Mouse models of Alzheimer disease based on overexpression of Aβ precursor protein (AβPP) may be run-of-the-mill these days, but how do we get to the kernel of the pathology? Is it just Aβ, or do the AβPP intracellular domains and the soluble components shed by α- and β-secretases play a role, too? In tomorrow’s Neuron, researchers report the use of a new mouse model that separates some of the wheat from the chaff. The model demonstrates that while Aβ alone is sufficient for amyloid deposits, it is specifically Aβ1-42 that generates parenchymal and vascular amyloids—Aβ1-40 alone fails in this regard. However, despite the presence of these deposits, the mice, even at 2 years old, show no overt pathology.

The new model, the result of a collaboration among Todd Golde’s lab at the Mayo Clinic, Jacksonville, Florida; Rong Wang’s lab at Mount Sinai School of Medicine, New York; and John Hardy’s at the National Institute on Aging, Bethesda, Maryland, uses a protein chimera to drive expression of either human Aβ42 or Aβ40 in transgenic mice in the absence of human AβPP. First author Eileen McGowan and colleagues fused the Aβ peptides to the BRI protein, which, incidentally, can lead to familial British and Danish dementias when mutated (see ARF related news story). BRI, like AβPP, is a transmembrane protein, but unlike AβPP, it is cleaved by a furin protease—not γ-secretase—resulting in release of a small peptide on the lumen side of the membrane. Taking advantage of this cleavage, McGowan and colleagues fused either Aβ42 or Aβ40 to BRI just downstream of the furin site so that the peptides would be released from the chimeric protein into the extracellular space. In this fashion, the authors generated and characterized three lines of transgenic mice, two expressing BRI-Aβ42 and one expressing BRI-Aβ40. All animals expressed the chimera in the brain (driven by the prion promoter).

Though the BRI-Aβ40 mice produced about threefold more Aβ than either of the BRI-Aβ42 lines, MGowan and colleagues failed to detect any detergent insoluble Aβ in brain extracts from these animals and failed to detect any amyloid-like pathology using antibodies or amyloid-binding dyes such as thioflavin S. In contrast, the authors found considerable amounts of insoluble Aβ in the BRI-Aβ42 animals as young as 3 to 6 months old. In fact, the amount of Aβ being deposited in these animals is about two- to threefold more than found in age-matched Tg2576 mice, which express human AβPP carrying the Swedish mutations that drive overproduction of Aβ and ultimately cause a rare, inherited form of AD.

When McGowan and colleagues examined the amyloid pathology in the BRI-Aβ42 animals, they found extensive parenchymal deposits of Aβ. These appeared earliest in the cerebellum and spread to the hippocampus and forebrain by the time the animals reached 6 to 12 months of age. The authors used electron microscopy to reveal that these animals had extensive cerebral amyloid angiopathy, as well.

The study suggests that Aβ42 is the “bad seed,” as John Fryer and David Holtzman call it in a related Neuron Preview. This view is supported by many earlier studies showing that the longer Aβ peptide is more fibrillogenic (see, e.g., ARF related news story) and by crosses made between BRI-Aβ42 and Tg2576 mice. McGowan and colleagues found that animals expressing both proteins showed accelerated deposition of Aβ over and above what would be expected from a simple additive effect. However, the BRI-Aβ42 mice show no signs of neuronal loss or neurofibrillary pathology, leading the authors to caution that “although our studies show that Aβ42 is necessary to initiate aggregation of Aβ, they do not demonstrate that aggregation of Aβ42, by itself, is sufficient to induce all the hallmark pathologies of AD in mice, including neurofibrillary tangles and cell loss.”

So where does this leave Aβ40? Recently, it was shown that shifting the balance of Aβ production toward the smaller peptide might favor production of vascular deposits (see ARF related news story), while last year, Koichi Iijima and colleagues showed that though Aβ42 alone is sufficient to cause amyloid buildup and neurodegeneration in fruit flies, production of Aβ40 alone was sufficient to cause learning deficits (see ARF related news story). So we shouldn’t be too quick to rule out a pathological role for Aβ40 just yet, and indeed the authors point out that there could be more complex phenomena at play that require the interaction of Aβ42 and Aβ40. Indeed, Fryer and Holtzman suggest that “crossing the Aβ40 and Aβ42 mice would be hypothesized to result in a higher ratio of CAA to parenchymal plaques.”

The availability of these new mouse models for such crossing experiments should help researchers unravel layers of complexity among many of the proteins and peptides considered central to Alzheimer pathology.—Tom Fagan


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News Citations

  1. BRIdging Alzheimer Disease and British/Danish Dementias
  2. Amyloid Formation—One Amino Acid Can Make a Difference
  3. Study Poses Cautionary Question: Will Knocking Down Aβ42 Promote Amyloid Angiopathy?
  4. What the Fly Forgot—Aβ Expression in <i>Drosophila</i>

Further Reading

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Primary Papers

  1. . Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron. 2005 Jul 21;47(2):191-199. PubMed.
  2. . The bad seed in Alzheimer's disease. Neuron. 2005 Jul 21;47(2):167-8. PubMed.