Senior Scholar Award in Aging
Rudolph E. Tanzi, Ph.D.
Massachusetts General Hospital

Role of the multiligand receptor, LRP. In Alzheimer’s disease-related neuropathogenesis: A model for age-related disorders involving LRP

Alzheimer’s disease (AD) is the most common form of dementia in the elderly afflicting over 20 million people worldwide. Overwhelming neuropathological and genetic data support the abnormal accumulation and deposition of a small protein called the Ab peptide as the critical event in AD pathology. Consequently, this peptide has been studied intensively over the past decade. Our laboratory has been intimately involved with the identification of all three of the known familial AD genes, all of which contain mutations that increase the generation of Ab in brain. In attempts to develop novel therapies for treating and preventing AD, academia and industry alike have been devising strategies aimed at reducing Ab levels in brain. Most of these efforts have centered on regulating the activity of the proteases (b and g -secretases) that release Ab from the amyloid protein precursor (APP) using protease inhibitors. While considerable progress has been made in this area, the identity and mechanism of action of the secretases remain very murky. More importantly, it remains unclear as to whether it will be possible to develop b or g -secretase inhibitors that possess sufficient specificity and potency while keeping side effects at manageable levels. For example, presenilin/g -secretase cleaves many more substrates than APP including proteins that are critical for nerve cell communication in the brain (at synapes). Other attempts to lower the accumulation of Ab in brain include Elan Pharmaceutical’s vaccine approach. However, dosing in this trial has been terminated due to adverse effects including severe brain inflammation. Meanwhile, as our elderly population continues to represent a progressively greater proportion of our population, it is estimated that by 2050, there will be over 14 million Americans with AD. This, it is imperative that we develop alternative therapies for effectively treating and preventing this devastating disease.

An alternative approach for attenuating the accumulation of Ab involves modulating its main receptor on nerve cells in brain, the low-density lipoprotein receptor-related protein (LRP). Our and other laboratories’ data have uncovered evidence that LRP is a “double-edged sword” that is able to control both the generation and clearance of Abin the brain (including the flushing of Ab from brain to blood where it can be safely cleared away.) Consequently, we propose to more fully characterize the process by which Ab is produced in the LRP-mediated pathway in human nerve cells while also exploring how LRP mediates the breakdown and clearance of Ab from the brain. In addition, we will attempt to develop agents that can enhance Ab clearance from brain in transgenic animal models of AD. Given the emerging problems with existing therapies (e.g., the Elan vaccine) for reducing Ab burden in the brain, targeting LRP-ligand interactions with APP and other AD-related proteins offers a potentially powerful and novel means for the treatment and prevention of AD. The consideration of LRP as a novel therapeutic target for the treatment of AD will also be useful beyond the area of AD research. For example, LRP is associated with other age-related diseases such as artherosclerosis and certain forms of cancer. Strong evidence also exists for the involvement of LRP in AIDS-related dementia and in the uptake of exogenous toxins. Thus, the likelihood is high that the understanding we obtain from these studies will likely spill over into these other research fields, providing useful data for ongoing studies against a number of other major age-related disorders.

Contact Dr. Tanzi.