Poorly defined structurally, our understanding of their mechanisms of action will be poor. However, even if assembly structure is defined at atomic resolution, we may not know formally whether biological studies recapitulate what occurs in the human brain. Nevertheless, I argue that: (1) in well-controlled experimental systems, the data derived from studies of A biological activity tell us something about pathways of A-induced cellular stress, injury, and death per se; and (2) the value of the information with respect to understanding AD pathobiology can be validated if in future work it can be shown that interventions based upon such information successfully modify or prevent the AD state. Again, formally, we cannot know whether our interventions operate in situ in vivo according to the mechanisms we promulgate. However, if our endpoints are preventing, ameliorating, decelerating progression of, or curing AD,Endnotes a The reader is encouraged to examine an excellent recent treatment of the oligomer field by Benilova et al. [99]. b Two recent reports do suggest that AD pathology can be propagated through prion-like cell-to-cell spread in mice following injection of brain homogenates from AD transgenic animals [100] or an AD patient [101]. c It should be emphasized once more that the thermodynamic arguments here refer to the final equilibrium state of a system. However, this state may not be reached (at least in our lifetimes) because of kinetic traps that, in practical terms, take a particular assembly out of a pathway. Protein precipitation, for example, is one process that can lead to a system state in which an insurmountable activation energy (under physiologic conditions) would be required to place the precipitated proteins back `on-pathway.’Abbreviations AD: Alzheimer’s disease; APP: Amyloid -protein precursor; A: Amyloid -protein; CSF: Cerebrospinal fluid; ELISA: Enzyme-linked immunosorbent assay; NMR: Nuclear magnetic resonance; SAR: Structure ctivity relationship. Competing interests The author declares that he has no competing interests. Acknowledgements The author gratefully acknowledges helpful discussions and editorial suggestions from Drs Eric Hayden and Robin Roychaudhuri, Mr Michael Hughes, Mr Joseph Conovaloff, and Ms Shiela Beroukhim. The author also acknowledges the work of others that could not be cited within the abstract [14,46,102,103]. The support of NIH grants NS038328, AG041295, and AG016570 is acknowledged.Published: 27 August 2013 References 1. Schwartz P: Amyloidosis ?Cause and Manifestations of Senile Dementia. Springfield: Charles C Thomas; 1970. 2. Alzheimer A: On an extraordinary, severe disease process of the cerebral cortex [in German]. Neurologisches Centralblatt 1906, 23:1129?136.Teplow Alzheimer’s Research Therapy 2013, 5:39 http://alzres.com/content/5/4/Page 10 of3.4.5.6.7.8.9.10. 11. 12.13.14. 15.16.17. 18. 19.20.21. 22.23.24.25.Glenner GG, Wong CW: Alzheimer’s Disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun 1984, 122:1131?135. Glenner GG, Wong CW: Alzheimer’s disease: initial report of the purification and characterization of a novel PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/27385778 cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984, 120:885?90. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, JNJ-26481585 web Muller-Hill B: The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 1987, 325:7.
