. Characterizing the appearance and growth of amyloid plaques in APP/PS1 mice. J Neurosci. 2009 Aug 26;29(34):10706-14. PubMed.

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  1. This is an excellent study by Lee and colleagues employing serial multiphoton microscopy (MPM) to provide more clues to the process of plaque formation in the living brain of a well-established APP/PS1 transgenic mouse model of Alzheimer disease. Previous work by Hyman and colleagues had provided novel observations on the remarkably rapid appearance of plaques, and had also noted that once formed, there was little additional growth in the size of plaques. The focus of the current study is less the appearance and more the growth in the size of existing plaques over a time frame of a few weeks using a thinned skull window approach. They provide intriguing evidence for the importance of the type of window used to visualize plaques. Specifically, Lee and colleagues show that the open craniotomy with coverslip approach used in previous MPM studies in AD prevents the further growth of plaques and even augments regression of some plaques when compared with the thin-skull method. With the open- but not thin-skull method, there is marked cortical activation of inflammatory cells below the cranial window. These data also provide further evidence for the importance of inflammatory cells in modulating plaque pathology. One wonders whether the different methods have a differential effect on neuritic dystrophy. Interestingly, they also show that in younger but not older mice, γ-secretase inhibition retards formation and growth of new plaques while not effecting existing plaques. They suggest that these data support the importance of early rather than later therapeutic intervention in AD, although one can note that AD is also an anatomically progressive disease; less vulnerable brain regions may be at an earlier pathological stage (and therefore more amenable to treatment) than more vulnerable/pathologically advanced brain regions. Additionally, they show that the growth of plaques correlates with extracellular β amyloid levels in the interstitial fluid, a pool of β amyloid that many but not all view as the origin of plaques. Overall, this new MPM study is another important contribution in elucidating the development of β amyloid plaque pathology.

  2. Yan and colleagues add another piece to the plaque kinetics puzzle by showing, with on multiphoton in vivo microscopy, that amyloid plaques in a bigenic PSAPP mouse model appear and grow over a period of weeks before reaching a mature size. These data seem to be in apparent conflict with earlier work using the same technique on related mouse models (Meyer-Luehmann et al. 2008), where dense plaques were shown to reach their maximum size in about a day and thereafter maintain a status quo.

    The present study also goes forward to propose a reason for this discrepancy. Amyloid imaging through large open-skull cranial windows (as utilized solely by Meyer-Luehmann and colleagues) seems to activate gliosis, in contrast to thinned-skull windows of ≈1/10th the size, where calvaria are merely thinned down to allow in vivo microscopy without exposing the dura mater. This seems logical, as activation of gliosis has been shown in several studies to be an important factor in limiting plaque growth (Meyer-Luehmann et al. 2008; Bolmont et al., 2008; Yan et al., 2009). The stage of disease also seems to be important, as six-month-old mice with a higher proportion of smaller plaques demonstrate more accelerated plaque growth compared to 12-month-old animals (Yan et al., 2009).

    Secondly, however carefully studies attempt to show that the sizes of the plaques estimated by in vivo imaging are true representatives of the plaques occurring at that or a later stage of disease, it is always difficult to do so. Lastly, it’s important to keep in mind that the methoxy-X04 used in multiphoton in vivo microscopy only binds to fibrillar Aβ and not to the soluble/oligomeric forms of Aβ that most likely provide the initial nidus of plaque formation. For this reason I don’t believe that we have had the final word on the kinetics and dynamics of plaque formation. Important from a therapy point of view is that anti-Aβ treatments have to be started as early as possible in order to be efficacious—that everyone agrees on.

    References:

    . Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease. Nature. 2008 Feb 7;451(7179):720-4. PubMed.

    . Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance. J Neurosci. 2008 Apr 16;28(16):4283-92. PubMed.

  3. This is excellent work. The authors make elegantly the case that the procedures used to visualize amyloid plaques in vivo may strongly affect the generation and dynamics of the plaques. It is also of strong interest that interstitial Aβ peptide is such an important contributor to the plaque dynamics, as this is a rather small pool of total Aβ in the brain, and also highly dynamic and influenced by medication. Finally, the fact that 20-30 percent changes in that pool strongly affect the plaque formation should indeed raise hope that a therapeutic window exists for secretase inhibitors.

    I strongly recommend the paper.

  4. In my opinion, the discussion above misses one important fact: Brad Hyman's group published already in 2001 that plaques do not grow over time and that there is a restriction on plaque growth (Christie et al., 2001). In that study, more than 300 plaques were analyzed with two-photon microscopy over a time period of up to five months, and the investigators found the majority of plaques remained unchanged in size over time. Even more importantly, the data were observed using the thinned-skull method, i.e., the same method used by Yan et al., 2009. Therefore, thinned-skull versus open-skull preparation alone cannot account for the opposing result.

    References:

    . Growth arrest of individual senile plaques in a model of Alzheimer's disease observed by in vivo multiphoton microscopy. J Neurosci. 2001 Feb 1;21(3):858-64. PubMed.

  5. We appreciate the comments of Dr. Meyer-Luehmann. However, the absence of plaque growth reported in the Christie et al. (2001) paper is very consistent with the data reported in our recent paper (Yan et al, 2009). Although we observed marked plaque growth in six-month-old APP/PS1 mice (early in plaque pathogenesis), we saw little to no growth in 10-month-old APP/PS1 mice. Of note, the Christie et al. paper did not see plaque growth in 18-month-old (mean age) Tg2576 mice. Therefore, our observations in older animals who have more advanced pathology are in agreement with the Christie et al. paper.

    References:

    . Growth arrest of individual senile plaques in a model of Alzheimer's disease observed by in vivo multiphoton microscopy. J Neurosci. 2001 Feb 1;21(3):858-64. PubMed.

  6. This and other research demonstrates the deposition of Aβ in vivo in an animal model. Do we know that the “structures” that are shown being formed are also the same structures that are identified histo- or immunochemically postmortem?

    Thus, are we confident that what is observed is the full process that results in the structures that we identify classically as plaques postmortem?

    The alternative is that we are observing one part of a process. In some instances what is deposited may eventually be removed or transformed to something else and it is this “something else” which we identify postmortem as senile plaques.

    Are senile (neuritic) plaques simply deposits of Aβ, or are they more than this?