The overall goal of the proposed pilot studies is to confirm the anti-oligomeric activity and reduced 1/2 adrenergic receptor binding activity of carvedilol analogs in vitro, and to further tes their physiological relevance in Alzheimer's disease (AD)-related mechanisms and phenotypes in vivo using TgCRND8 mouse model of AD. Alzheimer's disease is neuropathologically characterized by the accumulation of extracellular plaques composed of -amyloid (A) protein, intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein, and loss of neurons. Growing evidence suggests that cognitive deterioration in AD is directly linked to the accumulation of extracellular soluble oligomeric -amyloid (A) species rather than amyloid plaque deposition in the brain. Both high molecular weight (HMW) and Low-n A oligomers ranging from dimers to octamers are found in AD brain and have been shown to decrease long-term potentiation (LTP) in mouse models of AD both in vitro and in vivo. These A oligomers are powerful synaptotoxins and thus potential targets for new treatments of AD. In a previous drug screening study, we discovered that carvedilol, a brain bioavailable and bioactive small antihypertensive molecule could significantly attenuate A oligomerization and development of AD-type cognitive deterioration in two experimental transgenic mouse models of AD. However, the potential development of carvedilol for AD is complicated by its cardiovascular activities. Thus we propose to develop molecules with potential anti- A oligomerization effects of carvedilol without its cardiovascular effects. In preliminary screening of small library of carvediol analogs and testing commercially available compounds, we identified 6 bioactive small-molecule compounds that can significantly reduce both low-n oligomer and HMW soluble oligomer formation in vitro. In this application, we propose to further characterize the anti- A oligomeric properties of the 6 lead compounds and their cardiovascular features using diverse in vitro methods and further explore their in vivo translatability in preventing A oligomerization and AD-type cognitive dysfunction using TgCRND8 mouse model of AD. Outcome from these studies will provide critical basis for future follow-up studies exploring the bioavailability and pharmacokinetic characteristics of these lead compounds in animal models and in humans and eventually to an IND-directed pre-clinical safety assessment and Phase I clinical trial.

Public Health Relevance

Alzheimer's Disease (AD) is by far the most prevalent neurodegenerative disease of aging with an estimated prevalence of 5.3 million in the U.S. alone. A recently completed study using Veteran Administration data shows that 7.3% of Veterans, age 65 and over, who received VA services between 1997 and 2001 had a documented diagnosis of Alzheimer's disease or other dementia. Moreover, older Veterans who suffered from posttraumatic stress disorder (PTSD) are almost twice as likely to develop AD. Currently, there is no cure for AD and available treatments only modestly improve cognitive function with no clinical significance. Therefore, developing novel immediate therapeutic agents to prevent /slow AD progression and possibly delay the onset of dementia in the aging Veteran population is of fundamental importance.

National Institute of Health (NIH)
Veterans Affairs (VA)
Veterans Administration (I21)
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Neurobiology D (NURD)
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James J Peters VA Medical Center
United States
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