Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides

Despite increasing evidence supporting the neuroinflammatory theory of depression, little is known about cerebral macrophages in individuals suffering from major depression. In the present study, we investigated the morphology and distribution of cells immunostained for the macrophage-specific marker ionized calcium binding adaptor molecule 1 (IBA1) in the dorsal anterior cingulate cortex (dACC) white matter of middle-aged depressed suicides and matched non-psychiatric controls. This region is known for its implication in mood disorders, and its white matter compartment was previously found to display hypertrophic astrocytes in depressed suicides. Distributions of IBA1-immunoreactive (IBA-IR) microglial phenotypes were assessed using stereology and cell morphometry, and blood vessels were characterized as being intimately associated with either a high or a low density of IBA1-IR amoeboid-like cells. Total densities of IBA1-IR microglia did not differ between depressed suicides and controls. However, a finer analysis examining relative proportions of microglial phenotypes revealed that the ratio of primed over ramified (“resting”) microglia was significantly increased in depressed suicides. Strikingly, the proportion of blood vessels surrounded by a high density of macrophages was more than twice higher in depressed suicides than in controls, and this difference was strongly significant. Consistent with these observations, gene expression of IBA1 and MCP-1, a chemokine involved in the recruitment of circulating monocytes, was significantly upregulated in depressed suicides. Furthermore, mRNA for CD45, a marker enriched in perivascular macrophages, was also significantly increased in samples from depressed suicides. An increase compared to controls was also observed in the proportion of blood vessels surrounded by a high density of CD45-IR cells, but this difference did not reach significance. These histological and molecular data suggest the recruitment of monocytes in dACC white matter of depressed suicides, although it cannot be excluded that other types of macrophages (including microglia) account for the observed accumulation of macrophages closely associated with blood vessels. Altogether, these findings suggest that the previously reported depression- and suicide-associated increases in circulating pro-inflammatory cytokines may be associated with low-grade cerebral neuroinflammation involving the recruitment of circulating monocytes.     

Therapeutic implications of the prostaglandin pathway in Alzheimer's disease

An important pathologic hallmark of Alzheimer's disease (AD) is neuroinflammation, a process characterized in AD by disproportionate activation of cells (microglia and astrocytes, primarily) of the non-specific innate immune system within the CNS. While inflammation itself is not intrinsically detrimental, a delicate balance of pro- and anti-inflammatory signals must be maintained to ensure that long-term exaggerated responses do not damage the brain over time. Non-steroidal anti-inflammatory drugs (NSAIDs) represent a broad class of powerful therapeutics that temper inflammation by inhibiting cyclooxygenase-mediated signaling pathways including prostaglandins, which are the principal mediators of CNS neuroinflammation. While historically used to treat discrete or systemic inflammatory conditions, epidemiologic evidence suggests that protracted NSAID use may delay AD onset, as well as decrease disease severity and rate of progression. Unfortunately, clinical trials with NSAIDs have thus far yielded disappointing results, including premature discontinuation of a large-scale prevention trial due to unexpected cardiovascular side effects. Here we review the literature and make the argument that more targeted exploitation of downstream prostaglandin signaling pathways may offer significant therapeutic benefits for AD while minimizing adverse side effects. Directed strategies such as these may ultimately help to delay the deleterious consequences of brain aging and might someday lead to new therapies for AD and other chronic neurodegenerative diseases.     

SARS-CoV-2 consequences for mental health: Neuroinflammatory pathways linking COVID-19 to anxiety and depression

The coronavirus disease 2019 (COVID-19) pandemic has been linked to an increased prevalence of mental health disorders, particularly anxiety and depression. Moreover, the COVID-19 pandemic has caused stress in people worldwide due to several factors, including fear of infection; social isolation; difficulty in adapting to new routines; lack of coping methods; high exposure to social media, misinformation, and fake reports; economic impact of the measures implemented to slow the contagion and concerns regarding the disease pathogenesis. COVID-19 patients have elevated levels of pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α, and other inflammation-related factors. Furthermore, invasion of the central nervous system by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may potentially contribute to neuroinflammatory alterations in infected individuals. Neuroinflammation, a consequence of psychological stress due to the COVID-19 pandemic, may also play a role in the development of anxiety and depressive symptoms in the general population. Considering that neuroinflammation plays a significant role in the pathophysiology of depression and anxiety, this study investigated the effects of SARS-CoV-2 on mental health and focused on the impact of the COVID-19 pandemic on the neuroinflammatory pathways.     

Glial cells in Alzheimer’s disease: From neuropathological changes to therapeutic implications

Alzheimer's disease (AD) is a neurodegenerative disorder that usually develops slowly and progressively worsens over time. Although there has been increasing research interest in AD, its pathogenesis is still not well understood. Although most studies primarily focus on neurons, recent research findings suggest that glial cells (especially microglia and astrocytes) are associated with AD pathogenesis and might provide various possible therapeutic targets. Growing evidence suggests that microglia can provide protection against AD pathogenesis, as microglia with weakened functions and impaired responses to Aβ proteins are linked with elevated AD risk. Interestingly, numerous findings also suggest that microglial activation can be detrimental to neurons. Indeed, microglia can induce synapse loss via the engulfment of synapses, possibly through a complement-dependent process. Furthermore, they can worsen tau pathology and release inflammatory factors that cause neuronal damage directly or through the activation of neurotoxic astrocytes. Astrocytes play a significant role in various cerebral activities. Their impairment can mediate neurodegeneration and ultimately the retraction of synapses, resulting in AD-related cognitive deficits. Deposition of Aβ can result in astrocyte reactivity, which can further lead to neurotoxic effects and elevated secretion of inflammatory mediators and cytokines. Moreover, glial-induced inflammation in AD can exert both beneficial and harmful effects. Understanding the activities of astrocytes and microglia in the regulation of AD pathogenesis would facilitate the development of novel therapies. In this article, we address the implications of microglia and astrocytes in AD pathogenesis. We also discuss the mechanisms of therapeutic agents that exhibit anti-inflammatory effects against AD.     

腹腔注射LPS建立认知功能障碍相关的中枢神经系统免疫炎症小鼠模型

目的:建立认知功能障碍相关的中枢神经系统免疫炎症小鼠模型。方法:实验采用9~11周的C57/6J雄性小鼠,腹腔注射脂多糖(lipopolysaccharide,LPS)500μg/kg或750μg/kg。采用Morris水迷宫和避暗实验评价小鼠的认知功能,爬杆试验检测小鼠的运动协调性。免疫荧光法观察小鼠海马区神经元特异性微管相关蛋白2(microtubule-associated protein 2,MAP-2)的表达和小胶质细胞的形态和数量。Western blot实验检测小鼠脑组织匀浆液中环氧合酶2(cyclo-oxygenase-2,COX-2)和诱导型一氧化氮合酶(inducible nitric oxide synthase,iNOS)蛋白的表达。结果:Morris水迷宫结果提示,与对照组相比,LPS组小鼠逃避潜伏期延长,目标象限停留时间及穿越目标象限次数减少(P0.05);避暗实验结果提示LPS组均能使小鼠的潜伏期缩短,错误次数增加(P0.05);爬杆实验结果提示LPS组小鼠爬完全程时间高于正常对照组;LPS组小鼠海马区的神经元减少,小胶质细胞增加,COX-2和i NOS蛋白表达增加(P0.01)。结论:腹腔注射LPS可引起小鼠认知功能障碍,模拟认知功能障碍相关的中枢炎症动物模型。     

The effect of diesel exhaust exposure on blood–brain barrier integrity and function in a murine model

Epidemiological studies indicate that exposure to diesel exhaust (DE) is associated with vascular‐based disorders. To investigate the effect of DE on blood–brain barrier (BBB) function and integrity, 8‐week‐old BALB/c mice were randomized to DE in a cyclical treatment regimen over a 2‐week period. Functional integrity of BBB was determined by considering brain parenchymal abundance of IgG within the hippocampal formation and cortex at 6 h and 24 h intervals following final exposure treatment. Neurovascular inflammation was expressed as the abundance of glial fibrillar acidic protein. Two doses of DE were studied and compared to air‐only treated mice. Mice exposed to DE had substantially greater abundance of parenchymal IgG compared to control mice not exposed to DE. Increased parenchymal glial fibrillar acidic protein at 24 h post‐DE exposure suggested heightened neurovascular inflammation. Our findings are proof‐of‐concept that inhalation of DE can compromise BBB function and support the broader contention that DE exposure may contribute to neurovascular disease risk. Copyright © 2014 John Wiley & Sons, Ltd.     

Novel imaging tools for investigating the role of immune signalling in the brain

The importance of neuro-immune interactions in both physiological and pathophysiological states cannot be overstated. As our appreciation for the neuroimmune nature of the brain and spinal cord grows, so does our need to extend the spatial and temporal resolution of our molecular analysis techniques. Current imaging technologies applied to investigate the actions of the neuroimmune system in both health and disease states have been adapted from the fields of immunology and neuroscience. While these classical techniques have provided immense insight into the function of the CNS, they are however, inherently limited. Thus, the development of innovative methods which overcome these limitations are crucial for imaging and quantifying acute and chronic neuroimmune responses. Therefore, this review aims to convey emerging novel and complementary imaging technologies in a form accessible to medical scientists engaging in neuroimmune research.     

Measurement of Serum,Liver, and Brain Cytokine Induction,Thiamine Levels,and Hepatopathology in Rats Exposed to a 4‐Day Alcohol Binge Protocol

Background: In rodent and human studies, ethanol (EtOH) exposure is associated with elevated brain levels of the magnetic resonance spectroscopy (MRS) signal representing choline‐containing compounds (Cho). One interpretation of elevated brain Cho is that it is a marker of neuroinflammation, and some evidence suggests that EtOH exposure promotes neuroinflammation. This study aimed to determine whether binge EtOH exposure (intragastric 3 g/kg 25% EtOH every 8 hours for 4 days) would induce the expression of certain cytokines in blood, liver, or brain, thereby supporting the neuroinflammation hypothesis of elevated Cho. Methods: Ten of 18 wild‐type male Wistar rats (～322 g at baseline) were exposed to EtOH and attained average blood alcohol levels of ～315 mg/dl across 4 days. Blood for cytokine immunoassays was collected at baseline, after 5 doses of EtOH (binge), and immediately preceding euthanasia either 4 or 24 hours after the last dose of EtOH. Blood was additionally assayed for the levels of thiamine and liver enzymes; liver histopathology was performed postmortem; and tissue from liver and 6 brain regions was assayed for the potential induction of 7 cytokines. Results: There were no group effects on the levels of thiamine or its phosphate derivatives, thiamine monophosphate or thiamine diphosphate. ANOVAs of liver enzyme levels indicated that only alkaline phosphatase (ALP) levels were higher in the EtOH group than in control group at binge; ALP elevations, however, are difficult to explain in the absence of changes in the levels of additional liver enzymes. Postmortem liver pathology provided evidence for minimal microvesicular lipidosis and portocentric fibrosis in the EtOH group. Group effects on the levels of the measured cytokines in the blood (TNF‐α, IFN‐γ, IL‐1β, IL‐4, IL‐5, IL‐13, and GRO/CXCL1) were not significant. Similarly, postmortem evaluation of liver cytokines did not reveal group effects. Postmortem evaluation of the 7 cytokines in 6 brain regions (anterior cerebellar vermis, cingulate cortex, frontal cortex, hippocampus, hypothalamus, striatum) also failed to identify group effects. Conclusions: A single 4‐day bout of binge EtOH exposure alone was insufficient to induce the expression of 7 cytokines in blood, liver, or 6 brain regions of wild‐type Wistar rats. Alternative interpretations for elevations in brain Cho in response to a 4‐day binge EtOH treatment are therefore necessary and may include induction of cytokines not measured herein or other noninflammatory mechanisms.     

Long-lasting impairment in hippocampal neurogenesis associated with amyloid deposition in a knock-in mouse model of familial Alzheimer's disease

Neurogenesis in the adult hippocampus has been implicated in regulating long-term memory and mood, but its integrity in Alzheimer's disease (AD) is uncertain. Studies of neurogenesis in transgenic mouse models of familial AD are complicated by ectopic overexpression restricted to terminally differentiated neurons, while AD cases have been studied only at the pre-senile or end-stage of disease. To investigate further the fidelity of adult neurogenesis, we examined mice carrying targeted mutations in amyloid precursor protein (APP), presenilin-1 (PS-1), or both APP and PS-1, in which FAD-causing mutations have been inserted into their endogenous genes. The latter “double knock-in” mice developed aging- and region-dependent amyloid deposition starting around 6 months, and by 9 months exhibited microglial activation associated with the amyloid. In the 9-month-old dentate gyrus, the double knock-in mutations reduced the numbers of MCM2-positive neural stem and progenitor cells by 3-fold and doublecortin-positive neuroblasts by 2-fold. The reduction in dentate neuroblasts persisted at 18 months of age. The impairment in neurogenesis was confirmed by quantitative Western blot analysis of doublecortin content and was restricted to the hippocampal but not the olfactory bulb neurogenic system. In contrast, neither mutant PS-1 nor APP alone led to amyloid deposition or significant alterations in the two markers. These results demonstrate long-lasting and selective impairment in adult hippocampal neurogenesis in a knock-in mutant mouse model of FAD and suggest a novel mechanism by which amyloid and its attendant microglia-mediated neuroinflammation could contribute to the cognitive and behavioral abnormalities of AD.