Drug discovery for Alzheimer's disease: the end of the beginning.

Abstract

Journal of Molecular Neuroscience 1 Volume 24, 2004 Early in 1943, one of the great statesmen of the twentieth century, Winston Churchill, took the occasion of the surrender of the Axis armies in Tunisia to utter his famous words, stating, “These events did not mark the end or even the beginning of the end but merely the end of the beginning.” By analogy, our understanding of drug discovery for Alzheimer’s disease (AD) is at a similar point, the end of the beginning. The development of therapies for AD represents a major challenge to academic, biotechnological, and pharmaceutical scientists. One of the reasons for this lies in the fact that the human brain, the organ that is the focus of these therapies, is the most complex structure in all biology. Despite the difficult task, neuroscientists, using the tools of modern neuroscience, neurology, pharmacology, chemistry, genomics, proteomics, psychometrics, and bioinformatics, have made good progress not only in understanding the pathophysiology of AD but also in identifying and validating new drug targets that are the basis for novel therapeutic strategies. These developments mark the end of the beginning of our understanding of AD and hopefully open the way to an era of therapeutic breakthroughs against this dread disease. Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting approx 16 million people worldwide. The cause of AD is not known. What is known is that in most cases the disease is not simply caused by a single gene but by a combination of multiple genetic and environmental factors. Clinically, AD is characterized by memory and cognitive loss, and currently available therapy treats these symptoms. This therapy is based on the cholinergic hypothesis of AD, which states that ADrelated deficits in memory, learning, and cognition are caused by a decrease in cholinergic transmission owing to loss of cholinergic neurons in the septal and basalis nuclei (Allain et al., 2003). According to the cholinergic hypothesis, prolonging the actions of the cholingeric neurotransmitter acetylcholine at the synapse should improve memory and cognition in patients with AD. To accomplish this the most successful pharmacological approach has been to inhibit the enzymes, known as cholinesterases, which degrade acetylcholine. These cholinesterase inhibitors, donepezil, rivastigmine, and galantamine, were, until recently, the only FDA-approved drugs available for the treatment of AD. Although they certainly help sufferers of AD, cholinesterase inhibitors affect symptoms associated with late stages of the disease but have no effect on modifying the underlying disease or dementing process. Glutamate is the most important excitatory neurotransmitter in the central nervous system. Glutamatergic neurotransmission, an important process in learning and memory, is severely disrupted in patients with AD (Butterfield and Pocernich, 2003). The excitotoxic neurotransmitter glutamate has been implicated in the pathophysiology of AD; and under certain conditions, glutamate has a toxic action resulting from an activation of specific glutamate receptors, which leads to acute or chronic death of nerve cells. Because of the toxic consequences of excess glutamate, therapeutic strategies directed at the glutamatergic system might hold promise. The first of these glutamatergic therapies, memantine, an NMDA INTRODUCTION