A new glucocorticoid hypothesis of brain aging: implications for Alzheimer's disease - PubMed (original) (raw)

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A new glucocorticoid hypothesis of brain aging: implications for Alzheimer's disease

Philip W Landfield et al. Curr Alzheimer Res. 2007 Apr.

Abstract

The original glucocorticoid (GC) hypothesis of brain aging and Alzheimer's disease proposed that chronic exposure to GCs promotes hippocampal aging and AD. This proposition arose from a study correlating increasing plasma corticosterone with hippocampal astrocyte reactivity in aging rats. Numerous subsequent studies have found evidence consistent with this hypothesis, in animal models and in humans. However, several results emerged that were inconsistent with the hypothesis, highlighting the need for a more definitive test with a broader panel of biomarkers. We used microarray analyses to identify a panel of hippocampal gene expression changes that were aging-dependent, and also corticosterone-dependent. These data enabled us to test a key prediction of the GC hypothesis, namely, that the expression of most target biomarkers of brain aging should be regulated in the same direction (increased or decreased) by both GCs and aging. This prediction was decisively contradicted, as a majority of biomarker genes were regulated in opposite directions by aging and GCs, particularly inflammatory and astrocyte-specific genes. Thus, the initial hypothesis of simple positive cooperativity between GCs and aging must be rejected. Instead, our microarray data suggest that in the brain GCs and aging interact in more complex ways that depend on the cell type. Therefore, we propose a new version of the GC-brain aging hypothesis; its main premise is that aging selectively increases GC efficacy in some cell types (e.g., neurons), enhancing catabolic processes, whereas aging selectively decreases GC efficacy in other cell types (e.g., astrocytes), weakening GC anti-inflammatory activity. We also propose that changes in GC efficacy might be mediated in part by cell type specific shifts in the antagonistic balance between GC and insulin actions, which may be of relevance for Alzheimer's disease pathogenesis.

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Figures

Figure 1

Figure 1. Initial glucocorticoid (GC) hypothesis of hippocampal aging

Long-term exposure to adrenal GCs/stress hormones (red arrows) facilitates aging-related functional decline and vulnerability in hippocampal neurons. Affected cells show heightened sensitivity to extrinsic injuries and disease, causing hippocampal deterioration and eventual cognitive decline. Not shown are activated astrocytes which presumably react to the neuronal changes. See discussion in text. (Redrawn from [2] with permission.)

Figure 2

Figure 2. Possible variations on the interaction between aging and glucocorticoids

Four sub-hypotheses on the mode of positive cooperativity between aging and GCs. See discussion in text. (Redrawn from [2] with permission.)

Figure 3

Figure 3. Overlap of aging-related and corticosterone (Cort)-sensitive genes

Using microarray technology, the genes that were aging-sensitive (upper) and also Cort- sensitive (lower) were identified. Numbers shown represent the number of genes in each category of directional change (down or up). Most genes downregulated with aging are expressed primarily in neurons, whereas upregulated genes are primarily glial. More genes were altered in opposite directions by Cort and aging than in the same direction, contravening a key prediction of the original GC hypothesis. Selected processes (and some genes from which they were identified) are shown for each directional combination of Cort and aging changes.

Figure 4

Figure 4. New GC hypothesis of hippocampal aging

Model incorporating aging-dependent decreases as well as increases in GC efficacy, in different cell type-specific compartments. Target processes (from Fig. (3)) altered during aging by strengthening Cort efficacy (left) should shift with aging in the direction promoted by GCs, whereas targets altered by weakening Cort efficacy (right) should shift with aging in the direction opposite to that normally promoted by GCs. Therefore, in target cells where Cort and aging effects are in same direction (left), Cort efficacy is proposed to increase with aging, and in cells where Cort and aging effects are in opposite directions (right), Cort efficacy is proposed to decrease. Target processes that are regulated by either increased or decreased Cort efficacy may be normally suppressed (−) or activated (+) by GCs. Putative neuronal or glial loci of the effects are based on direction (down or up) of change with aging.

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