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The discovery that the stimulation of ionotropic glutamate receptors mediates not only the physiological action of glutamate but also a neurotoxic response provided the impetus for numerous investigations that sought to determine the role of glutamate in the pathophysiology of a number of neurodegenerative diseases, including Alzheimer's disease (AD). To date, nearly 200 articles have been published that specifically focus on the integrity and/or functional properties of the glutamate receptors in aging and AD. This chapter attempts to synthesize the results of these many studies and present them in as unbiased manner as possible. The chapter is divided into four main sections: (i) overview of the glutamate receptors, (ii) glutamate receptors in the aging (rodent) brain, (iii) glutamate receptors in the AD brain, and (iv) current topics of glutamate toxicity in AD. What will become obvious following the reading of this chapter is that data are at times inconsistent, with some investigators reporting that glutamate receptors are highly vulnerable in the aged and AD brain, whereas others state that these receptors are intact or even hyperfunctional. Contributing to these inconsistencies are a host of technical issues. To address this matter, the details of a number of studies (i.e., strain, species, age, brain region investigated, postmortem interval, when applicable) are presented in tabular form ( TABLE 20.1 , TABLE 20.2 , TABLE 20.3 , TABLE 20.4 , TABLE 20.5 , TABLE 20.6 , TABLE 20.7 , TABLE 20.8 , TABLE 20.9 , TABLE 20.10 , TABLE 20.11 , TABLE 20.12 , TABLE 20.13 , TABLE 20.14 ). By providing this information, it is our goal that the reader will be able to make some personal assessment of the extent to which technical details, may or may not, confound the biological relevance of the findings. It is also important to bear in mind that much of our knowledge of glutamate receptors in aging and AD has come about through studies employing autoradiographic techniques to investigate the anatomical distribution and density of various ligand-specific binding sites. Although these studies have been of considerable value in defining the role of glutamate in the aging brain and AD, it is clear from our knowledge of the molecular biology of the glutamate receptor that specific techniques are required allowing for the identification of individual glutamate receptor subtypes. Studies employing these latter techniques are currently underway in several laboratories and while much of the data remain unpublished it is clear that these works will play a critical role in the future in defining glutamates participation as an excitotoxic agent in the aging brain and AD. |
