A New Glucocorticoid Hypothesis of Brain Aging: Implications for Alzheimers Disease

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.

Increase in Alzheimer's related markers preceeds memory disturbances: Studies in vasopressin-deficient Brattleboro rat

“…(2) AVP is an important regulator of the HPA axis, which consist from corticotropin-releasing hormone (CRH) in the hypothalamus, adrenocorticotropin in the pituitary and glucocorticoids in the adrenal cortex. The glucocorticoid hypothesis of aging and AD proposed that chronic exposure to glucocorticoids induced hippocampal atrophy with a decline in learning abilities [30]. Aged-superior learners had lower expression of glucocorticoid receptor and CRH mRNA in the hypothalamus 15 compared with other groups [35].…”

“…Both during the sampling phase (genotype by factorial ANOVA F (1,35) =16.34, p<0.01) and the choice phase alone (genotype by repeated measure ANOVA F (1,30) =11.83 p<0.01) the effect of genotype remained significant. In point of the discrimination there was a significant difference between the time spent with old (object 1) and new (object 2) object during the choice phase by repeated measure ANOVA (old-new F (1,30) =18.03 p<0.01) and this effect was different between the two genotypes (old-new x genotype F (1,30) =9.26 p<0.01).…”

“…The discrimination index significantly differed between the two genotypes (genotype by factorial ANOVA F (1,30) =28.84 p<0.01) without any influence of age (Fig.2B). Based on the difference of the discrimination index from 0.5 by single sample t-test the AVP-deficient (di/di) animals were unable to discriminate (adult +/+: p<0.01; old +/+: p<0.01; adult di/di: p=0.94; old di/di: p=0.33).…”

“…During the whole object discrimination test (sampling + choice) the AVP-deficient rats spent significantly more time with the objects, than the +/+ ones based on repeated measure ANOVA (genotype F (1,30) =16.94, p<0.01) (Fig.2A). Both during the sampling phase (genotype by factorial ANOVA F (1,35) =16.34, p<0.01) and the choice phase alone (genotype by repeated measure ANOVA F (1,30) =11.83 p<0.01) the effect of genotype remained significant.…”

Stress Acts Cumulatively To Precipitate Alzheimer's Disease-Like Tau Pathology and Cognitive Deficits

“…Studies in humans and animals demonstrate a robust relationship among elevated GC secretion, cognitive impairment, and neuronal atrophy. The cognition-impairing actions of stress and high GC levels are largely ascribed to concomitant reductions in the volume of the hippocampus (Sousa et al, 2000;Landfield et al, 2007;Lupien et al, 2009), a brain area that displays some of the earliest neurodegenerative changes in AD. Stress and GC induce similar volumetric reductions in the prefrontal cortex (PFC) (Cerqueira et al, 2007;Schubert et al, 2008), which receives afferents from the hippocampus and is critical for the control of higher cognitive functions.…”