Stress‐induced anhedonia is associated with an increase in Alzheimer's disease‐related markers

Abstract

BACKGROUND AND PURPOSEStress is believed to be associated with the development of neuropsychiatric disorders, including Alzheimer's disease (AD). We have studied mechanisms implicated in vulnerability to stress and the relationship with changes in AD-related markers. EXPERIMENTAL APPROACHAnhedonia induced by a chronic mild stress (CMS) procedure, applied for 6 weeks, was used to select rats vulnerable or resistant to stress. Sucrose intake, the Porsolt forced swimming test and cognitive deficits in the novel object recognition test (NORT) were used to characterize vulnerable and resilient rats. The antidepressant venlafaxine (20 mg·kg -1 p.o.) or saline was administered daily during the last 2 weeks of CMS. Biochemical markers affected by stress, PKB, ERK and synaptophysin, and those associated with AD, amyloid b-protein (Ab), b-secretase (BACE1) and t phosphorylation, were measured in the hippocampus. KEY RESULTSAfter CMS, 40% of rats were resistant to the development of anhedonia (CMS-resistant to stress), whereas the remaining were responsive [CMS-anhedonic (CMSA)]. Only CMSA rats displayed significant increases in immobility time in the forced swimming test and cognitive deficits in the NORT, and significant decreases in synaptophysin, phosphorylated PKB and phosphorylated ERK1/2 expression in the hippocampus. Increased levels of Ab40, BACE1 and t phosphorylation were also found only in CMSA rats. All these effects in CMSA rats were reverted by treatment with venlafaxine. CONCLUSIONS AND IMPLICATIONSVulnerability to stress might constitute a risk factor for the development of AD, and pharmacological treatment with venlafaxine may represent a therapeutic strategy for the treatment of stress-related disorders, including AD.

The involvement of homocysteine in stress-induced Aβ precursor protein misprocessing and related cognitive decline in rats

“…Some clues came from the deposits of Aβ in the brain of stress-level glucocorticoid-treated wild-type mice (Wang et al 2011) and rats (Catania et al 2009;Martisova et al 2012). Our study showed that the level of Aβ could be upregulated by CUMS, which was similar to the data reported in stress-induced anhedonia rats (Briones et al 2012). These results added some new support to the causative effects of stress in the development of cognitive decline and AD.…”

Piromelatine ameliorates memory deficits associated with chronic mild stress-induced anhedonia in rats

“…The chronic mild stress (CMS) procedure was adopted the same as described previously (Briones et al 2012). Briefly, it consisted of a variety of unpredictable mild stressors and two to three of stressors were conducted in any 24-h period.…”

“…In this model, rodents are subjected to different and unpredictable mild psychological stressors for a period of time, mimicking some of the dysfunctions associated with human depressive disorder (Luo et al 2013). As such, CMS was reported to induce anhedonia and memory deficits, which could be reversed by treatment with antidepressant (Bessa et al 2009;Briones et al 2012). Also, CMS was shown to downregulate expression of BDNF and activation of cAMP-response element binding protein (CREB), both involved in the pathophysiology of depression and the mechanism of action of antidepressants (Hu et al 2010).…”

Sex differences in Alzheimer's disease risk: are we looking at the wrong hormones?

“…Interestingly, these effects are observed in only "stress-sensitive" (rather than "stress-resistant") animals (Briones et al, 2012), suggesting that the apparent AD-inducing effects of stress are not inevitable, but require a particular vulnerability to the effects of stress.…”