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Microglia become progressively activated and seemingly dysfunctional with age, and genetic studies have linked these cells to the pathogenesis of a growing number of neurodegenerative diseases. Here we report a striking buildup of lipid droplets in microglia with aging in mouse and human brains. These cells, which we call ‘lipid-droplet-accumulating microglia’ (LDAM), are defective in phagocytosis, produce high levels of reactive oxygen species and secrete proinflammatory cytokines. RNA-sequencing analysis of LDAM revealed a transcriptional profile driven by innate inflammation that is distinct from previously reported microglial states. An unbiased CRISPR–Cas9 screen identified genetic modifiers of lipid droplet formation; surprisingly, variants of several of these genes, including progranulin (GRN), are causes of autosomal-dominant forms of human neurodegenerative diseases. We therefore propose that LDAM contribute to age-related and genetic forms of neurodegeneration.Microglia in the aging hippocampus accumulate lipid droplets, and are functionally impaired and inflamed. Lipid droplet formation in microglia is regulated by genes linked to neurodegeneration such as progranulin.

As human life expectancy has improved rapidly in industrialized societies, age-related cognitive impairment presents an increasing challenge. Targeting histopathological processes that correlate with age-related cognitive declines, such as neuroinflammation, low levels of neurogenesis, disrupted blood–brain barrier and altered neuronal activity, might lead to structural and functional rejuvenation of the aged brain. Here we show that a 6-week treatment of young (4 months) and old (20 months) rats with montelukast, a marketed anti-asthmatic drug antagonizing leukotriene receptors, reduces neuroinflammation, elevates hippocampal neurogenesis and improves learning and memory in old animals. By using gene knockdown and knockout approaches, we demonstrate that the effect is mediated through inhibition of the GPR17 receptor. This work illustrates that inhibition of leukotriene receptor signalling might represent a safe and druggable target to restore cognitive functions in old individuals and paves the way for future clinical translation of leukotriene receptor inhibition for the treatment of dementias. The leukotriene receptor antagonist montelukast is an anti-asthmatic drug. Here, the authors show that montelukast reduces neuroinflammation, promotes hippocampal neurogenesis and restores learning and memory in old rats suffering from ageing-associated cognitive dysfunction.

Dementia with Lewy bodies (DLB) represents a huge medical need as it accounts for up to 30% of all dementia cases, and there is no cure available. The underyling spectrum of pathology is complex and creates a challenge for targeted molecular therapies. We here tested the hypothesis that leukotrienes are involved in the pathology of DLB and that blocking leukotrienes through Montelukast, a leukotriene receptor antagonist and approved anti-asthmatic drug, might alleviate pathology and restore cognitive functions. Expression of 5-lipoxygenase, the rate-limiting enzyme for leukotriene production, was indeed elevated in brains with DLB. Treatment of cognitively deficient human alpha-synuclein overexpressing transgenic mice with Montelukast restored memory. Montelukast treatment resulted in modulation of beclin-1 expression, a marker for autophagy, and in a reduction in the human alpha-synulcein load in the transgenic mice. Reducing the protein aggregation load in neurodegenerative diseases might be a novel model of action of Montelukast. Moreover, this work presents leukotriene signaling as a potential drug target for DLB and shows that Montelukast might be a promising drug candidate for future DLB therapy development.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

5-Bromo-2′-deoxyuridin (BrdU) is frequently used in anaylsis of neural stem cell biology, in particular to label and to fate-map dividing cells. However, up to now, only a few studies have addressed the question as to whether BrdU labeling per se affects the cells to be investigated. Here, we focused on the potential impact of BrdU on neurosphere cultures derived from the adult rat brain and on proliferation of progenitors in vivo. In vitro, neurospheres were pulsed for 48 h with BrdU, and cell proliferation, cell cycle, differentiation, survival and adhesion properties were subsequently analyzed. BrdU inhibited the expansion of neural progenitors as assessed by MTS assay and increased the fraction of cells in the G0/G1-phase of the cell cycle. Moreover, BrdU increased cell death and dose-dependently induced adherence of NPCs. Cell adherence was accompanied by a reduced amount of active matrix-metalloproteinase-2 (MMP-2). Furthermore, BrdU repressed neuronal and oligodendroglial differentiation, whereas astroglial fate was not affected. In contrast to the in vitro situation, BrdU apparently did not influence endogenous proliferation of NPCs or neurogenesis in concentrations that are typically used for labeling of neural progenitors in vivo. Our results reveal so far uncharacterized effects of BrdU on adult NPCs. We conclude that, because of its ubiquitous use in stem cell biology, any potential effect of BrdU of NPCs has to be scrutinized prior to interpretation of data.

Speculations on the involvement of hippocampal neurogenesis, a form of neuronal plasticity, in the aetiology of depression and the mode of action of antidepressive therapies, started to arise more than a decade ago. But still, conclusive evidence that adult neurogenesis contributes to antidepressive effects of pharmacological and physical therapies has not been generated yet. This review revisits recent findings on the close relation between the mode(s) of action of electroconvulsive therapy (ECT), a powerful intervention used as second-line treatment of major depression disorders, and the neurogenic response to ECT. Following application of electroconvulsive shocks, intricate interactions between neurogenesis, angiogenesis, and microglia activation, the hypothalamic-pituitary-adrenal axis and the secretion of neurotrophic factors have been documented. Furthermore, considering the fact that neurogenesis strongly diminishes along aging, we investigated the response to electroconvulsive shocks in young as well as in aged cohorts of mice.

Objective: Nontraumatic spinal cord injuries (NTSCIs) form a heterogeneous group of diseases, which may evolve into a life-threatening condition. We sought to characterize spectrum, causes of admission and predictors of death in patients with NTSCI treated at the neurological intensive care unit (NICU). Methods: We performed a retrospective observational analysis of NTSCI cases treated at a tertiary care center between 2001 and 2013. Among the 3937 NICU admissions were 93 patients with NTSCI (2.4%). Using multivariate logistic regression analysis, we examined predictors of mortality including demographics, etiology, reasons for admission and GCS/SAPS (Glasgow Coma Scale/Simplified Acute Physiology Score) scores. Results: Infectious and inflammatory/autoimmune causes made up 50% of the NTSCI cases. The most common reasons for NICU admission were rapidly progressing paresis (49.5%) and abundance of respiratory insufficiency (26.9%). The mortality rate was 22.6% and 2.5-fold higher than in the cohort of all other patients treated at the NICU. Respiratory insufficiency as the reason for NICU admission [odds ratio (OR) 4.97, 95% confidence interval (CI) 1.38–17.9; p < 0.01], high initial SAPS scores (OR 1.04; 95% CI 1.003–1.08; p = 0.04), and the development of acute kidney injury throughout the stay (OR 7.25, 1.9–27.5; p = 0.004) were independent risk factors for NICU death. Conclusions: Patients with NTSCI account for a subset of patients admitted to the NICU and are at risk for adverse outcome. A better understanding of predisposing conditions and further knowledge of management of critically ill patients with NTSCI is mandatory.

Members of the transforming growth factor (TGF)‐β family govern a wide range of mechanisms in brain development and in the adult, in particular neuronal/glial differentiation and survival, but also cell cycle regulation and neural stem cell maintenance. This clearly created some discrepancies in the field with some studies favouring neuronal differentiation/survival of progenitors and others favouring cell cycle exit and neural stem cell quiescence/maintenance. Here, we provide a unifying hypothesis claiming that through its regulation of neural progenitor cell (NPC) proliferation, TGF‐β signalling might be responsible for (i) maintaining stem cells in a quiescent stage, and (ii) promoting survival of newly generated neurons and their functional differentiation. Therefore, we performed a detailed histological analysis of TGF‐β1 signalling in the hippocampal neural stem cell niche of a transgenic mouse that was previously generated to express TGF‐β1 under a tetracycline regulatable Ca‐Calmodulin kinase promoter. We also analysed NPC proliferation, quiescence, neuronal survival and differentiation in relation to elevated levels of TGF‐β1 in vitro and in vivo conditions. Finally, we performed a gene expression profiling to identify the targets of TGF‐β1 signalling in adult NPCs. The results demonstrate that TGF‐β1 promotes stem cell quiescence on one side, but also neuronal survival on the other side. Thus, considering the elevated levels of TGF‐β1 in ageing and neurodegenerative diseases, TGF‐β1 signalling presents a molecular target for future interventions in such conditions.

Adult neurogenesis is a tightly regulated process continuously taking place in the central nervous system of most mammalian species. In neuroscience research, transgenic animals bearing the tamoxifen-inducible CreER -Lox system are widely used. In this study, we made use of a Nestin-CreER /R26R-YFP transgenic mouse model in which the CreER activates the expression of YFP in multipotent neural stem cells upon tamoxifen application. Humoral factors, such as the levels of estrogens, have been reported to affect the hippocampal neurogenesis. The application of tamoxifen, a mixed agonist/antagonist of the estrogen receptor that permeates the blood-brain-barrier, could thus influence adult neurogenesis. Although the functions of adult neurogenesis are yet to be fully deciphered, a reciprocal interaction between rates of neurogenesis on the one hand and learning and mood regulation on the other hand, has been suggested. The impact of tamoxifen on neurogenesis and behavior was therefore addressed following five daily applications according to the open field test, the elevated plus maze, and Morris water maze. In addition, the impact of short-term tamoxifen application on progenitor cell proliferation, morphology, and fate in the neurogenic niche of the dentate gyrus were investigated. Finally, the influence of the route of administration (oral vs. intra-peritoneal) and gender-specific response were scrutinized. The sub-acute analysis did neither reveal significant differences in behavior, such as voluntary motor activity, anxiety behavior, and spatial learning, nor in cell proliferation, cell survival, dendritic arborization or maturation rate within the dentate gyrus between saline solution-, corn oil-, and tamoxifen-treated groups. Finally, neither the route of application, nor the gender of treated mice influenced the response to tamoxifen. We conclude that short tamoxifen treatments used to activate the CreER system in transgenic mouse models does not have a measurable impact on adult neurogenesis or the here tested behavior, and is therefore appropriate for most studies in the field.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.