Apoptosis and Alzheimer's Disease

It is argued that neurons in AD have mounted an effective defense to apoptotic death rather than that they are succumbing, and that neuronal cell death in AD occurs over a lengthy period suggests distinct mechanisms from the classical apoptotic process.

Abstract

An article by Marcia Barinaga (Special Section, News, 28 Aug., p. [1303][1]) in the recent issue devoted to apoptosis presents the case for apoptotic neuronal death in Alzheimer's disease (AD) based on culture studies and histological analyses. We strongly disagree that this evidence supports widespread apoptosis in AD. Apoptosis requires only 16 to 24 hours for completion and, therefore, in a chronic disease like AD with an average duration of almost 10 years, less than one in about 4000 cells should be undergoing apoptosis at any given time (that is, observation of apoptotic events should be rare) ([1][2]). Indeed, if all the neurons reported with DNA cleavage were undergoing apoptosis, the brain would rapidly be stripped of neurons. This is certainly not the case in AD. ![Figure][3] Do neurons in a brain from an Alzheimer's patient (dotlike staining pattern) indicate cells undergoing apoptosis?CREDIT: CARL COTMAN, JOSEPH SU, AND CHRISTIAN PIKE Perhaps the greatest source of misunderstanding is that the criteria used for apoptosis have relied primarily on DNA fragmentation, where even the laddering pattern of fragmentation is not apoptosis-specific because histones protect DNA from a variety of insults, including those of necrosis and oxidative damage. When the more rigorous standard of nuclear condensation is examined, few neurons show apoptosis in AD. In fact, that we can observe neurons displaying many of the features of apoptosis argues that neurons in AD have mounted an effective defense to apoptotic death rather than that they are succumbing. The presence of a wide array of apoptotic markers is more likely indicative of an avoidance of apoptosis rather than actual completion of apoptosis. That neuronal cell death in AD occurs over a lengthy period suggests distinct mechanisms from the classical apoptotic process. 1. [↵][4]1. G. Perry, 2. A. Nunomura, 3. M. A. Smith , Nature Med. 4, 897 (1998). [OpenUrl][5][CrossRef][6][PubMed][7][Web of Science][8] [1]: /lookup/doi/10.1126/science.281.5381.1303 [2]: #ref-1 [3]: pending:yes [4]: #xref-ref-1-1 View reference 1 in text [5]: {openurl}?query=rft.jtitle%253DNature%2Bmedicine%26rft.stitle%253DNat%2BMed%26rft.aulast%253DPerry%26rft.auinit1%253DG.%26rft.volume%253D4%26rft.issue%253D8%26rft.spage%253D897%26rft.epage%253D898%26rft.atitle%253DA%2Bsuicide%2Bnote%2Bfrom%2BAlzheimer%2Bdisease%2Bneurons%253F%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnm0898-897%26rft_id%253Dinfo%253Apmid%252F9701239%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [6]: /lookup/external-ref?access_num=10.1038/nm0898-897&link_type=DOI [7]: /lookup/external-ref?access_num=9701239&link_type=MED&atom=%2Fsci%2F282%2F5392%2F1265.8.atom [8]: /lookup/external-ref?access_num=000075107400030&link_type=ISI