| Cellular and Molecular Neurosciences Section |
 |
| Apoptosis (programmed cell death) |
 |
| Schematic diagram showing several biochemical cascades that either promote cell death (apoptosis) or protect cells against death. Adverse conditions occur in the environment of neurons in the brain during aging and in neurodegenerative disorders. Such conditions include reduced levels of trophic factors (TFW) and increased oxidative stress. Increased levels of intracellular calcium and oxyradicals induce production of pro-apoptotic gene products such as prostate apoptosis response (Par-4) and pro-apoptotic Bcl-2 family members. These proteins may interact with mitochondria resulting in mitochondrial membrane depolarization, uptake of calcium, and cytochrome c release. Mitochondrial dysfunction leads to caspase activation and cleavage of a variety of protein substrates that effect the cell death program. Counteracting these cell death-promoting cascades are anti-apoptotic signals such as transduction pathways activated by neurotrophic factors, as well as conditioning responses such as can be stimulated by dietary restriction, for example. These anti-apoptotic signals can interrupt the cell death cascade at several different levels. It should be noted that most of the biochemical machinery for either promoting or preventing cell death is present in synapses and neurites, as well as the cell body. Activation of these pathways in synaptic terminals is believed to be critical to neuronal survival or death in aging brain. |
|
 |
| This diagram summarizes our current state of understanding of the mechanisms whereby the anti-aging enzyme telomerase may promote cell survival and might guard against age-related degenerative disorders including Alzheimer's disease and stroke. Telomerase consists of a catalytic subunit, TERT, an RNA component, and several telomere or telomerase-associated proteins, including proteins including TRF-1, TRF-2 and TEP-1. The well-established function of telomerase is to add a 6-base DNA repeat onto the ends of chromosomes. This activity of telomerase may protect the chromosome ends against damage and thereby suppress apoptotic signals emanating from damaged DNA. In addition, the TERT protein has been shown to suppress apoptosis of neurons at an early step in the cell death process prior to mitochondrial dysfunction and caspase activation. Modulation of the activity of the tumor suppressor p53 might play a role in this anti-apoptotic function of telomerase. |
