Molecular mechanisms of glutamate-induced neurodegeneration

One of the unanswered questions surrounding the causes of Alzheimer's disease is how the two neuropathological hallmarks of the disease, i.e. amyloid plaques and neurofibrillary tangles, arise. In fact, up to now, little is known of the molecular events which lead to the synthesis of these very insoluble proteins and initiate a cascade of interlocking pathologies characterized by nerve terminal aberrancies, reactive gliosis, abnormal neuronal growth, and neuronal death. We suggest that, after certain unknown conditions, a number of selective neurons may modify the pattern of expression of a number of gene products in such a way as to react to specific stimuli in an abnormal fashion, perhaps incompatible with survival. Although Alzheimer's disease is complex in its origin and development, we suggest that abnormal glutamate reactivity may be one cause of neuronal death. This review will focus on some of the mechanisms triggered by glutamate, interacting with specific glutamate receptors, in relationship to neurodegeneration. Particular emphasis will be devoted to studies of the regulation of βamyloid and tau protein expression.