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Honolulu: Wake-Up Call—Aβ Clearance, Not Production, Awry in AD

Series - Alzheimer's Association International Conference on Alzheimer's Disease 2010:

If β amyloid is indeed an early driver of Alzheimer disease pathogenesis, AD patients presumably churn out the peptide too quickly, clear it too slowly, or both. These possibilities have remained speculative, though, without in-vivo human data on Aβ’s comings and goings in the central nervous system (CNS). Now, scientists have measured real-time Aβ turnover in the cerebrospinal fluid (CSF) of AD patients and age-matched controls in the same study. As reported at the International Conference on Alzheimer’s Disease (ICAD) held 10-15 July in Honolulu, the AD patients kept pace with control subjects in generating Aβ, but didn’t get rid of it fast enough. Meanwhile, emerging evidence has highlighted an intriguing connection among Aβ, dementia, and sleep as a hypothesized nightly period of Aβ reduction, and several other ICAD studies seem to bear this out.

Several years ago, Randall Bateman, David Holtzman, and coworkers at Washington University School of Medicine, St. Louis, Missouri, developed a method using in-vivo labeling of proteins to quantify production and clearance of Aβ in people. The scientists collected CSF samples from each subject every hour for 36 hours, immunoprecipitated out the Aβ, and used liquid chromatography and mass spectrometry to measure amounts of freshly made Aβ relative to the person’s total CNS Aβ pool. Using this approach to quantify Aβ dynamics in healthy volunteers, the St. Louis team found that the peptide gets turned over at a steady clip, with 7 to 8 percent of the CNS Aβ pool made and cleared every hour (Bateman et al., 2006 and ARF related news story). More recently, Bateman and colleagues applied the technique to determine that a single dose of a candidate AD drug could curb Aβ production 50 to 90 percent over 12 hours (Bateman et al., 2009 and ARF related news story).

At ICAD, Bateman presented preliminary data from a study in which he measured Aβ production and clearance rates in 12 mild AD patients (CDR 0.5 or 1), comparing them with 12 age-matched healthy controls. Aβ production rates (Aβ42 and Aβ40) were essentially the same for both groups, hovering just under 7 percent per hour. Aβ42 and Aβ40 clearance rates in healthy volunteers fell just above 7 percent per hour, consistent with measurements from prior publications using the in vivo labeling technique. However, the AD patients cleared Aβ42 about 30 percent more slowly, and their Aβ40 clearance was down 25 percent, relative to controls.

The data suggest that in AD, “the primary processing impairment is one of clearance,” Bateman said. Another takeaway is “the magnitude of the change—30 percent,” he added, noting that the field has long wrestled with how much one needs to modulate Aβ production or clearance to make a difference. On a broader level, the new findings should guide future mechanistic studies. Identifying aging-related changes that stymie Aβ clearance would help “get at how we might prevent or mitigate effects of those changes to delay amyloidosis,” Bateman told ARF.

A recent study by Holtzman and colleagues suggests that sleep may have something to do with CNS Aβ levels. Using microdialysis to track extracellular Aβ in the brains of living mice, the scientists found that Aβ levels fall during sleep, and that chronic sleep deprivation drives up plaque formation in Tg2576 AD transgenic mice (Kang et al., 2009 and ARF related news story).

A poster presented at ICAD suggests this could also hold true in people. First author Ricardo Osorio, Centro Alzheimer de la Fundacion Reina Sofia, Madrid, Spain, and colleagues led by senior investigator Blas Frangione, New York University, analyzed 86 cognitively normal adults and found that those reporting poor sleep quality had reduced CSF Aβ42 or Aβ42/Aβ40 (biomarkers for brain amyloid burden) relative to the sound sleepers. In addition, a study by Kristine Yaffe of the University of California, San Francisco, suggests that dementia-free older women with sleep-disordered breathing were more likely to develop mild cognitive impairment or dementia in five years compared to those without the sleep disorder. This backs large epidemiological studies suggesting that sleep complaints drive up a person’s risk of developing AD at follow-up (Lobo et al., 2008).—Esther Landhuis.

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References

News Citations

  1. CSF Aβ—New Approach Shows Rapid Flux, May Help Evaluate Therapeutics
  2. Studies Reveal New Hope, Old Problems With AD Biomarkers
  3. Sleep Deprivation Taxes Neurons, Racks Up Brain Aβ?

Paper Citations

  1. Bateman RJ, Munsell LY, Morris JC, Swarm R, Yarasheski KE, Holtzman DM. Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med. 2006 Jul;12(7):856-61. PubMed.
  2. Bateman RJ, Siemers ER, Mawuenyega KG, Wen G, Browning KR, Sigurdson WC, Yarasheski KE, Friedrich SW, Demattos RB, May PC, Paul SM, Holtzman DM. A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system. Ann Neurol. 2009 Jul;66(1):48-54. PubMed.
  3. Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science. 2009 Nov 13;326(5955):1005-7. PubMed.
  4. Lobo A, López-Antón R, de-la-Cámara C, Quintanilla MA, Campayo A, Saz P, . Non-cognitive psychopathological symptoms associated with incident mild cognitive impairment and dementia, Alzheimer's type. Neurotox Res. 2008 Oct;14(2-3):263-72. PubMed.

Other Citations

  1. Tg2576 AD transgenic mice

Further Reading

Papers

  1. Bateman RJ, Siemers ER, Mawuenyega KG, Wen G, Browning KR, Sigurdson WC, Yarasheski KE, Friedrich SW, Demattos RB, May PC, Paul SM, Holtzman DM. A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system. Ann Neurol. 2009 Jul;66(1):48-54. PubMed.
  2. Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science. 2009 Nov 13;326(5955):1005-7. PubMed.
  3. Bateman RJ, Munsell LY, Morris JC, Swarm R, Yarasheski KE, Holtzman DM. Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med. 2006 Jul;12(7):856-61. PubMed.

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