COMMENT Reading this paper from the laboratories of Michel Goedert and Sjors Scheres at the MRC in Cambridge, U.K., is like opening a box of chocolates for the holidays and finding a delightful assortment of shapes and structures: treats as food for thought. I ha
COMMENT I am a co-author on the Lesne Aβ*56 paper because we supplied one of the antibodies used, A11, with standards to authenticate it. Sadly, this was not the first or the last high-profile paper in our field that could not be replicated. I don’t think Aβ*56 h
COMMENT This interesting and exciting paper by Nixon and co-workers confirms and extends a model for neuritic plaque formation that we previously reported (see Fig 4 below from Pensalfini et al., 2014). We used a fibril-specific monoclonal antibody, mOC78, which
COMMENT This is an interesting and important study. The authors report the first structure of Aβ42 fibrils from the brain and although there have been other reports of Aβ42 fibril structures assembled from monomer in vitro, previous work has indicated that the st
COMMENT This paper by Huang et al. reports a number of interesting observations that provide significant insights into the role of microglia in Alzheimer’s disease and into the mechanism of plaque biogenesis that have a number of implications for the amyloid hypo
Charles Glabe on Alzheimer's Disease "Non-amyloidogenic" p3 Peptide Revisited: A Case for Amyloid-α.
COMMENT This is an interesting paper that reports that Aβ17-40 (also known as P3) forms β-sheet amyloid fibrils with properties like that of its longer sibling, Aβ1-40. Aβ variants at the carboxyl terminus and amino terminus have been extensively investigated whi
COMMENT Cognitive deficit is not a side effect of Alzheimer's disease treatment. It is the primary manifestation of disease. The simplest explanation is that you are thinking about the mechanistic relationship between Aβ secretion and pathogenesis backwards.
COMMENT Cell models for prion infection, replication, and strain behavior have long been available to prion researchers. These include stable lines producing transmissible prion aggregates and inducible cell lines that are dependent on the addition of exogenous p
Charles Glabe on Aβ(1-42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer's disease.
COMMENT This is an interesting paper that underscores the conformational polymorphisms in β-sheet aggregates of Aβ. This one is unique in two aspects: It is the first structure that is a triple parallel, in-register sheet, and it is unique to Aβ42. I’m not sure h
COMMENT Arguing about whether it is Aβ40, Aβ42 or not is missing the important point: It is aggregated in an amyloid-like fashion, because it reacts with a large number of antibodies that only react with aggregated or fibrillar conformations. If it is aggregated
COMMENT The clinical trial of semagacestat is fascinating because it reported the first disease-modifying drug for Alzheimer’s. The critical question is why the drug made the patients cognitively worse. A number of people have pointed to an off-target effect on o
Charles Glabe on Alzheimer's disease-linked mutations in presenilin-1 result in a drastic loss of activity in purified γ-secretase complexes.
COMMENT If it turns out that FAD mutations are generally loss of function, then the phenotype of haploinsufficiency would be the same as partial inhibition with γ-secretase inhibitors. Is this is why γ-secretase inhibitors failed in Phase 3? Maybe degrading APPβ
Charles Glabe on Localization of a toxic form of superoxide dismutase 1 protein to pathologically affected tissues in familial ALS.
COMMENT This recent paper by Glass and coworkers reports further insight into the recognition of misfolded SOD1 by the conformation-dependent antibody C4F6. This antibody was originally isolated by Jean-Pierre Julien in 2007. This antibody was prepared by immuniz
Charles Glabe on Intraneuronal APP, not free Aβ peptides in 3xTg-AD mice: implications for tau versus Aβ-mediated Alzheimer neurodegeneration.
COMMENT Virginia Lee and coworkers have convincingly demonstrated that the perinuclear, intracellular Aβ immunoreactivity observed in a subset of neurons in the 3xTg-AD mouse is predominantly, if not exclusively, APP and not Aβ. Moreover, they demonstrate that th
Charles Glabe on Aplysia CPEB can form prion-like multimers in sensory neurons that contribute to long-term facilitation.
COMMENT This is a fascinating example of what appears to be another "functional amyloid." In this, the function is more active and interesting because it is regulated by neuronal activity, rather than serving as a scaffold for melanin, or as a storage f