Neurodegenerative disorders and ischemic brain diseases

Degeneration and death of neurons is the fundamental process responsible fo r the clinical manifestations of many different neurological disorders of a ging, incuding Alzheimer's disease, Parkinson's disease and stroke. The dea th of neurons in such disorders involves apoptotic biochemical cascades inv olving upstream effectors (Par-4, p53 and pro-apoptotic Bcl-2 family member s), mitochondrial alterations and caspase activation. Both genetic and envi ronmental factors, and the aging process itself, contribute to intiation of such neuronal apoptosis. For example, mutations in the amyloid precursor p rotein and presenilin genes can cause Alzheimer's disease, while head injur y is a risk factor for both Alzheimer's and Parkinson's diseases. At the ce llular level, neuronal apoptosis in neurodegenerative disorders may be trig gered by oxidative stress, metabolic compromise and disruption of calcium h omeostasis. Neuroprotective (anti-apoptotic) signaling pathways involving n eurotrophic factors, cytokines and "conditioning responses" can counteract the effects of aging and genetic predisposition in experimental models of n eurodegenerative disorders. A better understanding of the molecular underpi nnings of neuronal death is leading directly to novel preventative and ther apeutic approaches to neurodegenerative disorders.