Previous Research

Alzheimer's Disease and Oxygen Deprivation

Figure 1

A receptor is a cell surface acceptor site which selectively engages molecules in the cell's microenvironment (termed ligands), and triggers cellular responses (see Figure 1). RAGE is a receptor discovered by intestigators working in the Division of Surgical Science (the receptor is displayed schematically in Figure 2).

Figure 2

Figure 3

In constrast to some receptors which interact with only one ligand, RAGE binds several different classes of ligands, including advanced glycation endproducts or AGEs (molecules that accumulate in blood vessels and tissues in patients with diabetes), amyloids (associated with Alzheimer's disease), amphoterin (a molecule associated with tumors) and S100/calgranulins (a family of inflammatory mediators). RAGE is an acronym for Receptor for Advanced Glycation Endproducts, since AGEs were the first known ligands of the receptor. When ligands bind to RAGE, many mechanisms are activated within the cell, and the process is difficult to turn off (Fig. 3). Thus, investigators in the Division have been working on strategies to block RAGE-ligand interaction.

RAGE is expressed at increased levels in brains of patients with Alzheimer's disease. This includes brain cells (neurons) and cerebral blood vessels (endothelial cells and smooth muscle cells) Alzheimer's patients. Based on this observation, investigators in the Division have hypothesize that when fibrils of Aß, which comprise the amyloid in Alzheimer's disease, bind to RAGE-bearing cells (Fig. 4), their functional properties are distorted. Such altered function may have multiple consequences, such as decreased cerebral blood flow and diminished synaptic plasticity, ultimately leading to neuronal dysfunction underlying dementia.

Figure 4

In recent studies in collaboration with investigators at the University of Rochester and the University of Kentucky, investigators in the Division have found that RAGE has a critical role in the ability of Aß to decrease cerebral blood flow as well as the transfer of Aß from the blood to the brain parenchyma. Administration of a truncated (shortened) form of RAGE into the brain dramatically decreases Aß load. Studies in transgenic animals overexpressing RAGE in an Aß-rich environment display exaggerated behavioral, biochemical and neuropathologic abnormalities compared with the presence of Aß alone. These data are consistent with results of a past study by investigators of the Division with systemic amyloidosis. In the latter case, blockade of RAGE suppressed cellular dysfunction and amyloid deposition in parallel.

Because of these data, investigators in the Division are excited about the possibility that blockade of RAGE might be a valuable therapeutic strategy for patients with Alzheimer's disease.