. Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat Neurosci. 2004 Sep;7(9):954-60. PubMed.

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  1. The work provides insights into the significance of conformational versus metabolic properties in the occurrence of pathological phenotypes, i.e., amyloid angiopathy versus parenchymal amyloidosis.

  2. The exciting data presented in the Herzig et al. paper provide key insights into some of the mechanistic differences in the deposition of the Aβ peptide in brain parenchyma vs. cerebrovasculature. Hereditary cerebral hemorrhage with amyloidosis-Dutch type is an autosomal dominant form of cerebral amyloid angiopathy (CAA) resulting from a mutation within the Aβ coding region at amino acid 22. Expression of the human APP-Dutch transgene under control of the neuron-specific Thy1.2 promoter in mice results in almost exclusive deposition of the Aβ peptide in the cerebrovasculature, leading to smooth muscle cell degeneration, hemorrhage, and inflammation. Thus, this model recapitulates many key aspects of the human disease. Expression of wild-type human APP transgene resulted in mostly parenchymal plaque deposition as has been seen with expression of many of the APP mutations that result in familial AD. They also show that APP-Dutch mice have a higher ratio of Aβ40:Aβ42 as compared to the wild-type human APP mice. Crossing the APP-Dutch mice to mice expressing a mutant presenilin-1 gene (a mutation known to favor generation of Aβ42) results in a striking redistribution of amyloid pathology from the cerebrovasculature to the parenchyma.

    Previous studies have suggested that a higher ratio of Aβ40:Aβ42 promotes the formation of CAA. To date, the data in this paper provide the best mechanistic evidence in vivo that the ratio of Aβ40:Aβ42 is a key determinant of whether Aβ deposits in brain parenchyma vs. the cerebrovasculature. These data also suggest that therapeutics that decrease the amount of Aβ42 in the brain may result in a reduction of parenchymal amyloid plaques at the expense of generating an increase in the amount of CAA by simply altering the ratio of Aβ40:Aβ42. Further studies of the effects of potential therapeutics in mouse models known to produce significant CAA vs. models known to have much less CAA will be necessary to sort out these possibilities.

    View all comments by John Fryer
  3. The beautiful series of papers by Jucker and colleagues begin to paint a picture of how cerebrovascular amyloid deposition (or CAA) might occur:

    1. Neuronally produced Aβ peptide appears to have the opportunity to deposit in the brain parenchyma as plaques, to reach the vessel wall and perivascular space, and deposit as CAA, or to be cleared without depositing.
    2. Various factors, including amount of Aβ, ratio of Aβ42:Aβ40, and pathogenic mutations within the Aβ sequence (among a host of factors involved in Aβ deposition and clearance) can predispose Aβ to deposit or be cleared.
    3. For extensive CAA to occur, these amyloidogenic factors need to happen in exquisitely fine balance. Too much "amyloidogenicity" causes Aβ to deposit primarily as plaques; too little, and it is cleared without depositing. The E693Q APP transgenic mouse described in this paper appears to hit the CAA "sweet spot" with almost exclusive vascular deposition; addition of mutant presenilin tips the balance squarely towards plaque deposition.

    Though clearly an oversimplification, it will be interesting to see if this model makes useful predictions as further data from transgenic mice emerge—and as they are translated into therapeutic approaches to human AD and CAA.

    View all comments by Steven Greenberg