There is good cholesterol and there is bad cholesterol. Should we be thinking about amyloid-β (Aβ) in the same way? While it is well established that the slightly longer Aβ42—the “bad” Aβ—is more amyloidogenic, could Aβ40 be anti-amyloidogenic? In the January 17 Journal of Neuroscience, Eileen McGowan and colleagues at the Mayo Clinic College of Medicine, Jacksonville, Florida, report that bumping up levels of Aβ40 in transgenic mice dramatically reduces the deposition of amyloid plaques. The finding suggests that the smaller of the two peptides can prevent Aβ aggregation.

The finding also speaks to a Forum Discussion held last year on gain or loss of function in mutant presenilin. Many presenilin mutations that cause early onset familial AD increase the Aβ42/Aβ40 ratio, raising the fundamental question of what has greater pathological relevance, more Aβ42 or less Aβ40? As Peter Davies, Albert Einstein College of Medicine, New York, wrote in this discussion, “Importantly, one must measure separately how each of the ratio’s components change to know what is driving the change in the ratio.” McGowan and colleagues approached this challenge genetically. They altered the levels of Aβ40 not by tweaking γ-secretase activity, but by independently expressing the peptide from an entirely different construct. Indeed, the paper delivers data on an experiment Matthew Hass and Bruce Yankner suggested during the discussion. McGowan’s new finding also ties into a second, ongoing Forum discussion on the broader question of presenilin function in neurodegenerative disease.

First author Jungsu Kim and colleagues crossed their previously described BRI-Aβ40 mice (see ARF related news story) with APP (Tg2576) and with BRI-Aβ42A transgenic mice, which both produce substantial amounts of Aβ42. Because cleavage of the BRI-chimera by furin proteases releases Aβ in a γ-secretase-independent manner, Kim was able to adjust the Aβ40 level without changing the Aβ42 levels. The authors found that in both Tg2576/BRI-Aβ40 and BRI-Aβ42A/BRI-Aβ40 mice the plaque load in the brain was substantially lower than in the single transgenic controls. Amyloid plaque load was reduced by about 80 percent in 20-month-old Tg2576/BRI-Aβ40 mice and by about 75 percent in 8-month BRI-Aβ40/BRI-Aβ42A animals. These reductions were despite increases in total Aβ (Aβ40 and Aβ42) of between two- and 10-fold, respectively, in the Tg2576 and BRI/BRI strains.

The results suggest that Aβ40 prevents amyloid aggregation. In-vitro experiments on Aβ42 aggregation in the presence or absence of Aβ40 support this idea—the authors found that an Aβ40/Aβ2 ratio of 2:1 was sufficient to prevent aggregation. However, there are reasons to question whether Aβ 40 can truly be protective. First, Aβ40 has been linked numerous times to the vascular Aβ deposits found in cerebral amyloid angiopathy (see ARF related news story), so while it may help in the parenchyma, it could be detrimental to the vasculature. Kim and colleagues found that the BRI-Aβ40 addition decreased CAA severity in the Tg2576 mice by about 60 percent, suggesting that Aβ40 may be good for the vasculature, too. Second, considerable evidence points to soluble oligomeric Aβ species as being the most toxic (see ARF related news story), and it is unclear if Aβ40 would have any effect on such oligomers. This question requires additional investigation, the authors note.

In the meantime, there is other evidence to support the “good” Aβ theory, notably the two papers that spurred last year’s Forum Discussion, one from Bart De Strooper’s lab at K.U. Leuven, and the other from Christine Van Broeckhoven and colleagues at the University of Antwerp, both in Belgium. In the former, Mostafa Bentahir and colleagues reported that some presenilin FAD mutations reduce production of Aβ40, rather than increase Aβ42, while in the second, Samir Kumar-Singh and colleagues report that the age of onset of familial AD correlates with increased Aβ42 and decreased Aβ40. The finding echoes another instance in neurodegeneration where β-synuclein somehow counteracts aggregation of its near-twin, α-synuclein (e.g., Hashimoto et al., 2001). Data that upping Aβ40 can improve learning and memory in APP mouse models would be icing on the “good Aβ” cake.—Tom Fagan

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  1. This paper seems to skirt many years of autopsy studies finding that the senile plaques have marginal statistical capacity to distinguish normal from AD patients, such as Davis et al., 1999. Also in 1999, Lue et al. concluded that soluble Aβ posed the greatest toxicity, and that Aβ40 was particularly toxic to synapses. But the issue of deposits seems to pale in the face of new MRI studies concerning gross atrophy of the brain, that is, gross death of brain cells and connectivity. See, for example Stroub and colleagues’ 2006 article on MCI. Is the senile plaque issue becoming a tempest in the teapot?

    References:

    . Alzheimer neuropathologic alterations in aged cognitively normal subjects. J Neuropathol Exp Neurol. 1999 Apr;58(4):376-88. PubMed.

    . Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am J Pathol. 1999 Sep;155(3):853-62. PubMed.

    . Hippocampal disconnection contributes to memory dysfunction in individuals at risk for Alzheimer's disease. Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):10041-5. PubMed.

References

Webinar Citations

  1. Gain or Loss of Function—Time to Shake up Assumptions on γ-Secretase in Alzheimer Disease?
  2. Presenilin Loss of Function—Plan B for AD?

News Citations

  1. Aβ and AβPP—Separating the Wheat from the Chaff
  2. Amyloid-β—On or off the Wall?
  3. Aβ Star is Born? Memory Loss in APP Mice Blamed on Oligomer

Paper Citations

  1. . Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem. 2006 Feb;96(3):732-42. PubMed.
  2. . Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40. Hum Mutat. 2006 Jul;27(7):686-95. PubMed.
  3. . beta-Synuclein inhibits alpha-synuclein aggregation: a possible role as an anti-parkinsonian factor. Neuron. 2001 Oct 25;32(2):213-23. PubMed.

Further Reading

Primary Papers

  1. . Abeta40 inhibits amyloid deposition in vivo. J Neurosci. 2007 Jan 17;27(3):627-33. PubMed.