The E ffec t of Exposure to Glucocorticoids on the Retention of a Spatial Task in Rats Injected Bilaterally with Beta-Amyloid into the Hippocampus

The pathology of Alzheimer's disease is characterized by neuritic plaques and neurofibrillary tangles. The core component of the plaques is an amino acid named Beta-amyloid (AB). A recent study done by Dornan, Kang, McCampbell, and Kang (1993) reported that bilateral injections of AB along with a subthreshold dose of ibotenic acid (IBO) into the hippocampus significantly impaired the acquisition of a spatial learning task in rats. Dornan et al suggest that the results seen in their study maybe due to AB+IBO working synergistically via NMDA receptors to cause calcium dyshomeostasis. Another way that calcium dyshomeostasis occurs in the brain is via glucocorticoids. In a study done by Sapolsky (1985), exposure to stress levels of glucpcorticoids exacerbated kianic acid damage to hippocampal neurons, suggesting the possibility that glucocorticoids may endanger neurons by making them more vulnerable to outside toxic insults. Therefore, in this study we assessed the effects of glucocorticoids (7mg of corticosterone in 1ml of sesame oil, injected daily for two weeks) on the retention of a spatial task in animals that received bilateral intrahippocampal injections of AB. Animals injected with 7mg of corticosterone along with bilateral injections of Betaamyloid did not have significant differences in the retention of the spatial task as compared to control animals. 3 Exposure to stress Alzheimer's disease (AD), is a progressive neurodegenerative disease reSUlting in impairment of memory, visuospatial ability, language skills, and cognitive skills, like decision making and abstract thinking. AD is the most common form of age related dementia. Epidemiological studies indicate that over 4 million people suffer from late onset AD in the U.S. alone (Yankner, 1991). AD accounts for approximately 70% of all dementia cases, in the U.S.A. It afflicts an estimated 5-11% of the population over 65 and more than 47% over the age of 85 (Yankner, 1991; Katzman, 1991). The pathological hallmarks of AD, as first described by Alois Alzheimer in 1907, are the accumulation of extracellular neuritic plaques (NP) and intracellular neurofibrillary tangles (NFT) in the hippocampus, neocortex, and parahippocampal structures, including the cholinergic forebrain, entorhinal cortex, olfactory bulb, dorsal tegmental serotonergic nuclei, and the locus coeruleus noradrengic nuclei (Katzman, 1991; Selkoe, 1993; Rosenberg, 1993). These brain areas, especially the hippocampus are associated with learning and memory. The neuritic plaques found in AD brains are comprised of a core of extracellular fibrous amyloid protein and degenerating nerve endings, and abnormal mitochondria (Katzman, 1991; Rosenberg, 1993). The amyloid core of NP, has been identified as a 39-43 amino acid long peptide with a beta pleated structure and has been named beta amyloid (AB) (Yankner, 1991) . Beta amyloid is derived from 4 Exposure to stress Amyloid precursor protein (APP) (Yankner, 1991; Murphy, 1992; Cai, 1993; Rosenberg, 1993). APP is a naturally occurring glycoprotein that exists in several forms as a result of differential RNA splicing (Mattson, 1993; Mullan, 1993; Cai, 1993). Two forms of APP contain protease inhibitor domains (Yankner, 1991; Murphy, 1992). APP spans the cell membrane (transmembrane protein) and contains an intracellular carboxyl terminal and an extracellular amino terminal. Within the APP sequence, AB is located in a segment that lies partially in the extracellular space and partially within the cell membrane (Siman, 1992; Rosenberg, 1993; Mattson, 1993). APP is cleaved via two different pathways (Mattson, Cheng, Culwell, Esch, "Lieberburg and Rydel, 1993). Enzymatic cleaving of APP by the a-secretase pathway through the AB sequence results in the release of secreted forms of APP (APPs), and non amyloidgenic peptide fragments (Mattson, 1993; Rosenberg, 1993; Murphy, 1992). The secreted forms of APP are believed to be important in protease regulation (in forms containing the protease inhibitor domain), cell adhesion and proliferation, calcium regulation and neuro protection (Mattson, "1993). For example, Mattson, Barger, Cheng, Leiberbug, Swintosky, and Rydell (1993) reported that APPs reduced the increase in calcium that mediates hypoglycemic damage and protected cultured rat hippocampal and septal neurons, as well as human cortical neurons. Alternate cleaving of APP at the amino terminal of AB by the