Protein Modification in Alzheimer Disease

Neurofibrillary tangles and senile plaques are two brain abnormalities, or lesions, that characterize and diagnose Alzheimer disease. The role of these lesions in the initiation and progression of the disease is not yet known. However, studies do show that neurofibrillary tangles and senile plaques correlate with clinical dementia and that everyone with Alzheimer disease has both lesions.

We are interested in the processes that lead to the formation of these lesions and for this proposal are concentrating on the processes that could form neurofibrillary tangles. It is known that neurofibrillary tangles are formed from the cytoskeleton or the normal supporting filaments of a brain cell. This raises the question as to what factors are important in changing normal cytoskeletal components into neurofibrillary tangles. One key change that was described in the 1980’s is that neurofibrillary tangles are very insoluble and it is thought that this property prevents them being removed. Recently, we were one of the first to describe chemical modifications that might effect this transformation. First, after careful analysis we found that chemical modification of cytoskeletal components gave them with the same properties as neurofibrillary tangles. The chemical modifications are called carbonyl-modifications and involved the formation of crosslinks. Second, we were able to identify these carbonyl modifications in Alzheimer brain indicating that this modification is active in Alzheimer disease. The aim of this proposal is to characterize the nature of these modifications in Alzheimer disease and to recapitulate these changes using a model system. Further characterization of these events should provide new clues as to whether these processes can be modulated, and the progression of the disease halted.

We have shown that the carbonyl modification described in Alzheimer disease might originate from abnormal regulation of highly reactive chemicals. There are many different chemicals that can cause modification and we shall determine which ones are important in Alzheimer disease. By doing this one has a clue as to the origin of the chemical defect and can set about recreating this in a model system. Indeed, the therapeutic value of this proposal are several fold. First, only by a full understanding of carbonyl modification in neurons can a rational therapeutic strategy be proposed. Second, monitoring the carbonyl modifications at different stages in the disease might provide insights for a therapeutic window. Third, a well established model system to measure cytoskeletal modifications will provide a very good system to test possible therapeutic agents that could prevent these changes and hence slow down or even prevent these same changes in Alzheimer disease.