VA St. Louis Healthcare System

St. Louis, MO GRECC Program

• Reversal of Memory deficits in a mouse model of Alzheimer’s disease (SAMP8) by antibody and antisense technology. The deficits in learning and memory can be reversed in old SAMP8 mice to the levels seen in young mice. Initially, this was demonstrated by direct application of antibodies to beta-amyloid into the brain hippocampus. More recently, this has been demonstrated with the addition of antisense RNA designed to block the production of beta-amyloid. Significantly, the antisense RNA may be administered systematically.

• Discovery that triglycerides may be responsible for leptin resistance. These studies indicate that triglycerides may interfere with the movement of leptin across the blood-brain barrier and the suppression of appetite. In addition, hypertriglyceridemia is a potent cause of cognitive dysfunction.

• Demonstration that amyloid beta efflux from the brain is impaired with aging. These studies showed that the exit of amyloid beta from the brain is decreased in mouse models of Alzheimer’s disease. This could contribute to the buildup of amyloid beta in the brain and subsequent memory loss.

• Characterization of hormonal changes contributing to age-related osteoporosis. These studies indicate that there is decreased capacity of parathyroid hormone to stimulate the renal production of the active form of vitamin D (1,25(OH)₂D) with age. In addition, there is an age-related decrease in the capacity of 1,25(OH)₂D to stimulate the absorption of calcium in the diet by the small intestine. We also demonstrated that there is a decline in serum 25(OH)D, the precursor to 1,25(OH)₂D, over a 14 year period.

A. Age-Related Changes in Cognitive Function

Cognitive function declines with age and this decline can be accelerated by diseases such as Alzheimer's disease. This research program uses a mouse model of cognitive decline, the SAMP8 mouse, to study the biochemical mechanisms involved. Dr. Kumar studies biochemical factors such as the amount of beta-amyloid in the hippocampus, the role of oxidative stress, and the involvement of inflammation in memory loss. Dr. Sue Farr characterizes learning and memory changes with age and after interventions. Dr. Jim Armbrecht is identifying the biochemical pathways involved in memory loss in the hippocampus. Dr. John Morley oversees this project and develops potential interventions to be tested in this animal model.

B. The Blood-Brain Barrier in Aging and Age-Related Diseases

The blood-brain barrier is not just a passive physical barrier between the brain and the rest of the body but actively controls the movement of substances in and out of the brain. We have used this concept to study its role in a number of diseases. These include obesity (regulation of leptin transport), HIV dementia (entry of HIV into the brain), inflammation (cytokine regulation), and alcoholism (ethanol movement into the brain). Dr. John Morley collaborates with Dr. Bill Banks to develop strategies for modifying the movement of these substances as they relate to specific diseases.

C. Age-Related Bone Loss

Bones become thinner with age in both men and women, resulting in an increased risk of fracture. This bone loss is separate from bone loss in women with menopause. Dr. Jim Armbrecht uses rats and mice as animal models to study the hormonal changes that contribute decreased absorption of dietary calcium and subsequent bone loss. Dr. Mike Perry studies mechanisms of bone loss in middle-aged men and women as it relates to vitamin D status, sex hormones, and alcohol intake.

GRECC Research Highlights