Targeting Multiple Functional and Pathological Deficits

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Although the above discussion of different therapeutic approaches was structured according to their effects on particular AD deficits, some of them may have a wide range of effects across symptoms and pathologies. For example, amyloid immunotherapy has been shown to provide acute cognitive improvement [135] and reduction in both amyloid and tau pathologies [136] in animal models. The peroxisome proliferator-activated receptor-y (PPARy) is a ligand-activated transcription factor. It regulates expression of a wide variety of genes including those involved in lipid and glucose metabolism and inflammatory responses. Activation of PPARy also suppresses BACE1 ex pression [137,138]. PPARy agonists may thus address the amyloid pathology, neuroinflammatory responses and risk factors (e.g. hypercholesterolemia, obesity, and diabetes) of AD (see Chapter 3). An FDA approved drug on the market for the treatment of diabetes, Avandia, has been shown to provide benefits for AD patients who do not carry the apoE4 gene [139]. A phase III clinical trial is ongoing to test its efficacy in AD patients (Table 1).

Five different mechanisms of actions for the treatment of AD are discussed separately in the following chapters. In the opening chapter Drs. Jeffrey Kao and George Grossberg review the use of cholinesterase inhibitors currently on the market as symptomatic treatments for AD. The next four chapters discuss potential disease modifying therapeutic opportunnities that have entered clinical studies. In Chapter 2 Drs. Holly Soares and Larry Sparks review the pleiotropic effects of HMG-CoA reductase inhibitors (statins) that may affect AD pathogenesis. In Chapter 3 Drs. Qingguang Jiang, Shweta Mandrekar and Gary Landreth discuss how PPAR-y agonists can be used to regulate metabolism of lipids and glucose and inflammatory responses to ameliorate deficits in AD patients. Both mechanisms discussed in Chapters 2 and 3 have benefited from the availability of marketed drugs for a different indication and have been fast tracked to Phase III clinical trials for the treatment of AD. In Chapter 4 Drs. Anthony White and Ashley Bush review metal chelating agents as a mechanism to reduce Aft oligomerization and neurotoxicities. Small clinical trials have provided encouraging results and new metal chelating agents have been advanced to Phase II trials. Finally, in Chapter 5 Drs. Ratan V. Bhat, Stefan Berg, Jeremy Burrows, and Johanna Lindquist summarize the role of glycogen synthase kinase 3 (GSK-3) in AD and the potential benefits of GSK3 inhibitors, a couple of which have recently entered Phase I clinical trials.

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