Lipocalin 2 as a link between ageing, risk factor conditions and age-related brain diseases.

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.

Vaccination Prevented Short-Term Memory Loss, but Deteriorated Long-Term Spatial Memory in Alzheimer's Disease Mice, Independent of Amyloid-ß Pathology.

BACKGROUND: Soluble oligomeric amyloid-ß (Aß), rather than Aß plaques, seems to be the culprit in Alzheimer's disease (AD). Accordingly, a new concept vaccine of small cyclic peptide conjugates, selectively targeting oligomeric Aß, 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 Aß pathology were studied by plaque load (immunohistochemistry; 6E10) and antibody titers against Aß (ELISA). AD behavioral phenotype was evaluated by performance in a battery of cognitive tests. RESULTS: J20 mice displayed age-related Aß plaque development and an AD-like behavioral phenotype. A consistent antibody response to the cyclic peptides was, however, not extended to Aß, 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-Aß treatment. Early vaccination prevented short-term memory loss at later ages, but deteriorated long-term spatial memory, however without affecting Aß pathology. Later vaccination had no effects, but optimal timing may require further investigation.

Neutrophil gelatinase-associated lipocalin and microglial activity are associated with distinct postoperative behavioral changes in rats.

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.

Differences in the association between behavior and neutrophil gelatinase-associated lipocalin in male and female rats after coronary artery ligation.

Heart failure is associated with an increased risk of developing depression and cognitive dysfunction, which negatively affects prognosis. Plasma levels of neutrophil gelatinase associated lipocalin (NGAL) are increased in heart failure and depression. Moreover, NGAL levels are associated with depression in heart failure patients. Since women are at a higher risk of developing comorbid depression with heart failure, the aim of this study was to examine sex differences in the link between NGAL and behavior in a rat model of heart failure. In young adult male and female Wistar rats, myocardial infarction (MI) was induced by means of coronary artery ligation, while control rats received sham surgery. We analyzed aspects of cognition and depression/anxiety using various behavioral tests starting three weeks after surgery. Hemodynamic measurements were performed and hearts and lungs were weighed. NGAL levels in plasma, cerebrospinal fluid (CSF) and brain tissue were analyzed. MI induced impairment in cardiac contractility and relaxation, and an increase in lung weight. NGAL correlated with signs of heart failure in male, but not female rats. Male MI rats displayed cognitive problems, but not depressive-like or anxiety-like behavior. No behavioral effects of MI were observed in female rats. Plasma NGAL levels were higher in male than female rats with higher concentrations in MI compared to sham. CSF NGAL was higher in MI rats compared to sham and higher in males compared to females. The number of NGAL positive cells in the paraventricular nucleus of the hypothalamus (PVN) was only increased in male MI rats. In male, but not in female rats, NGAL levels correlated with depressive-like behavior and cognitive dysfunction. Data indicate that while MI increased NGAL levels in plasma, CSF and PVN, correlations of NGAL with behavior are sex-specific, but independent of whether sham or MI surgery was performed. This suggests that inflammatory processes related to thorax surgery and their potential effects on depressive-like behavior and cognition may be sex-specific.

NGAL and other markers of inflammation as competitive or complementary markers for depressive symptom dimensions in heart failure.

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.

Neutrophil Gelatinase-Associated Lipocalin and depression in patients with chronic heart failure.

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 12months 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; 12months: 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 (6min 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.