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.As in other cells, the major targets of oxidative damage in thebrain are proteins, DNA, and the lipids found in cellular membranes.Researchers have noted for a dozen years or more an age-relatedincrease in oxidatively damaged molecules, particularly lipids, in thehuman brain.Oxidative damage to DNA (especially mitochondrialDNA) is up to three-fold higher in brain samples from Alzheimer'spatients and is substantially increased in very old patients without clinically detectable disease.There is also an age-dependent increase inendogenous antioxidant enzymes, in an apparent attempt by neuronsto deal with the oxidative challenge.One theory of how oxidative damage is generated in neuriticplaques focuses on the oxidative properties of ABR Studies with highlypurified synthetic A²P have shown that it is capable of reacting withoxygen dissolved in water (the form of oxygen present in extracellularfluids, where A²P is found), and that dissolved oxygen is necessary togenerate the ²-amyloid sheets that are a characteristic feature of neu-184 THE AGING BRAINritic plaques.The oxygen radicals generated by the interaction of A²Pwith molecular oxygen could then damage surrounding neurons, hastening their death.In fact, damage very similar to that caused by A²Pin cultures of nerve cells can be reproduced by adding oxidants such ashydrogen peroxide to the cultures, and the damage by A²P is at leastpartially reversible by antioxidants.Another source of oxidative damage is thought to be phagocytes attracted to the neuritic plaques by thelarge numbers of dead and dying cells; oxygen radicals spilled duringthe "cleaning-up" process engaged in by phagocytes surrounding andinfiltrating neuritic plaques could further exacerbate the damage.Thedamage caused by A²P-generated oxygen radicals would be additivewith any oxidative damage generated within nerve cells themselves asa concomitant of aging.Thus damage triggered by A²P would essentially accelerate a normal endogenous process, consistent with our viewof what Alzheimer's disease represents.All forms of Alzheimer's disease described so far involve in one way or another a perturbation inthe processing of APP to A²P.That oxidative damage might contribute to neuronal degradationhas been supported by numerous studies in experimental animals.Adetailed study in gerbils showed that as these animals age, there is anincrease in the levels of oxidized proteins in their brain tissues.Thisage-related increase could be prevented, and even reversed, by treatment of the animals over time with a potent antioxidant called PBN.That this reversal had functional significance was demonstrated in aso-called radial maze test, which analyzes spatial and temporal learning and memory.Young gerbils made an average of four mistakes inworking their way through this maze problem.Old gerbils made eightmistakes on average in the same test.But old gerbils that had beenmaintained on PBN not only had less oxidative brain damage, but theymade only four mistakes in the maze test.That the effect of the PBNwas truly on an age-dependent change in the older animals was shownby the fact that the number of mistakes made by young gerbils did notchange as a result of PBN treatment.An important animal model for studying senescence, developed inJapan, is the senescence-accelerated mouse.These mice develop conditions that are in many ways reminiscent of the human progeriasdescribed in Chapter 5, in that they display in an accelerated fashionmany of the hallmarks of the normal aging process.Various substrains185 A MEANS TO AN ENDof this mouse have been developed, each displaying in isolation one ora few of the many deficits seen in the original strain.One of these sub-strains, called P8, ages normally in most of its body, but goes throughage-dependent changes in the brain and in mental capacity in a greatlyaccelerated fashion.Functionally, P8 mice are similar to Alzheimer'spatients, in that they undergo premature and aggressive degenerationof neurons, particularly pyramidal neurons in associative regions of thebrain.This process is accompanied by the retraction and degradationof dendrites, a process usually seen only in old age.As in the normallyaging brain, neuronal death results in a shrinkage of the brain tissuesand in a loss of cognitive functions, especially learning and memory.Another substrain, P10, also shows a more Alzheimer's-like pathol-ogy, with premature accumulation of amyloid-filled neuritic plaques inthe brain.A possible involvement of oxidative damage in this process wasrecently examined by the same laboratory that carried out the gerbilstudies just described.They found an accelerated increase in the accu-mulation of oxidatively damaged proteins, as well as membrane lipids,in the neurons of P8 mice.They also examined the effect of PBN onthe development of disease in these mice.They found that adminis-tration of PBN over time reduced the accumulation of oxidative dam-age to both proteins and membranes in brain tissue.Experiments inother laboratories showed that antioxidants were able both to increasethe lifespan of P8 mice and to significantly improve cognitive function.If brain aging can be accelerated by oxidative damage, and thisacceleration retarded by antioxidants, then it might be expected thatcaloric restriction, which is presumed to operate at least in partthrough a system-wide reduction in the generation of oxidative dam-age, should have a positive impact on brain damage and cognitivefunction as animals age.This has proved to be the case in a recent studyin mice.As a measure of oxidation in aging brain cells, researchersagain looked at the intracellular accumulation of oxidized proteins, thistime in normal mice.Oxidatively damaged proteins were found toincrease from eight through twenty-seven months of age, particularlyin the hippocampus and other associative regions of the brain, in fullyfed mice.Animals placed on a calorically restricted diet at weaningshowed reductions of up to 50 percent in the amounts of intracellularoxidized protein; significant reductions were seen even when caloric186 THE AGING BRAINrestriction was started in adult mice.These researchers also comparedthe ability of fully fed and calorically restricted mice to learn andremember tasks as a function of age.In a shock-avoidance learningtest, calorically restricted mice required only about half as many trialsto learn how to avoid a mildly discomfiting shock as did age-matchedfully fed controls.These results agree with earlier findings that calor-ically restricted animals show superior neurological function comparedwith fully fed animals.In the end, the aging of the cells that make up the human brain turnsout to be no different from the processes at work to guarantee thegradual post-reproductive decline of all the body's systems [ Pobierz caÅ‚ość w formacie PDF ]
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.As in other cells, the major targets of oxidative damage in thebrain are proteins, DNA, and the lipids found in cellular membranes.Researchers have noted for a dozen years or more an age-relatedincrease in oxidatively damaged molecules, particularly lipids, in thehuman brain.Oxidative damage to DNA (especially mitochondrialDNA) is up to three-fold higher in brain samples from Alzheimer'spatients and is substantially increased in very old patients without clinically detectable disease.There is also an age-dependent increase inendogenous antioxidant enzymes, in an apparent attempt by neuronsto deal with the oxidative challenge.One theory of how oxidative damage is generated in neuriticplaques focuses on the oxidative properties of ABR Studies with highlypurified synthetic A²P have shown that it is capable of reacting withoxygen dissolved in water (the form of oxygen present in extracellularfluids, where A²P is found), and that dissolved oxygen is necessary togenerate the ²-amyloid sheets that are a characteristic feature of neu-184 THE AGING BRAINritic plaques.The oxygen radicals generated by the interaction of A²Pwith molecular oxygen could then damage surrounding neurons, hastening their death.In fact, damage very similar to that caused by A²Pin cultures of nerve cells can be reproduced by adding oxidants such ashydrogen peroxide to the cultures, and the damage by A²P is at leastpartially reversible by antioxidants.Another source of oxidative damage is thought to be phagocytes attracted to the neuritic plaques by thelarge numbers of dead and dying cells; oxygen radicals spilled duringthe "cleaning-up" process engaged in by phagocytes surrounding andinfiltrating neuritic plaques could further exacerbate the damage.Thedamage caused by A²P-generated oxygen radicals would be additivewith any oxidative damage generated within nerve cells themselves asa concomitant of aging.Thus damage triggered by A²P would essentially accelerate a normal endogenous process, consistent with our viewof what Alzheimer's disease represents.All forms of Alzheimer's disease described so far involve in one way or another a perturbation inthe processing of APP to A²P.That oxidative damage might contribute to neuronal degradationhas been supported by numerous studies in experimental animals.Adetailed study in gerbils showed that as these animals age, there is anincrease in the levels of oxidized proteins in their brain tissues.Thisage-related increase could be prevented, and even reversed, by treatment of the animals over time with a potent antioxidant called PBN.That this reversal had functional significance was demonstrated in aso-called radial maze test, which analyzes spatial and temporal learning and memory.Young gerbils made an average of four mistakes inworking their way through this maze problem.Old gerbils made eightmistakes on average in the same test.But old gerbils that had beenmaintained on PBN not only had less oxidative brain damage, but theymade only four mistakes in the maze test.That the effect of the PBNwas truly on an age-dependent change in the older animals was shownby the fact that the number of mistakes made by young gerbils did notchange as a result of PBN treatment.An important animal model for studying senescence, developed inJapan, is the senescence-accelerated mouse.These mice develop conditions that are in many ways reminiscent of the human progeriasdescribed in Chapter 5, in that they display in an accelerated fashionmany of the hallmarks of the normal aging process.Various substrains185 A MEANS TO AN ENDof this mouse have been developed, each displaying in isolation one ora few of the many deficits seen in the original strain.One of these sub-strains, called P8, ages normally in most of its body, but goes throughage-dependent changes in the brain and in mental capacity in a greatlyaccelerated fashion.Functionally, P8 mice are similar to Alzheimer'spatients, in that they undergo premature and aggressive degenerationof neurons, particularly pyramidal neurons in associative regions of thebrain.This process is accompanied by the retraction and degradationof dendrites, a process usually seen only in old age.As in the normallyaging brain, neuronal death results in a shrinkage of the brain tissuesand in a loss of cognitive functions, especially learning and memory.Another substrain, P10, also shows a more Alzheimer's-like pathol-ogy, with premature accumulation of amyloid-filled neuritic plaques inthe brain.A possible involvement of oxidative damage in this process wasrecently examined by the same laboratory that carried out the gerbilstudies just described.They found an accelerated increase in the accu-mulation of oxidatively damaged proteins, as well as membrane lipids,in the neurons of P8 mice.They also examined the effect of PBN onthe development of disease in these mice.They found that adminis-tration of PBN over time reduced the accumulation of oxidative dam-age to both proteins and membranes in brain tissue.Experiments inother laboratories showed that antioxidants were able both to increasethe lifespan of P8 mice and to significantly improve cognitive function.If brain aging can be accelerated by oxidative damage, and thisacceleration retarded by antioxidants, then it might be expected thatcaloric restriction, which is presumed to operate at least in partthrough a system-wide reduction in the generation of oxidative dam-age, should have a positive impact on brain damage and cognitivefunction as animals age.This has proved to be the case in a recent studyin mice.As a measure of oxidation in aging brain cells, researchersagain looked at the intracellular accumulation of oxidized proteins, thistime in normal mice.Oxidatively damaged proteins were found toincrease from eight through twenty-seven months of age, particularlyin the hippocampus and other associative regions of the brain, in fullyfed mice.Animals placed on a calorically restricted diet at weaningshowed reductions of up to 50 percent in the amounts of intracellularoxidized protein; significant reductions were seen even when caloric186 THE AGING BRAINrestriction was started in adult mice.These researchers also comparedthe ability of fully fed and calorically restricted mice to learn andremember tasks as a function of age.In a shock-avoidance learningtest, calorically restricted mice required only about half as many trialsto learn how to avoid a mildly discomfiting shock as did age-matchedfully fed controls.These results agree with earlier findings that calor-ically restricted animals show superior neurological function comparedwith fully fed animals.In the end, the aging of the cells that make up the human brain turnsout to be no different from the processes at work to guarantee thegradual post-reproductive decline of all the body's systems [ Pobierz caÅ‚ość w formacie PDF ]