Amyloid plaques appear to be the primary cause of Alzheimer’s disease, but what causes the buildup of beta-amyloid? Amyloid precursor protein (APP) is cleaved by two enzymes—beta-secretase and presenilin—to form extracellular beta-amyloid that builds up. Some neurons take up the beta-amyloid and then form neurofibrillary tangles in response. Another enzyme, apolipoprotein E (ApoE), breaks down beta-amyloid (Bu, 2009). Mutations in each of the genes that produce these proteins have been associated with Alzheimer’s disease, with presenilin mutations by far the most common (Bertram and Tanzi, 2008). Transgenic mice that produce extra beta-amyloid show progressive memory deficits as they age (Lesné et al., 2006).
This scenario, depicted in Figure 1, suggests several treatment strategies. One strategy is to inject antibodies that will bind beta-amyloid and slow the formation of plaques, but that approach does not seem to be effective (Holmes et al., 2008). Another strategy is to develop drugs that interfere with beta-secretase and/or presenilin activity (Singer et al., 2005), reducing beta-amyloid production. In the meantime, and in keeping with the repeated theme of this chapter—that genes and experience interact—there is good evidence that physical activity (LaFerla et al., 2007), mental activity (Willis et al., 2006), and adequate sleep (Kang et al., 2009) can postpone the appearance of Alzheimer’s disease.
Bertram, L., and Tanzi, R. E. (2008). Thirty years of Alzheimer’s disease genetics: The implications of systematic meta-analyses. Nature Reviews. Neuroscience 9: 768–778.
Bu, G. (2009). Apolipoprotein E and its receptors in Alzheimer’s disease: Pathways, pathogenesis and therapy. Nature Reviews. Neuroscience 10: 333–344.
Holmes, C., Boche, D., Wilkinson, D., Yadegarfar, G., et al. (2008). Long-term effects of Abeta42 immunisation in Alzheimer’s disease: Follow-up of a randomized, placebo-controlled phase I trial. Lancet 372: 216–223.
Kang, J.-E., Lim, M. M., Bateman, R. J., Lee, J. J., et al. (2009). Amyloid-β dynamics are regulated by orexin and the sleep-wake cycle. Science 326: 1005–1007.
LaFerla, F. M., Green, K. N., and Oddo, S. (2007). Intracellular amyloid-β in Alzheimer’s disease. (2007). Nature Reviews. Neuroscience 8: 499–508.
Lesné, S., Koh, M. T., Kotilinek, L., Kayed, R., et al. (2006). A specific amyloid-β protein assembly in the brain impairs memory. Nature 440: 352–357.
Singer, O., Marr, R. A., Rockenstein, E., Crews, L., et al. (2005). Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model. Nature Neuroscience 8: 1343–1349.
Willis, S. L., Tennstedt, S. L., Marsiske, M., Ball, K., et al. (2006). Long-term effects of cognitive training on everyday functional outcomes in older adults. JAMA 296: 2805–2814.