Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by cognitive decline and the presence of two core pathologies, amyloid β plaques and neurofibrillary tangles. Over the last decade, the presence of a sustained immune response in the brain has emerged as a third core pathology in AD. The sustained activation of the brain's resident macrophages (microglia) and other immune cells has been demonstrated to exacerbate both amyloid and tau pathology and may serve as a link in the pathogenesis of the disorder. In the following review, we provide an overview of inflammation in AD and a detailed coverage of a number of microglia-related signaling mechanisms that have been implicated in AD. Additional information on microglia signaling and a number of cytokines in AD are also reviewed. We also review the potential connection of risk factors for AD and how they may be related to inflammatory mechanisms.

Several lines of evidence suggest that a hypoglutamatergic condition may induce a phenotypic loss of cortical parvalbumin (PV)-positiveGABAergic interneurons, such as that observed in brain tissue of schizophrenic subjects. However, it is not known whether the loss of PV interneurons is a consequence of the hypoglutamatergic condition or a secondary aspect of the disease. We characterized the signaling and subunit expression of NMDA receptors in cultured cortical PV interneurons and determined whether a hypoglutamatergic condition, created by direct application of sublethal concentrations of ketamine or subunit-selective NMDA receptor antagonists, can affect the expression of the GABAergic markers as observed in vivo. Real-time PCR performed on mRNA isolated from single neurons showed that PV interneurons present a fivefold higher NR2A/NR2B ratio than pyramidal neurons. Brief, nontoxic, exposure to NMDA led to an increase in ERK1/2 (extracellular signal-regulated kinase 1/2) and cAMP response element-binding protein phosphorylation in PV interneurons, and this increase was blocked by the NR2A-selective antagonist NVP-AAM077. Application of the nonselective NMDA receptor antagonist ketamine, at sublethal concentrations, induced a time and dose-dependent decrease in parvalbumin and GAD67 immunoreactivity specifically in PV interneurons. These effects were reversible and were also observed with the NR2A-selective antagonist, whereas the NR2B-selective antagonist Ro-25-6981 only partially reduced GAD67 immunoreactivity. Coexposure to the calcium channel opener BayK, or the group I metabotropic glutamate receptor agonist DHPG [(RS)-3,5-dihydroxyphenylglycine] attenuated the decrease in GAD67 and parvalbumin induced by the NMDA receptor antagonists. These results suggest that the activity of NR2A-containing NMDA receptors play a pivotal role in the maintenance of the GABAergic function of PV interneurons.

The neuropeptide galanin coexists with norepinephrine and serotonin in neural systems mediating emotion. Previous findings suggested that galanin modulates anxiety-related behaviors in rodents. Three galanin receptor subtypes have been cloned; however, understanding their functions has been limited by the lack of galanin receptor subtype-selective ligands. To study the role of the galanin GAL-R1 receptor subtype in mediating anxiety-related behavior, we generated mice with a null mutation in the Galr1 gene. GAL-R1 À/À are viable and show no abnormalities in health, neurological reflexes, motoric functions, or sensory abilities. On a battery of tests for anxietylike behavior, GAL-R1 À/À showed increased anxiety-like behavior on the elevated plus-maze test. Anxiety-related behaviors on the light/dark exploration, emergence, and open field tests were normal in GAL-R1 À/À. This test-specific anxiety-like phenotype was confirmed in a second, independent cohort of GAL-R1 null mutant mice and +/+ controls. Principal components factor analysis of behavioral scores from 279 mice suggested that anxiety-like behavior on the elevated plus-maze was qualitatively distinct from behavior on other tests in the battery. In addition, exposure to the elevated plus-maze produced a significantly greater neuroendocrine response than exposure to the light/dark exploration test, as analyzed in normal C57BL/6J mice. These behavioral findings in the first galanin receptor null mutant mouse are consistent with the hypothesis that galanin exerts anxiolytic actions via the GAL-R1 receptor under conditions of relatively high stress.

Selective serotonin reuptake inhibitors, such as fluoxetine (FLX), are the most commonly used drugs in the treatment of major depression. However, there is a limited understanding of their molecular mechanism of action. Although the acute effect of selective serotonin reuptake inhibitors in elevating synaptic serotonin concentrations is well known, the clinical amelioration of depressive symptoms requires 14 -21 days of treatment, suggesting that numerous other rearrangements of function in the CNS must take place. In the present study, we demonstrated that 14 days of FLX treatment up-regulated galanin mRNA levels by 100% and GalR2-binding sites by 50%, in the rat dorsal raphe nucleus, where galanin coexists with serotonin. Furthermore, a galanin receptor antagonist, M40, attenuated the antidepressant-like effect of FLX in the forced swim test, a rodent preclinical screen commonly used to evaluate antidepressant-like efficacy. Direct activation of galanin receptors by a galanin receptor agonist, galnon, was found to produce an antidepressant-like effect in the same task. Two other antidepressant treatments also affected the galaninergic system in the monoaminergic nuclei: Electroconvulsive shock elevated galanin mRNA levels in dorsal raphe nucleus, whereas sleep deprivation increased galanin mRNA levels in the locus coeruleus, further underlining the connection between activation of the galaninergic system and antidepressant action of various clinically proven treatments. O ur understanding of the molecular mechanism of action of fluoxetine (FLX), beyond its effect of elevating synaptic serotonin [5-hydroxytryptamine (5-HT)] concentration, is limited. The delay in the onset of clinical antidepressant effect suggests that transcriptional and translational events, leading to functional changes in signaling within the major serotoninergic nucleus dorsal raphe nucleus (DRN) and in its projection areas, may be required for these therapeutic effects (1-3). One potential player in mediating the long-term effects of FLX, besides 5-HT, is the neuropeptide galanin. Galanin, through its three G-protein-coupled receptors, GalR1, GalR2, and GalR3 (4), regulates homeostatic and motivated behaviors including pain perception, sleep, food intake, sexual activity, learning, and memory (5). Galaninergic transmission modulates the activity of monoaminergic neurons in the ventral tegmental area, DRN, and locus coeruleus (LC) (6-10). Galanin receptor subtypes GalR1 (7) and GalR2 are expressed in DRN neurons (11) that can be activated by galanin dendritically released from the dorsal raphe 5-HT neurons (9, 12) or from surrounding galanin immunoreactive terminals (7). In the noradrenergic nucleus LC, an area that is closely connected both structurally and functionally to DRN (13,14), GalR1 expression is induced by morphine withdrawal (15), and the galanin receptor agonist, galnon, was shown to attenuate several withdrawal signs (16). It is worth noting that drug withdrawal often precipitates symptoms of depression, and depression is a ...

BackgroundWe assessed the impact of retinoid X receptor (RXR) agonist bexarotene on brain amyloid measured by amyloid imaging in patients with Alzheimer’s disease (AD) in a proof-of-concept trial.MethodsTwenty patients with AD [Mini Mental State Examination (MMSE) score 10–20 inclusive] with positive florbetapir scans were randomized to receive 300 mg of bexarotene or placebo for 4 weeks. The amyloid imaging result was the primary outcome. Whole-population analyses and prespecified analyses by genotype [apolipoprotein E ε4 (ApoE4) carriers and ApoE4 noncarriers] were conducted. Secondary outcomes included scores on the Alzheimer’s Disease Assessment Scale–Cognitive subscale, Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale, MMSE, Clinical Dementia Rating scale, and Neuropsychiatric Inventory. Serum amyloid-β (Aβ) peptide sequences Aβ1–40 and Aβ1–42 measurements were collected as biomarker outcomes.ResultsThere was no change in the composite or regional amyloid burden when all patients were included in the analysis. ApoE4 noncarriers showed a significant reduction in brain amyloid on the composite measure in five of six regional measurements. No change in amyloid burden was observed in ApoE4 carriers. There was a significant association between increased serum Aβ1–42 and reductions in brain amyloid in ApoE4 noncarriers (not in carriers). There were significant elevations in serum triglycerides in bexarotene-treated patients. There was no consistent change in any clinical measure.ConclusionsThe primary outcome of this trial was negative. The data suggest that bexarotene reduced brain amyloid and increased serum Aβ1–42 in ApoE4 noncarriers. Elevated triglycerides could represent a cardiovascular risk, and bexarotene should not be administered outside a research setting. RXR agonists warrant further investigations as AD therapies.Trial registrationClinicalTrials.gov identifier NCT01782742. Registered 29 January 2013.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-016-0173-2) contains supplementary material, which is available to authorized users.