AUTHOR=Holtzman Jordan L. TITLE=Cellular and animal models for high-throughput screening of therapeutic agents for the treatment of the diseases of the elderly in general and Alzheimer’s disease in particular† JOURNAL=Frontiers in Pharmacology VOLUME=4 YEAR=2013 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2013.00059 DOI=10.3389/fphar.2013.00059 ISSN=1663-9812 ABSTRACT=
It is currently thought that the dementia of Alzheimer’s disease is due to the neurotoxicity of the deposits or aggregates of amyloid-β (Aβ) in the extracellular space of the cerebral cortex. This model has been widely criticized because there is a poor correlation between deposits and dementia. Others have questioned whether Aβ is truly neurotoxic. Yet, in spite of these concerns, the search for therapeutic agents has been based on the development of mouse models transfected with mutant genes associated in humans with early onset Alzheimer’s disease. A major limitation of these models is that although they exhibit many of the pathological and clinical manifestation of the human disease, the bulk of individuals who develop the dementia of Alzheimer’s disease have none of these mutant genes. Furthermore, nine clinical trials of drugs that were effective in transgenic mice failed to show any benefit in patients. Finally, a major unresolved issue with the Aβ model is that since Aβ is produced in everyone, why are deposits only seen in the elderly? This issue must be resolved if we are to understand the etiology of the disease and develop test systems for both diagnosis and drug discovery. Published studies from my laboratory demonstrate that in human cerebrospinal fluid immunoreactive Aβ is only present as a complex with two chaperones, ERp57 and calreticulin and is