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Many cellular and molecular aspects of brain aging are shared with other organ systems, including increased oxidative damage to proteins, nucleic acids and membrane lipids, impaired energy metabolism, and the accumulation of intracellular and extracellular protein aggregates. However, as a result of the molecular and structural complexity of neural cells, which express approximately 50 to 100 times more genes than cells in other tissues, there are age-related changes that are unique to the nervous system. For example, complex cellular signal transduction pathways involving neurotransmitters, trophic factors, and cytokines that are involved in regulating neuronal excitability and plasticity are subject to modification by aging. This chapter describes cellular and molecular changes that occur in the brain during aging and how such changes may predispose neurons to degeneration in disorders such as Alzheimer's disease (AD), Parkinson disease (PD), and Huntington disease (HD).

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All of the major cell types in the brain undergo structural changes during aging. These changes include nerve cell death, dendritic retraction and expansion, synapse loss and remodeling, and glial cell (astrocytes and microglia) reactivity. Such structural changes may result from alterations in cytoskeletal proteins and the deposition of insoluble proteins such as tau and α-synuclein inside of cells and amyloid in the extracellular space. Alterations in cellular signaling pathways that control cell growth and motility may contribute to both adaptive and pathological structural changes in the aging brain.

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Cytoskeletal and Synaptic Changes

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The cell cytoskeleton consists of polymers of different sizes and protein compositions. The three major types of polymers are actin microfilaments (6 nm in diameter); microtubules (25 nm in diameter), comprising of tubulin; and intermediate filaments (10–15 nm in diameter), which are made of specific intermediate filament proteins that are different in different cell types (e.g., neurofilament proteins in neurons and glial fibrillary acidic protein in astrocytes). To regulate the processes of filament assembly and depolymerization, and to link the cytoskeleton to membranes and other cell structures, neurons and glial cells employ an array of cytoskeleton-associated proteins. For example, neurons express several microtubule-associated proteins (MAPs) that are differentially distributed within the complex architecture of the cells; MAP-2 is present in dendrites but not in the axon, whereas tau is present in axons but not in dendrites. While there are no major changes in the levels of the most abundant cytoskeletal proteins with aging, there are changes in the cytoskeletal organization and in posttranslational modifications of cytoskeletal proteins. For example, increased amounts of phosphorylated tau occur in some brain regions, particularly those involved in learning and memory (e.g., hippocampus and basal forebrain). In addition, there is evidence that calcium-mediated proteolysis of MAP-2 and spectrin (a protein that links actin filaments to membranes) is increased in some neurons during aging. Oxidation of certain cytoskeletal proteins is suggested by studies demonstrating their modification by glycation and covalent binding of the lipid peroxidation product 4-hydroxynonenal (see “Free Radicals and the Aging Brain” later in this chapter). ...

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