. The Cellular Phase of Alzheimer's Disease. Cell. 2016 Feb 11;164(4):603-15. PubMed.


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  1. De Strooper and Karran’s thoughtful review takes us past the initiating events in AD, to think about the entirety of the pathogenesis. With all the new genetic risk factors we have discovered, this is an entirely appropriate development. We have been thinking of AD as a neuronal disease, when these new genetic risk loci, and indeed an examination of the pathology, shows it is a tissue disease. This review is the first attempt to fully incorporate these new insights into the amyloidogenic framework.

  2. Left unexplored in this otherwise inclusive analysis of the pathogenesis of AD is any discussion of the factors that initiate the various pathogenic processes that precede and lead to the accumulations of “toxic” amyloid and tau. A case can be made for oxidative modifications of DNA and RNA, DNA strand breakage and aberrant repair, and the still-unaccounted consequences of telomere senescence and aging. Early white-matter changes, which seem to precede the toxic accumulations of amyloid and tau, can be explained by vascular damage of large and small blood vessels that result in both ischemic injury and glymphatic drainage problems. Identifying and dealing with these primary causes is a path yet to be vigorously explored.

  3. The cellular phase, defined by De Strooper and Karran, appears to largely represent intracellular and intercellular interactions responsible for AD development. They probably involve both gain of toxic functions and loss of normal functions. In my understanding, De Strooper and Karran intend to incorporate into their four-dimensional scheme all the major cellular reactions that lead to neurodegeneration. This is why we need to understand cellular reactions in vivo, possibly on a single-cell basis. I guess that complexity of the brain will make us work for a long time. Also, some reactions probably constitute “AND” circuits, others “OR” circuits. In this respect, recent mathematical neuroscience, the advancement of which is incredible, may help untangle the complexity issue.

    I am not, however, a big fan of systems biology because it depends on past publications, many of which are unreproducible or irrelevant. The best way probably would be to observe humans from their preclinical stage for 25 years in biochemical, cellular, and clinical terms, and this is impossible. The second-best classic way is to reconstitute all the major mechanisms in animal models. We have to keep in mind that all the rodent models that accumulate Aβ are not perfect models of AD; they are, at best, just models of preclinical AD, which might develop symptomatic AD if they lived for 25 years, by when many of us will have retired. The answer still remains behind the veil.

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