NEURODEGENERATION AND PLASTICITY OF THE BRAIN

Abstract

Aging involves neural circuitry rearrangements that are broadly referred to as synaptic plasticity. This is the result of several events, mainly of synaptic activity. Long-term potentiation (LTP), learning and memory promote plasticity of synapses, notably in the hippocampus. There are also pathological conditions that trigger plasticity. For example, in ischemic stroke, damaged neurons (penumbra), sprout and reestablish connections, partially or wholly recovering function. In epileptogenesis, aberrant synaptic plasticity involve a network of intra- and extracellular messengers that modulate receptors, ion channels, and gene expression. Intracellular pathways of signal transduction modulate neuronal survival. Often, upregulation of certain steps of these pathways leads to neuronal damage or death. An early event is phospholipase A2 activation and the release of arachidonic acid (and subsequent synthesis of prostaglandins and other bioactive derivatives), as well as PAF (platelet-activating factor). PAF is a retrograde messenger in LTP and also, when over-produced, becomes an endogenous neurotoxin by enhancing glutamate release and activating the transcription of the inducible cyclooxygenase (COX)-2 (gene linked to synaptic plasticity and also to the inflammatory response). Molecular events involved in neuronal plasticity to be described involve messenger-activated stress sensitive protein quinces, the subsequent stimulation of transcription factors, and how these DNA-binding proteins modulate gene expression by interacting with consensus sequences in gene promoters. NFK-B (an inflammation-related transcription factor) may be critical in turning on the COX-2 gene in human neocortical samples from Alzheimer's patients. This highlights the potential importance of inflammatory signaling and plasticity in neurodegenerative disease. The identification of the cellular and molecular mechanisms of plasticity of neural circuitry is opening up avenues for novel interventions in aging and in neurodegenerative diseases. (NIH NS23002)