The scope of this proposal is to develop a novel pre-clinical therapeutic strategy with a candidate drug for future clinical testing to treat or prevent Alzheimer's disease (AD). AD affects a growing number of individuals worldwide and there is no cure for it. 5-Lipoxygenase (5LO) is an enzyme abundantly present in the central nervous system (CNS), where its activation depends on the presence of a membrane associated protein called FLAP (5-LO activating protein). In the brain, FLAP-dependent 5LO activation increases with aging, one of the strongest risk factors for developing AD. Interestingly, these levels are even higher in AD brains compared with controls. On the other hand, recently we have shown that genetic absence of 5LO enzymatic activity results in a significant reduction of Amyloid 2 (A2) levels in an animal model of AD. Taken together these data suggest an involvement of this pathway in the AD pathogenesis, and support our central hypotheses: FLAP/5LO enzymatic pathway plays a functional role in AD development;its pharmacological modulation represents a novel AD therapeutic target. The objective of this proof-of-principle study is to validate FLAP as a novel and functionally important molecular target in the neurobiology of AD. With this pre-clinical type of studies we want to test the hypothesis that FLAP pharmacological inhibition will ameliorate the AD-like neuropathology and behavioral deficits of a transgenic mouse model of AD. To achieve this goal, we will use a selective FLAP inhibitor, i.e. MK-591, in the following specific aims:
Specific Aim 1 : Test the hypothesis that early FLAP pharmacological inhibition will delay and or prevents the development of AD-like neuropathology and behavioral deficits in young APP transgenic mice.
Specific Aim 2 : Assess the efficacy of FLAP pharmacological inhibition in APP transgenic mice after the AD-like neuropathology and behavioral deficits are established. With these studies we intend to complete the initial step in the pipeline for the pre-clinical development of FLAP inhibitors as potential therapeutics for AD. If we demonstrate that MK-591 administration results in a modulation (decrease) of brain amyloidosis, and improvement of behavioral impairments in this AD model, our findings will represent the biologic basis for a subsequent and more comprehensive project submission (i.e., UO1) where several different FLAP inhibitors will be tested and compared for efficacy in this as well as in other AD models. As part of this future research program we will also focus on the pre-clinical optimization (doses, efficacy) and testing of any of the identified lead compounds in individuals with a clinical diagnosis of mild cognitive impairment (MCI) and AD. These studies, if successful, could ultimately lead to an investigation new drug (IND) application to the Food and Drug Administration.
Alzheimer's disease (AD) is a disorder of the brain that causes a dramatic loss of cognitive function and affects millions of elderly individuals worldwide. However, its causes(s) remain unknown and there is no cure for it. Five-Lipoxygenase Activating Protein (FLAP) is an indispensable part of an important enzymatic pathway whose levels are increased in AD when compared with control brains, and for this reason it could be directly involved in the development of the disease. MK-591 is a potent, specific and selective drug orally active that blocks FLAP and prevents the activation of this enzymatic pathway. With these proof-of-principle studies we want to test that FLAP is a novel target for AD prevention and/or treatment. To this end, we will administer MK-591 to a transgenic mouse model of AD and look for its potential beneficial effects on brain pathology (amyloid beta levels and deposition) as well as behavioral deficits in these animals. If we prove that a FLAP inhibitor ameliorates the phenotype of these mice, our findings will provide the biological basis for future human studies with this class of drugs in AD.
Discl aim er: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of the individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.
|Giannopoulos, P F; Chu, J; Joshi, Y B et al. (2014) Gene knockout of 5-lipoxygenase rescues synaptic dysfunction and improves memory in the triple-transgenic model of Alzheimer's disease. Mol Psychiatry 19:511-8|
|Giannopoulos, Phillip F; Joshi, Yash B; Praticò, Domenico (2014) Novel lipid signaling pathways in Alzheimer's disease pathogenesis. Biochem Pharmacol 88:560-4|
|Joshi, Yash B; Giannopoulos, Phillip F; Chu, Jin et al. (2014) Modulation of lipopolysaccharide-induced memory insult, ?-secretase, and neuroinflammation in triple transgenic mice by 5-lipoxygenase. Neurobiol Aging 35:1024-31|
|Chu, J; Lauretti, E; Di Meco, A et al. (2013) FLAP pharmacological blockade modulates metabolism of endogenous tau in vivo . Transl Psychiatry 3:e333|
|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|
|Giannopoulos, Phillip F; Chu, Jin; Joshi, Yash B et al. (2013) 5-lipoxygenase activating protein reduction ameliorates cognitive deficit, synaptic dysfunction, and neuropathology in a mouse model of Alzheimer's disease. Biol Psychiatry 74:348-56|
|Chu, Jin; Praticò, Domenico (2013) 5-Lipoxygenase pharmacological blockade decreases tau phosphorylation in vivo: involvement of the cyclin-dependent kinase-5. Neurobiol Aging 34:1549-54|
|Chu, Jin; Pratico, Domenico (2012) Involvement of 5-lipoxygenase activating protein in the amyloidotic phenotype of an Alzheimer's disease mouse model. J Neuroinflammation 9:127|