No abstract

Background Resolution is the final stage of the inflammatory response, when restoration of tissue occurs. Failure may lead to chronic neuroinflammation, known as part of pathology in Alzheimer’s disease (AD) brain. Methods Specialized pro-resolving mediators (SPMs), receptors, biosynthetic enzyme, and downstream effectors involved in resolution were analyzed in post mortem hippocampal tissue from AD-patients and non-AD subjects. SPMs were analyzed in cerebrospinal fluid (CSF). Results Presence of SPMs and SPM receptors was demonstrated in the human brain. Levels of the SPM lipoxin A4 (LXA4) were reduced in AD - both in CSF and hippocampus. An enzyme involved in LXA4 synthesis and two SPM receptors were elevated in AD brains. LXA4 and RvD1 levels in CSF correlated to mini-mental state examination (MMSE) scores. Conclusions The resolution pathway exists in the brain and described alterations strongly suggest its dysfunction in AD. Correlations with MMSE suggest a connection with cognitive function in AD.

The prevalence of obesity is growing and now includes at least one-third of the adult population in the United States. As obesity and dementia rates reach epidemic proportions, an even greater interest in the effects of nutrition on the brain have become evident. This review discusses various mechanisms by which a high fat diet and/or obesity can alter the brain and cognition. It is well known that a poor diet and obesity can lead to certain disorders such as type II diabetes, metabolic syndrome, and heart disease. However, long-term effects of obesity on the brain need to be further examined. The contribution of insulin resistance and oxidative stress is briefly reviewed from studies in the current literature. The role of inflammation and vascular alterations are described in more detail due to our laboratory’s experience in evaluating these specific factors. It is very likely that each of these factors plays a role in diet-induced and/or obesity-induced cognitive decline.

Inflammation in the brain is a prominent feature in Alzheimer’s disease (AD). Recent studies suggest that chronic inflammation can be a consequence of failure to resolve the inflammation. Resolution of inflammation is mediated by a family of lipid mediators (LMs), and the levels of these specialized pro-resolving mediators (SPMs) are reduced in the hippocampus of those with AD. In the present study we combined analysis of LMs in the entorhinal cortex (ENT) from AD patients with in vitro analysis of their direct effects on neurons and microglia. We probed ENT, an area affected early in AD pathogenesis, by liquid chromatography-tandem mass spectrometry (LC-MS-MS), and found that the levels of the SPMs maresin 1 (MaR1), protectin D1 (PD1) and resolvin (Rv) D5, were lower in ENT of AD patients as compared to age-matched controls, while levels of the pro-inflammatory prostaglandin D2 (PGD2) were higher in AD. In vitro studies showed that lipoxin A4 (LXA4), MaR1, RvD1 and protectin DX (PDX) exerted neuroprotective activity, and that MaR1 and RvD1 down-regulated Aβ42-induced inflammation in human microglia. MaR1 exerted a stimulatory effect on microglial uptake of Aβ42. Our findings give further evidence for a disturbance of the resolution pathway in AD, and indicate that stimulating this pathway is a promising treatment strategy for AD.

While some research has indicated that ovarian hormone therapy (HT) benefits memory and decreases risk of Alzheimer's disease in menopausal women, several newer studies have shown null or detrimental effects. Despite the null and negative cognitive findings, the numerous studies showing positive effects beg the question of what factors determine whether HT acts as a neuroprotectant or a risk factor for brain functioning. Using middle-aged female rats, we directly compared six HTs. We evaluated the effects of ovariectomy, tonic low-dose, tonic high-dose and biweekly cyclic estradiol treatment, as well as whether progesterone altered the effectiveness of any one of these oestrogen regimens. Animals were tested on spatial and complex cued (intramaze patterns) reference memory using variants of the Morris maze. The tonic low-dose and cyclic estradiol treatments improved spatial performance, while the addition of progesterone reversed these beneficial cognitive effects of estradiol. Additionally, all groups learned to locate the platform on the cued task; however, an egocentric circling strategy was used with sham ovary-intact and hormone-replacement groups showing the most efficient search strategy. Although the question of memory retention 8 weeks after the first cognitive assessment was addressed, a large number of animals died between the first and second test, rendering the retest uninterpretable for many group comparisons. Specifically, both doses of tonic estradiol dramatically increased the number of deaths during the 17-week experiment, while the cyclic estradiol treatment did not. Progesterone decreased the number of deaths due to tonic estradiol treatment. Our findings suggest that the dose of estradiol replacement as well as the presence of progesterone influences the cognitive outcome of estradiol treatment. Further, there appears to be a dissociation between HT effects on cognition and mortality rates.