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Chronic (neuro)inflammation plays an important role in many age-related central nervous system (CNS) diseases, including Alzheimer's disease, Parkinson's disease and vascular dementia. Inflammation also characterizes many conditions that form a risk factor for these CNS disorders, such as physical inactivity, obesity and cardiovascular disease. Lipocalin 2 (Lcn2) is an inflammatory protein shown to be involved in different age-related CNS diseases, as well as risk factor conditions thereof. Lcn2 expression is increased in the periphery and the brain in different age-related CNS diseases and also their risk factor conditions. Experimental studies indicate that Lcn2 contributes to various neuropathophysiological processes of age-related CNS diseases, including exacerbated neuroinflammation, cell death and iron dysregulation, which may negatively impact cognitive function. We hypothesize that increased Lcn2 levels as a result of age-related risk factor conditions may sensitize the brain and increase the risk to develop age-related CNS diseases. In this review we first provide a comprehensive overview of the known functions of Lcn2, and its effects in the CNS. Subsequently, this review explores Lcn2 as a potential (neuro)inflammatory link between different risk factor conditions and the development of age-related CNS disorders. Altogether, evidence convincingly indicates Lcn2 as a key constituent in ageing and age-related brain diseases.

BACKGROUND: Myocardial infarction (MI) coinciding with depression worsens prognosis. Although Tumor Necrosis Factor alpha (TNF) is recognized to play a role in both conditions, the therapeutic potential of TNF inhibition is disappointing. TNF activates two receptors, TNFR1 and TNFR2, associated with opposite effects. Therefore, anti-inflammatory treatment with specific TNF receptor interference was compared to non-specific TNF inhibition regarding effects on heart, (neuro)inflammation, brain and behavior in mice with MI.METHODS: Male C57BL/6 mice were subjected to MI or sham surgery. One hour later, MI mice were randomized to either non-specific TNF inhibition by Enbrel, specific TNFR1 antagonist-, or specific TNFR2 agonist treatment until the end of the protocol. Control sham and MI mice received saline. Behavioral evaluation was obtained day 10-14 after surgery. Eighteen days post-surgery, cardiac function was measured and mice were sacrificed. Blood and tissue samples were collected for analyses of (neuro)inflammation.RESULTS: MI mice displayed left ventricular dysfunction, without heart failure, (neuro) inflammation or depressive-like behavior. Both receptor-specific interventions, but not Enbrel, doubled early post-MI mortality. TNFR2 agonist treatment improved left ventricular function and caused hyper-ramification of microglia, with no effect on depressive-like behavior. In contrast, TNFR1 antagonist treatment was associated with enhanced (neuro)inflammation: more plasma eosinophils and monocytes; increased plasma Lcn2 and hippocampal microglia and astrocyte activation. Moreover, increased baseline heart rate, with reduced beta-adrenergic responsiveness indicated sympathetic activation, and coincided with reduced exploratory behavior in the open field. Enbrel did not affect neuroinflammation nor behavior.CONCLUSION: Early receptor interventions, but not non-specific TNF inhibition, increased mortality. Apart from this undesired effect, the general beneficial profile after TNFR2 stimulation, rather than the unfavourable effects of TNFR1 inhibition, would render TNFR2 stimulation preferable over non-specific TNF inhibition in MI with comorbid depression. However, follow-up studies regarding optimal timing and dosing are needed.

Background: Soluble oligomeric amyloid-β (Aβ), rather than Aβ plaques, seems to be the culprit in Alzheimer's disease (AD). Accordingly, a new concept vaccine of small cyclic peptide conjugates, selectively targeting oligomeric Aβ, has been developed.Objective: Study the therapeutic potential of this new vaccine in a mouse model for AD.Methods: J20 mice, overexpressing human amyloid precursor protein, were validated for an AD-like phenotype. Then, J20 mice were vaccinated at 2, 3, and 4 months of age and AD phenotype was evaluated at 6, 9, and 12 months of age; or at 9, 10, and 11 months with evaluation at 12 months. Effects on Aβ pathology were studied by plaque load (immunohistochemistry; 6E10) and antibody titers against Aβ (ELISA). AD behavioral phenotype was evaluated by performance in a battery of cognitive tests.Results: J20 mice displayed age-related Aβ plaque development and an AD-like behavioral phenotype. A consistent antibody response to the cyclic peptides was, however, not extended to Aβ, leaving plaque load unaffected. Nevertheless, immunization at young ages prevented working- and short-term spatial memory loss, but deteriorated long-term spatial learning and memory, at 12 months of age. Immunization at later ages did not affect any measured parameter.Conclusion: J20 mice provide a relevant model for AD to study potential anti-Aβ treatment. Early vaccination prevented short-term memory loss at later ages, but deteriorated long-term spatial memory, however without affecting Aβ pathology. Later vaccination had no effects, but optimal timing may require further investigation.

Patients with cardiovascular disease have a higher risk to develop mental dysfunction, like depression or memory impairment. To better treat this group of patients we need to better understand the causes of this relationship. Previous studies have indicated that inflammation plays a role in both conditions. In our study we have studied (neuro)inflammation and behavioural changes in animal models of heart attack (myocardial infarction, MI). We specifically looked at microglia and the two inflammatory markers tumour necrosis factor alpha (TNF-α) and neutrophil gelatinase-associated lipocalin (NGAL). Microglia are immune cells in the brain, we know they are involved in conditions such as Alzheimer’s disease and depression. TNF-α is an inflammatory marker that is raised in the blood of patients after MI and also in depression. NGAL is another inflammatory marker that is raised in the blood of patient with heart failure and is associated with symptoms of depression in heart failure patients. In our mouse model of MI we found that TNF-α was raised in the brain after MI, we also found localized activation of microglia. In rats NGAL was raised after MI and NGAL levels were associated with behavioral changes. Microglia activation was also associated with behavioural changes. A final study in a model for abdominal surgery also showed changes in microglia and NGAL, indicating these are not specific for MI, but more likely a general response to physical damage.

Depression is more common in patients with cardiovascular disease than in the general population. Conversely, depression is a risk factor for developing cardiovascular disease. Comorbidity of these two pathologies worsens prognosis. Several mechanisms have been indicated in the link between cardiovascular disease and depression, including inflammation. Systemic inflammation can have long-lasting effects on the central nervous system, which could be associated with depression. NGAL is an inflammatory marker and elevated plasma levels are associated with both cardiovascular disease and depression. While patients with depression show elevated NGAL levels, in patients with comorbid heart failure, NGAL levels are significantly higher and associated with depression scores. Systemic inflammation evokes NGAL expression in the brain. This is considered a proinflammatory effect as it is involved in microglia activation and reactive astrocytosis. Animal studies support a direct link between NGAL and depression/anxiety associated behavior. In this review we focus on the role of NGAL in linking depression and cardiovascular disease.

Depression adversely affects prognosis in heart failure (HF) patients. Inflammation is indicated as potential biological pathway in this co-morbidity. Since increased levels of the cytokine Neutrophil Gelatinase-Associated Lipocalin (NGAL) are predictive for HF prognosis, and recently indicated in patients with major depression, this study examined the association of serum NGAL levels with symptoms of depression in patients with HF. Serum NGAL levels were measured in 104 patients with HF (left ventricular ejection fraction, LVEF ⩽ 40). Depression, evaluated using the Beck Depression Inventory (BDI; total score, somatic and cognitive component), and the Hamilton Depression Rating scale (HAMD), at baseline and 12 months follow-up, was associated with NGAL levels using mixed model analysis. Analyses were adjusted for demographics measures, disease severity indicators, inflammation, comorbidity and medication. Increased serum NGAL levels were significantly associated with depression measured by HAMD (baseline: r = 0.25, p < .05) and BDI (baseline: r = 0.22, p < .05; 12 months: r = 0.37, p < .01). This association remained significant after adjustment for covariates; age, sex, time, LVEF, and creatinine (HAMD, t = 2.01, p = .047; BDI, t = 2.28, p = .024). NGAL was significantly associated with somatic- (p = 0.004), but not cognitive depressive symptoms (p = 0.32). NGAL levels were associated with the experienced HF-related functional limitations (6 min walk test), rather than the severity of cardiac dysfunction (LVEF). This study indicates that depression in patients with chronic HF is associated with elevated NGAL levels, independent of clinical severity of the underlying disease. Keywords: Lipocalin 2, Depression, Cognitive and somatic depressive symptoms, Inflammation, Heart failure, Follow-up

Neutrophil gelatinase-associated lipocalin (NGAL) has recently gained interest as a marker for neuroinflammation and associated behavioral dysfunction. We aimed to explore the link between NGAL and behavior in a rat model of postoperative cognitive dysfunction (POCD). Material collected in two previous studies on POCD was analyzed and associated with outcomes for exploratory behavior and spatial learning. Plasma and hippocampal NGAL and microglial activity were analyzed. Pearson's correlations and backward linear regression were performed to study the associations between behavioral parameters, NGAL concentrations, and microglial activity. Plasma and hippocampal NGAL were increased following surgery. Plasma NGAL was associated with impaired spatial learning only, microglial activity was associated with exploratory behavior only, while hippocampal NGAL was associated with both behavioral aspects. Spatial learning was best predicted by a model containing plasma NGAL concentrations and hippocampal microglial activity. NGAL may serve as a sensitive marker in connecting the peripheral inflammatory state to POCD, while postoperative changes in exploratory behavior are better reflected by hippocampal neuroinflammation. These findings warrant further exploration in the role of NGAL in development of postoperative behavioral deficits.

Objectives. Neutrophil gelatinase-associated lipocalin (NGAL) is an inflammatory marker associated with the pathophysiology of heart failure (HF), the psychopathology of depression and the co-existing symptoms of depression in HF patients. The aim of this study is to determine whether the association of serum NGAL levels with depressive symptoms dimensions in HF is independent of well-known inflammatory markers. Methods. Serum NGAL, high sensitive C-reactive protein (hsCRP), tumour necrosis factor-α (TNF-α), its two soluble receptors; sTNFR1, sTNFR2, Interleukin-6 (IL-6) and leukocytes were measured in 104 patients with HF at baseline and 12 months. Depressive symptoms were evaluated using the Beck Depression Inventory (BDI) at both timepoints. Correlations between NGAL and inflammatory markers and depressive symptoms dimensions were determined. The effect of hsCRP, IL-6, TNF-α, sTNFR1, sTNFR2 and leukocytes on the association of NGAL with depressive symptoms was determined and adjusted for time, demographics, cardiac disease severity, and kidney function. Results. NGAL levels were significantly correlated with hsCRP, TNF-α, sTNFR1, sTNFR2 and leukocytes. NGAL was significantly associated with somatic depressive symptoms, independent of abovementioned markers. Conclusions. Serum NGAL is an independent inflammatory marker for somatic depressive symptoms in HF and may function as an immunopathogen linking somatic symptoms of depression to HF.Keywords:: Lipocalin 2, cognitive and somatic depressive symptoms, tumor necrosis factor alpha, interleukin-6, C reactive protein

Heart failure increases the risk to develop depression, which worsens prognosis. Plasma Neutrophil Gelatinase-Associated Lipocalin (NGAL), associated with heart failure as well as with depression, is found increased in cardiomyocytes weeks after myocardial infarction (MI) in rats. This study was aimed to investigate the role of NGAL in depressive symptoms in MI rats. Male Wistar rats were subjected to coronary artery ligation (MI) or sham surgery. Three weeks later, depressive symptoms were obtained from the open field test. Plasma levels of NGAL were measured with Elisa, and NGAL expression in the brain was obtained using immunohistochemistry. Plasma NGAL levels were increased related to infarct size (r=0.78, p=0.013, N=9). NGAL expression in the paraventricular nucleus of the hypothalamus was increased in MI compared to sham rats (45±7 vs 26±3 NGAL+ cells per high power field), irrespective of plasma NGAL levels. The increased number of NGAL positive cells in the paraventricular nucleus of the hypothala...

It is now recognized that myocardial infarction (MI) leads to changes in the brain, which may be linked to mental problems. Myocardial infarction (MI) evokes TNF-alpha expression and microglia activation in the paraventricular nucleus of the hypothalamus (PVN), reflecting neuroinflammation. Here we studied the effect of TNF-alpha interference on microglia activity after MI. Male 12-week old c57bl/6 mice underwent coronary artery ligation or sham surgery. MI mice were treated with either saline, Etanercept, a TNF-R1 antagonist or a TNF-R2 agonist. Sham mice received saline injections. Mice were sacrificed 18 days later and the PVN and hippocampus were stained for microglia. Microglia activity score was based on morphology, as we calculated the ratio of cell body/total cell size. In the PVN, we found a significant decrease in the number of microglia in the MI + TNF-R2 agonist group compared to sham ( p p