Protein Homeostasis in Mouse Models of Alzheimer’s Pathology

Project Summary

Alzheimer’s disease (AD) is the most common form of dementia in people over 65 years of age. There is no cure for it; in fact scientists have not found a cure for any neurodegenerative disease so far. The detailed mechanisms of the causes and progression of the disease are not completely understood. Under a microscope, AD patients’ brains show high levels of amyloid plaques (caused by accumulation of small piece of protein called Aβ) and tangles (filled with another insoluble protein, called tau). It is known that Aβ deposition is the fundamental cause of the disease, but we do not know how this first entity triggers the downstream changes in the brains, such as tangle formation and brain cell death, which is the direct cause of dementia.

For our research, we will investigate the global protein solubility changes during the conditions of high levels of Aβ or tau is forming. The process of cell handling protein metabolism is essential to the normal functioning of the brain. In work prior to this proposal, we have identified a new pathology associated with Alzheimer’s disease that we call “secondary misfolding,” which describes how some normally soluble proteins become insoluble when high levels of Aβ accumulate in the brain. In the mice that model familial cases of Alzheimer’s disease, we found accumulation of Aβ caused about 30 highly soluble proteins to lose their solubility. Many of these proteins are crucial to basic functions of the nerve cells. We do not know whether or not this change causes AD to progress.We hypothesize that tau protein is one of the “secondary misfolded” proteins that happens as human Alzheimer’s disease progresses, although in the mouse models, tau protein’s solubility did not change. In this proposal, we will investigate deeper to understand how “secondary misfolding” may affect the brain function. We will use two mouse models, one of which mimics amyloid plaques in the human brain and the other of which mimics neurofibrillary “tau tangles.” Both mouse models are genetically engineered to have their human disease protein production switched on or off by simply feeding them tetracycline. Using these models, we will find out how the newly produced amyloid or tau affects the balance of regular protein production and disposal that cells must handle. Based on the previous studies, in both models, once the human disease genes were switched off, the memory of the mice improved to close to normal levels. We wonder whether “secondary misfolding” of certain important proteins related to memory or/and cell survival holds the key to memory changes. If we can determine how stopping the production of the disease-related toxic proteins causes the brain function to return to normal, we may be able to predict how much benefit patients will derive from future drugs which can stop Aβ or tau production are developed.