PT  - JOURNAL ARTICLE
AU  - Mary L. Michaelis
TI  - Drugs Targeting Alzheimer's Disease: Some Things Old and Some Things New
AID  - 10.1124/jpet.102.035840
DP  - 2003 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 897--904
VI  - 304
IP  - 3
4099  - http://jpet.aspetjournals.org/content/304/3/897.short
4100  - http://jpet.aspetjournals.org/content/304/3/897.full
SO  - J Pharmacol Exp Ther2003 Mar 01; 304
AB  - Enormous effort is now being devoted to developing drugs that slow neurodegeneration in Alzheimer's disease (AD), although insights into AD genetics and molecular pathogenesis only arose in the last 15 years. Acetylcholinesterase inhibitors that temporarily slow loss of cognitive function remain the only approved AD drugs. Discovery of mutations in three genes leading to severe early onset AD was critical in focusing attention on the role of amyloid peptides (Aβ) in neuronal cell death, and enhanced understanding of the biology of these peptides has led to an array of mechanism-based drug discovery strategies. These include inhibitors for Aβ-generating proteases, agents that prevent or reverse Aβ oligomerization, immunotherapies to reduce Aβ in brain and plasma, and drugs to modulate cholesterol-mediated effects on Aβ transport. Strategies are also underway to minimize toxic effects of Aβ fibrils on neurons, and these include antioxidants, blockers of glutamate-mediated excitotoxicity, and modulators of inflammatory responses within the brain. Although several approaches involve new agents for recently discovered targets, many are based on new applications of existing drugs such as statins and nonsteroidal anti-inflammatory drugs. Discovery of abnormally phosphorylated τ protein in neurofibrillary tangles in AD brain has led to strategies for identifying selective inhibitors of τ kinases and central nervous system/brain-permeable drugs that help maintain microtubule integrity. Clearly, a large gap exists between our understanding of the cellular cascades targeted in drug discovery and widespread failure of the nervous system that AD represents. Nevertheless, the pace of recent research clearly supports optimism that slowing progression of AD will soon be possible. The American Society for Pharmacology and Experimental Therapeutics