Hippocampal Neurodegeneration in Aging

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Abstract
Recent articles (I. Wickelgren, Horizons in Aging, News, 5 July, p. 48; Research News, [1 Mar., p. 1229][1]) have addressed the question of hippocampal cell death in normal aging. Although newly developed stereological methods have demonstrated cell loss in some regions of aged mammalian brain, including areas associated with the hippocampus in humans, these methods have not detected a loss of principal neurons in the CA1-CA3 regions of hippocampus in human, monkey, and rodent brain ([1][2], [2][3], [3][4]). These findings contrast with earlier reports of age-related cell loss in those regions of hippocampus based on decreases in neuron density ([4][5], [5][6], [6][7]). Because the new stereological techniques are not confounded by many factors, such as changes in brain volume or size and orientation of cells within the structure, the discrepancy could be due to methodology alone. A letter (P. W. Landfield et al ., [31 May, p. 1249][8]) and commentary by Wickelgren and elsewhere ([7][9]) touch on other issues that might account for the discrepancy, apart from differences in neuroanatomical methods. The presentation of this debate has given the impression of different perspectives and disagreement where little may actually exist. In subsequent communications among the various investigators, we find broad agreement on a number of issues. Although differences in sampling procedures and counting methods cannot be excluded as contributing factors, it is unlikely that age-related changes in the volume of the hippocampus or strain differences can account for the discrepancies. Increases in the volume of the rodent hippocampus are observed into adulthood ([8][10]), but the magnitude of this change is small relative to the decreases in cell density (30 to 40%) reported in comparisons of aged rats with young rats in the 6- to 8-month range ([4][5], [6][7]). Moreover, stereological studies have now reported no hippocampal neuron loss in the Long-Evans rat strain used in a number of the earlier studies reporting cell density measures ([3][4]). In addition, a behavioral characterization for hippocampal-dependent cognitive decline in that study ([3][4]) demonstrated no cell loss in aged rats with cognitive impairment. Similar findings have been reported for Wistar rats ([2][3]). On the basis of these results, we are in substantial agreement that neuron loss of the type reported earlier is not required for age-associated cognitive impairment. It is also possible that aging may not lead to neurodegeneration in the hippocampus, but rather may increase vulnerability to other factors that do cause cell death ([9][11]); these factors may have differed across study populations. We all agree that the effects of aging on neuronal function in the hippocampus that precede neuron loss are likely to play an important role in cognitive decline and may also render neurons more vulnerable to degeneration precipitated by other causes. 1. 1.[↵][12] 1. M. J. West , Neurobiol. Aging 14, 287 (1993); [OpenUrl][13][CrossRef][14][PubMed][15][Web of Science][16] 1. M. West, 2. D. G. Amaral, 3. P. R., Rapp , Soc. Neurosci. Abstr. 19, 599 (1993). [OpenUrl][17][CrossRef][18][PubMed][19][Web of Science][20] 2. 2.[↵][21] 1. T. Rasmussen, 2. T. Schliemann, 3. J. C. Sorensen, 4. J. Zimmer, 5. M. J. West , Neurobiol. Aging 17, 143 (1996). [OpenUrl][22][Abstract/FREE Full Text][23] 3. 3.[↵][24] 1. P. R. Rapp, 2. M. Gallagher , Proc. Natl. Acad. Sci. U.S.A. 93, 9926 (1996). [OpenUrl][25][Abstract/FREE Full Text][26] 4. 4.[↵][27] 1. P. W. Landfield, 2. R. K. Baskin, 3. T. A. Pitler , Science 214, 581 (1981). [OpenUrl][28] 5. 5.[↵][29] 1. M. J. Meaney, 2. D. H. Aitken, 3. C. van Berkel, 4. S. Bhatnagar, 5. R. M. Sapolsky , ibid. 239, 766 (1988). [OpenUrl][30][Abstract][31] 6. 6.[↵][32] 1. A. M. Issa, 2. W. Rowe, 3. S. Gauthier, 4. M. J. Meaney , J. Neurosci. 10, 3247 (1990). [OpenUrl][33][CrossRef][34] 7. 7.[↵][35] 1. J. Travis , Sci. News 150, 150 (1996). [OpenUrl][36][CrossRef][37][PubMed][38][Web of Science][39] 8. 8.[↵][40] 1. P. D. Coleman, 2. D. C. Flood, 3. M. West , J. Comp. Neurol. 266, 300 (1987). 9. 9.[↵][41] For example, exposure to pathogens, susceptibility to disease, dietary conditions, exposure to stress, and so forth, might interact with age-related cellular changes to cause neurodegeneration (4, 10). 10. 10. 1. S. R. Bodnoff 2. et al. , J. Neurosci. 15, 61 (1995) Sapolsky, R. M., Krey, L. C., McEwen, B. S., ibid. 5 , 1221 (1985); Kerr, D. S., Campbell, L. W., Applegate, M. D., Brodish, A., Landfield, P. W., ibid. 11 , 1316 (1991). 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