responses, such modalities suffer from repeated administrations of antibodies, leading to a large financial and physical burden to AD patients. We hypothesize that scFvs against A? are effective and safe in treating AD patients as well as AD mouse models. We propose to use novel immune gene therapy for Alzheimer's disease, whereby recombinant adeno-associated virus (rAVV) vectors encoding anti-A? scFvs are directed to skeletal muscles in order to deliver the scFvs into the circulation and, probably, into the brain. This study will serve as a proof of principle to demonstrate if this gene therapy modality can deliver anti-A? scFvs into the circulation enough to reduce brain A? load and improve learning and memory deficits in an AD mouse model.
In Specific Aim 1, we will evaluate prophylactic effects of muscle directed gene therapy modality by an rAAV vector encoding anti-A? scFv on prevention of A? deposits and behavioral deficits in an AD mouse model.
In Aim 2, we will evaluate therapeutic effects of muscle-directed gene therapy modality by an rAAV vector encoding anti-A? scFv on clearance of A? deposits as well as improvement of behavioral deficits in an AD mouse model. We utilize neuropathological, biochemical, immunological, and behavioral analyses to determine the prophylactic and therapeutic effects and safety of the modality. The long-term goal is to establish the logical basis for developing safe and effective gene therapy modalities for AD utilizing rAAV and scFv. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AG029818-02
Application #
7433188
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Buckholtz, Neil
Project Start
2007-06-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2010-03-31
Support Year
2
Fiscal Year
2008
Total Cost
$193,673
Indirect Cost
Name
University of Illinois at Chicago
Department
Biology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Yang, Junling; Pattanayak, Abhinandan; Song, Min et al. (2013) Muscle-directed anti-A? single-chain antibody delivery via AAV1 reduces cerebral A? load in an Alzheimer's disease mouse model. J Mol Neurosci 49:277-88
Lim, Jeong-Eun; Song, Min; Jin, Jingji et al. (2012) The effects of MyD88 deficiency on exploratory activity, anxiety, motor coordination, and spatial learning in C57BL/6 and APPswe/PS1dE9 mice. Behav Brain Res 227:36-42
Kou, Jinghong; Song, Min; Pattanayak, Abhinandan et al. (2012) Combined treatment of A? immunization with statin in a mouse model of Alzheimer's disease. J Neuroimmunol 244:70-83
Song, Min; Jin, Jingji; Lim, Jeong-Eun et al. (2011) TLR4 mutation reduces microglial activation, increases A? deposits and exacerbates cognitive deficits in a mouse model of Alzheimer's disease. J Neuroinflammation 8:92
Kou, Jinghong; Kim, HongDuck; Pattanayak, Abhinandan et al. (2011) Anti-Amyloid-? Single-Chain Antibody Brain Delivery Via AAV Reduces Amyloid Load But May Increase Cerebral Hemorrhages in an Alzheimer's Disease Mouse Model. J Alzheimers Dis 27:23-38
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
Kou, Jinghong; Kim, Hong-Duck; Jin, Jingji et al. (2010) Simvastatin enhances immune responses to Aýý vaccination and attenuates vaccination-induced behavioral alterations. Brain Res 1356:102-11
Jin, Jing-Ji; Kim, Hong-Duck; Maxwell, J Adam et al. (2008) Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer's disease. J Neuroinflammation 5:23