Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the central nervous system (CNS) and is the most common cause of dementia in the elderly. Currently, an estimated 4.5 million Americans have AD and by the year 2050 there are projected to be 11.5 to 16 million Americans with the disease. Learning and memory deficits are the hallmark of Alzheimer's disease and amyloid beta protein (A?) plays a key role in these deficits. Elevated brain levels of A? lead to oxidative damage in the brain resulting in learning and memory deficits. Reduced levels in the blood-brain-barrier (BBB) of low density lipoprotein receptor-related protein-1 (LRP-1), the brain-to-blood transporter of A?, has been hypothesized as a possible mechanism contributing to the accumulation of A? in the brain (Neurovascular Hypothesis of Zlokovic). Animal models of AD have proved useful tools in the study of AD and its possible treatments. For example, we and others have characterized the SAMP8 mouse as having a natural mutation that produces an age-related impairment in learning and memory that is driven by an age-related increase in brain levels of A?. SAMP8 mice also develop a decrease in Ab efflux from the brain, have increased oxidative damage to the brain, and an impaired cholinergic system. All of these AD-like characteristics are reversed by administration into the brain of antibody to A?. However, due to the problems of giving antibody to Ab, we have more recently developed an antisense oligonucleotide, termed OL-1, that is directed at amino acids 17-30 of A?1-42, a region homologous between human and mouse. This antisense lowers A? levels in the brain, reverses learning and memory deficits, decreases the oxidative tissue damage in the brain, and restores A? efflux by the BBB in SAMP8 mouse. The SAMP8 mouse, however, overproduces mouse A? this raises the question of whether antisense the antisense would work in humans. The availability of mice overexpressing human APP provides a translational model for OL-1. Therefore, we propose to determine whether OL-1 is effective in a transgenic mouse model of AD, the Tg2576 that overexpresses the human APP gene. We hypothesize that the antisense oligonucleotide OL-1 will improve learning and memory, decrease levels of A?, improve efflux of A? from the brain across the BBB, and decrease free radical damage in the Tg2576 transgenic mouse model of AD. We will determine whether OL-1 can reverse the learning and memory deficits present in 13 month Tg2576, increase cholinergic tone, decrease A? levels, decrease plaque, reverse oxidative damage in the Tg2576 mice , and if OL-1can restore A? efflux and LRP-1 levels in Tg2576 mice.
AD is steadily increasing in the United States and in the veteran population. For the VA, the cost of treating patients with AD is steadily increasing as well. At the present there is a shortage of pharmacological therapies for AD that produce clinically significant effects. A new drug that can not only halt but reverse the symptoms of AD would be invaluable to veterans and could greatly reduce health care costs for the VA. The work in this proposal could lead to a revolutionary treatment for AD.
