lease can be briefly summarized as follows. Apoptosis is essential for brain plasticity, synaptic turnover, and selective removal of dysfunctional neurons and glia. A healthy apoptotic response mechanism is critical in the aging brain to allow for efficient adaptive remodeling of neural networks. Inflammation is critical in the acute phase response to provide basic "housekeeping" functions, including the removal of debris from dying cells and their exudates (e.g., amyloid). Reactive glia are the most critical components in maintaining neuronal homeostasis with increasing age. Free radicals released during inflammation by reactive glia are aimed at destroying foreign invaders in the brain and thus comprising a basic immune protection mechanism for brain functioning.

These processes can become detrimental when they go out of balance, for example, shifting from "acute" responses to brain injuries to a "chronic" response pattern. Unbridled apoptosis, inflammation, and free radical release would quickly shift the balance from neural health to neural dysfunction and ultimately to rampant neurodegeneration. Such a shift might either be localized to small subsets of neurons or be widespread, affecting entire neural networks. The extent to which apoptosis, inflammation, and free radical release act as beneficial as opposed to detrimental events in the central nervous system would dictate whether the neural circuit is maintained in a healthy manner or is chronically disrupted, eventually leading to neurodegenerative changes. A hypothesis worthy of investigation is that progressive dysregulation of these processes with age is intimately involved with neural dysfunction and mild cognitive impairment relatively early in life, whereas chronic activity of these events over many years leads eventually to neuronal and synaptic deficits and to dementia.

This hypothesis is described in more detail by Cotman (Appendix B), who discusses the relevant evidence and proposes that although the initiation of acute events of the above-mentioned processes is beneficial for the maintenance of the neural circuitry, problems arise when "initiation" shifts to "propagation." For example, acute apoptosis can facilitate neuronal plasticity in the central nervous system, but chronic apoptosis can promote dysfunctional neurons (e.g., in those undergoing chronic caspase activation and managing to survive with compromised function). Chronic apoptosis would ultimately result in neurodegeneration, leading to major neural network abnormalities. Thus, in the early stages of chronic apoptosis, one would expect the promulgation of dysfunctional neurons and abnormally altered afferent/efferent profiles in the neural network. This would eventually proceed to neurodegenerative events, including neuronal cell loss, requiring robust plastic responses to maintain the integrity of the neural network. Likewise, the nurturing activities of reactive glia can shift from enhancing adaptive mechanisms in the brain to killing neurons (e.g., via free radical release) if acute phase responses become chronic ones.

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