The Aging Mind Opportunities in Cognitive Research (2000) / Chapter Skim
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Appendix B: Homeostatic Processes in Brain Aging: The Role of Apoptosis, Inflammation, and Oxidative Stress in Regulating Healthy Neural Circuitry in the Aging Brain
Appendix B: Homeostatic Processes in Brain Aging: The Role of Apoptosis, Inflammation, and Oxidative Stress in Regulating Healthy Neural Circuitry in the Aging Brain
Pages 114-143
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From page 114... ...
This paper presents the hypothesis that brain aging at a mechanistic level is resolvable into a series of distinct phases. These phases are associated with discrete molecular events that evolve into cascades, and, importantly, each phase may require different intervention strategies and certainly must be resolved in order to understand 114
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From page 115... ...
The literature discussed in support of this hypothesis has been limited due to space constraints and thus some citations may have been unintentionally omitted. BRAIN AGING, A MULTIPHASE PROCESS: INITIATION AND PROPAGATION PHASES Several investigators have suggested that Alzheimer's disease may represent an accelerated decline of the normal processes of brain aging.
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From page 116... ...
In terms of ,13-amyloid accumulation, this phase is largely independent of APOE-£4, although it may have gender factors. Examples of possible autocatalytic cascades that could contribute to a propagation phase include the ability of amyloid to induce the amyloid precursor protein (APP)
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From page 117... ...
To identify events associated with the initiation phase, we are now using subthreshold levels of A,13 that do not cause overt neuronal death to determine the sequence of events that occur early in response to an injury. These events may be subtle indicators of neuron dysfunction that develops prior to the classic forms of pathology found in the aged brain, such as senile plaques, neurofibrillary tangles, and cell death.
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From page 118... ...
, and it is hypothesized that this decline may have a role in memory decrements. While a direct mechanism or causal effect of declines in pCREB has not been established in normal aging in humans or animals, it is hypothesized that shortterm memory deficits that occur as mild cognitive impairment in humans or as memory impairments in individual old canines may be a consequence of neuronal dysfunction associated with decreased phosphorylation of CREB signal transduction mechanisms or other transcription factors.
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From page 119... ...
However when TNFoc is combined with an insult such as ischemia, TIFF induces a robust increase in neuronal death (Rothwell and Hopkins, 1995~. In addition to having a direct effect on cellular physiology, TNFoc has been shown to disrupt the signal transduction pathways induced by other physiological ligands, such as insulin (Peraldi et al., 1996; Paz et al., 1997~.
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From page 120... ...
< < < i- CREB ~ ~i- CREB ~ < FIGURE B-2 Neurons subjected to sublethal pro-apoptotic insults may be deficient in their ability to regulate key signal transduction pathways serving functional plasticity. The presence of sublethal concentrations of B-amyloid results in an inability to phosphorylate CREB and thus control of essential transcriptional mechanisms.
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From page 121... ...
Three weeks of environmental enrichment significantly stimulated cell proliferation, BDNF expression and resistance to insults, and inhibited apoptotic cell death (Young et al., 19991. Proliferating cell nuclear antigen (PCNA)
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From page 122... ...
Interestingly, prior to causing cell death, ,13-amyloid also induces the formation of dystrophic-like neurite morphology in cultured neurons (Pike et al., 1992; Fraser et al., 19941. Oxidative insults also readily initiate apoptosis (Whittemore et al., 1994)
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The amyloid precursor protein itself appears capable of initiating apoptosis. There is growing evidence that the amyloid precursor protein is a receptor resembling a polypeptide hormone receptor (Nishimoto et al., 19971.
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These death receptors in the immune system serve to maintain homeostasis through selective cell death by way of apoptosis. In the brain, acute inflammatory responses are part of the natural repair process, but chronic inflammation probably drives degeneration, much like a chronic infection.
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From page 125... ...
Free radicals can also damage DNA, and a 50 percent increase in DNA oxidative damage has been reported in the human brain (Lyres et al., 1997; Gabbita et al., 1998; Mecocci et al., 1994; Lovell et al., 19991. Indeed, extensive DNA damage appears to accumulate with age and is particularly prominent in the aged dog brain and in humans (Su et al., 1997; Anderson et al., in press)
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From page 126... ...
and thus would make cells at risk for activating pro-apoptotic mechanisms similar to that reported in the aging immune system. one lipid peroxidation product, 4-hydroxynonenal (HNE)
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From page 127... ...
/ caspase \ / + ~ ~ - ctivation ~ ;~ Syna~ use Loss AD DNA Damage Deposition CELL DYSFUNCTION/CELL DEATH + FIGURE B-4 Oxidative stress is an early and continued event in brain aging, leading to increases in expression of proteins involved with promoting cell survival (bc1-21. Oxidation causes damage to lipids, proteins, and DNA/RNA.
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From page 128... ...
The accumulation of amyloidogenic fragments, in turn, accelerates existing molecular cascades associated with oxidative stress. ,13-amyloid also promotes cell dysfunction by increasing the expression levels of ban, decreasing levels of bc1-2 (Paradis et al., 1996)
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From page 129... ...
Antioxidants can also significantly aid the human brain. Over 4 years ago, the inclusion of Vitamin E into a clinical trial of patients with mild to moderate Alzheimer's disease resulted in the finding that Vitamin E supple
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This concept of an apoptosis checkpoint cascade may help to understand an apparent puzzle in the neuronal apoptosis literature: the prolonged presence of indices of DNA damage and apoptotic regulatory protein expression may be a result of a counteractive strategy that neurons mobilize to hold apoptosis
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From page 131... ...
This possibility may make the study of signal transduction pathways particularly critical, because it may provide an opportunity for early interventions. Taken together, this hypothesis may suggest that neurons could activate an "apoptosis checkpoint cascade," in which injured neurons may regulate the activation of pro-apoptotic proteins such as bax with anti-apoptotic proteins such as Bc1-2.
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From page 132... ...
In a follow-up study, two additional members of the Fas family of receptors, TNFRI and TNFRII, were examined in lymphocytes from aged individuals (Aggarwal et al., 19991. Once again, the investigators found increased sensitivity to undergo apoptosis, this time induced by TNFoc.
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From page 133... ...
Importantly, caloric restriction, which is the only really true intervention known to retard aging in mammals, almost completely prevented the gene expression pattern changes that occur with aging. This is a technology that should find particular use in the study of brain aging and cognition but will probably be difficult to get funded through peer review panels because it will be considered just a "fishing expedition." These gene patterns summarize in one experiment the literature for the past 10 years of individual gene expression patterns.
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From page 134... ...
There is also a growing body of literature indicating that, in the course of brain aging, more of the brain has to be involved in a task that would normally require only minimal activation of circuits; thus, the circuits are working much harder to accomplish the same task. This would indicate that use-dependent change and practice effects, together with appropriate pharmaceuticals, might have a rational basis for cognitive rehabilitation.
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From page 135... ...
Many behavioral theories, particularly in the practice of neuropsychology, lack solid mechanistic foundations and quantitative support, handicapping the growth of the field. There is, in general, a gap between cognitive research and molecular mechanistic studies in brain aging.
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From page 136... ...
Markesbery, and M.P. Mattson 1998 4-hydroxynonenal, a product of lipid peroxidation, damages cholinergic neurons and impairs visuospatial memory in rats.
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From page 137... ...
Yankner 1994 Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative. Journal of Biological Chemistry 269(18)
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McEwen, and P.C. Bickford 1999 Reversals of age-related declines in neuronal signal transduction, cognitive and motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation.
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Uchida, and M.P. Mattson 1997 Amyloid ,B peptide impairs glucose transport in hippocampal and cortical neurons: Involvement of membrane lipid peroxidation.
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Milliman, and S.J. Korsmeyer 1993 Bc1-2 heterodimerizes in vivo with a conserved homolog, bax, that accelerates programmed cell death.
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Mills, and R.G. Miller 1993 Relegation of the T cell receptor after primary activation of mature T cells inhibits proliferation and induces apoptotic cell death.
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Deng, and C.W. Cotman 1997 Neuronal DNA damage precedes tangle formation and is associated with up-regulation of nitrotyrosine in Alzheimer's disease brain.
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From page 143... ...
1999 Impaired phosphorylation of cyclic AMP response element binding protein in the hippocampus of dementia of the Alzheimer type. Brain Research 824(2)
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