Cholesterol is eliminated from neurons by oxidization, which generates oxysterols. Cholesterol oxidation is mediated by the enzymes cholesterol 24-hydroxylase (CYP46A1) and cholesterol 27-hydroxylase (CYP27A1). Immunocytochemical studies show that CYP46A1 and CYP27A1 are expressed in neurons and some astrocytes in the normal brain, and CYP27A1 is present in oligodendrocytes. In Alzheimer's disease (AD), CYP46A1 shows prominent expression in astrocytes and around amyloid plaques, whereas CYP27A1 expression decreases in neurons and is not apparent around amyloid plaques but increases in oligodendrocytes. Although previous studies have examined the effects of synthetic oxysterols on the processing of amyloid precursor protein (APP), the actions of the naturally occurring oxysterols have yet to be examined. To understand the role of cholesterol oxidation in AD, we compared the effects of 24(S)-and 27-hydroxycholesterol on the processing of APP and analyzed the cell-specific expression patterns of the two cholesterol hydroxylases in the human brain. Both oxysterols inhibited production of A␤ in neurons, but 24(S)-hydroxycholesterol was ϳ1000-fold more potent than 27-hydroxycholesterol. The IC 50 of 24(S)-hydroxycholesterol for inhibiting A␤ secretion was ϳ1 nM. Both oxysterols induced ABCA1 expression with IC 50 values similar to that for inhibition of A␤ secretion, suggesting the involvement of liver X receptor. Oxysterols also inhibited protein kinase C activity and APP secretion following stimulation of protein kinase C. The selective expression of CYP46A1 around neuritic plaques and the potent inhibition of APP processing in neurons by 24(S)-hydroxycholesterol suggests that CYP46A1 affects the pathophysiology of AD and provides insight into how polymorphisms in the CYP46A1 gene might influence the pathophysiology of this prevalent disease.

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The lateral bed nucleus of the stria terminalis (BSTL) and central nucleus of the amygdala (Ce) are amygdaloid nuclei that have similar afferent and efferent connections within the brain. Previous studies have demonstrated that both regions send axonal projections to the dorsal vagal complex (dorsal motor nucleus and nucleus tractus solitarii). The present study used the combined retrograde fluorescence-immunofluorescence method to examine whether cells contributing to this pathway contained any of the following neuropeptides: corticotropin-releasing factor, neurotensin, somatostatin, substance P, enkephalin, or galanin. The inputs to the dorsal vagal complex originated mainly from ventral BSTL and medial Ce, although a significant number of neurons within the dorsal BSTL and lateral Ce also contributed. Corticotropin-releasing factor, neurotensin, and somatostatin neurons mainly located within the dorsal BSTL and the lateral Ce contained retrograde tracer after injections into the vagal complex. Substance P neurons in the ventral BSTL and medial Ce provide a sparse input to the dorsal vagal complex. Enkephalin and galanin neurons within the BSTL and Ce did not appear to project to the dorsal vagal complex. Corticotropin-releasing factor and neurotensin neurons within the lateral hypothalamus also project to the dorsal vagal complex. Approximately 22% of the Ce and 15% of the BSTL retrogradely labeled neurons were peptide immunoreactive. Thus, it is concluded the Ce and BSTL are sources of a significant peptidergic pathway to the dorsal vagal complex. However, it is also apparent that the majority of putative transmitter types within the amygdaloid vagal projection still are unknown. The results suggest that the dorsal and ventral BSTL and the lateral and medial Ce, respectively, are homologous zones with regard to chemoarchitecture and connections. The data is discussed considering the possible function of peptides within descending amygdaloid pathways to the brainstem.

The amygdala, particularly the central amygdaloid nucleus, is important for the expression of adrenocorticotropin and corticosterone responses during stress. The aim of the present study was to determine if the central amygdaloid nucleus directly innervated the hypothalamic paraventricular nucleus. To accomplish this aim, the Phaseolus vulgaris leucoagglutinin lectin antero-grade tracing method was used. Injections of the tracer into the medial central amygdaloid nucleus resulted in axonal and terminal labeling within the medial and lateral parvocellular parts of the caudal paraventricular nucleus. A dense patch of labeling was observed within the lateral wing of the lateral part of the parvocellular paraventricular nucleus. Only a few labeled axons were observed within the paraventricular nucleus of animals that had lectin injections localized to the lateral part of the central nucleus. Tracer injections localized to the medial amygdaloid nucleus resulted in axonal and terminal labeling primarily within the anterior parvocellular and periventricular regions of the paraventricular hypothalamic nucleus. Sparse to moderate axonal and terminal labeling was observed within the magnocellular parts of the paraventricular nucleus in animals that had injections of tracer into either the medial central nucleus or the medial nucleus. No labeling was observed within the paraventricular nucleus of animals that had injections of lectin within other amygdaloid nuclei or adjacent regions of the striatum. The results demonstrated a topographically organized projection from the amygdala to the hypothalamic paraventricular nucleus. The central nucleus mainly innervates the caudal lateral and medial parvocellular paraventricular nucleus. The medial nucleus innervates the rostral parvocellular parts of the paraventricular nucleus. These pathways could form the anatomical substrates of amygdaloid modulation of neuroendocrine responses to stressors.

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