Tau therapeutics for Alzheimer's disease: the promise and the challenges.
The pathological diagnosis of Alzheimer's disease (AD) depends on the presence of plaques consisting of the beta-amyloid peptide as well as neurofibrillary tangles consisting of paired helical filaments (PHFs) of the tau (tau) protein. The role of each type of pathology in the pathogenesis and progression of AD remains unclear. Previous hypotheses suggested that these two processes were independent, whereas more recent data suggest that there may be a bidirectional interaction between these two pathological processes. The identification of the neurotoxic effects of beta-amyloid and the discovery of mutations responsible for early-onset Alzheimer's disease (EOAD) and their linkage to beta-amyloid overproduction, has made the amyloid hypothesis of AD the predominant influence for therapeutic targets. Several approaches have emerged from preclinical testing and have entered early phases of clinical developments. The recent identification of tau mutations and their linkage to progressive neurodegenerative disorders provides a counterbalancing influence on the search for therapeutic targets for AD. Therapeutic approaches that are targeted to either beta-amyloid or tau share certain features at the level of pharmacology and will face many of the same challenges as they progress through drug development paradigms. The aim of this article is to provide a brief overview of some of the commonalities and the challenges faced by tau-related therapeutic strategies. The issues discussed in this article are not exhaustively dealt with in either scope or detail.
Gold
Michael
M
Global Clinical Research and Development, CNS/Analgesia, Johnson & Johnson Pharmaceutical Research and Development, Titusville, NJ 08560, USA. mgold1@prdus.jnj.com
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D015195:Drug Design; D015507:Drugs, Investigational / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D010770:Phosphotransferases / Q000037:antagonists & inhibitors; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D015507:Drugs, Investigational; D004791:Enzyme Inhibitors; D016875:tau Proteins; D010770:Phosphotransferases