Neurodegenerative Diseases: Apoptosis in neurodegenerative diseases

Introduction Although reports on the morphological characteristics of apoptosis in neurodegenerative diseases remain controversial, accumulating evidence suggests that the molecular and biochemical pathways of apoptosis are involved in neuronal death of various neurodegenerative disorders and in related cellular and animal models. This includes stroke, head trauma, Huntington's (HD), Parkinson's (PD), Alzheimer's disease (AD and amyotrophic lateral sclerosis (ALS)). This evidence includes the activation of the mitogen activated protein (MAP) kinase pathway, the induction of Bax, prostate apoptosis response-4 (Par-4) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), evidence of aberrant activation of the cell cycle machinery, and the activation of caspases. Caspases are the mammalian cell-death-effector proteins. They may have an important role in acute and chronic neurodegenerative diseases. They execute cell death but may also be linked to the initiation of chronic neurodegenerative diseases. Peptide or protein inhibitors of caspases protect neurons in vitro or in animal models of neurological disorders. Although preclinical results are promising, clinical studies have not been performed because of the lack of synthetic caspase inhibitors that cross the blood–brain barrier. Such agents are a major focus in current programs of drug development and will hopefully become available soon. However, in some cell culture and animal models caspase inhibitors block cell death but may result in survival of a dysfunctional neuron. In contrast, therapeutic interference with the signaling phase of apoptosis, e.g. inhibition of the MAP kinase pathway, or the combination of caspase inhibitors with neurotrophins may provide morphological and functional protection.