Animal Model of Neonatal Immune Challenge by Lipopolysaccharide: A Study of Sex Influence in Behavioral and Immune/Neurotrophic Alterations in Juvenile Mice.

INTRODUCTION: The prenatal/perinatal exposure to infections may trigger neurodevelopmental alterations that lead to neuropsychiatric disorders such as autism spectrum disorder (ASD). Previous evidence points to long-term behavioral consequences, such as autistic-like behaviors in rodents induced by lipopolysaccharide (LPS) pre- and postnatal (PN) exposure during critical neurodevelopmental periods. Additionally, sex influences the prevalence and symptoms of ASD. Despite this, the mechanisms underlying this influence are poorly understood. We aim to study sex influences in behavioral and neurotrophic/inflammatory alterations triggered by LPS neonatal exposure in juvenile mice at an approximate age of ASD diagnosis in humans. METHODS: Swiss male and female mice on PN days 5 and 7 received a single daily injection of 500 µg/kg LPS from Escherichia coli or sterile saline (control group). We conducted behavioral determinations of locomotor activity, repetitive behavior, anxiety-like behavior, social interaction, and working memory in animals on PN25 (equivalent to 3-5 years old of the human). To determine BDNF levels in the prefrontal cortex and hippocampus, we used animals on PN8 (equivalent to a human term infant) and PN25. In addition, we evaluated iba-1 (microglia marker), TNFα, and parvalbumin expression on PN25. RESULTS: Male juvenile mice presented repetitive behavior, anxiety, and working memory deficits. Females showed social impairment and working memory deficits. In the neurochemical analysis, we detected lower BDNF levels in brain areas of female mice that were more evident in juvenile mice. Only LPS-challenged females presented a marked hippocampal expression of the microglial activation marker, iba-1, and increased TNFα levels, accompanied by a lower parvalbumin expression. DISCUSSION/CONCLUSION: Male and female mice presented distinct behavioral alterations. However, LPS-challenged juvenile females showed the most prominent neurobiological alterations related to autism, such as increased microglial activation and parvalbumin impairment. Since these sex-sensitive alterations seem to be age-dependent, a better understanding of changes induced by the exposure to specific risk factors throughout life represents essential targets for developing strategies for autism prevention and precision therapy.

Optimal Formula of Angelica sinensis Ameliorates Memory Deficits in ß-amyloid Protein-induced Alzheimer's Disease Rat Model.

OBJECTIVE: Angelica (A.) sinensis is used as a traditional medical herb for the treatment of neurodegeneration, aging, and inflammation in Asia. A. sinensis optimal formula (AOF) is the best combination in A. sinensis that has been screened to rescue the cognitive ability in ß-amyloid peptide (Aß25-35)-treated Alzheimer's disease (AD) rats. The objective of this study was to investigate the effect of AOF on the learning and memory of AD rats as well as to explore the underlying mechanisms. METHODS: Male Wistar rats were infused with Aß25-35 for AD model induction or saline (negative control). Five groups of AD rats were fed on AOF at 20, 40, or 80 mL/kg every day, donepezil at 0.9 mg/kg every day (positive control), or an equal volume of water (AD model) intragastrically once a day for 4 weeks, while the negative control rats were fed on water. The Morris water maze test was used to evaluate the cognitive function of the rats. The Aß accumulation, cholinergic levels, and antioxidative ability were detected by ELISA. Additionally, the candidate mechanism was determined by gene sequencing and quantitative real-time polymerase chain reaction. RESULTS: The results showed that AOF administration significantly ameliorated Aß25-35-induced memory impairment. AOF decreased the levels of amyloid-ß precursor protein and Aß in the hippocampus, rescued the cholinergic levels, increased the activity of superoxide dismutase, and decreased the malondialdehyde level. In addition, AOF inhibited the expression of IL1b, Mpo, and Prkcg in the hippocampus. CONCLUSION: These experimental findings illustrate that AOF prevents the decrease in cognitive function and Aß deposits in Aß25-35-treated rats via modulating neuroinflammation and oxidative stress, thus highlighting a potential therapeutic avenue to promote the co-administration of formulas that act on different nodes to maximize beneficial effects and minimize negative side effects.

Postnatal exposure to lipopolysaccharide combined with high-fat diet consumption induces immune tolerance without prevention in spatial working memory impairment.

High-fat diet (HFD) consumption has been related to metabolic alterations, such as obesity and cardiovascular problems, and has pronounced effects on brain plasticity and memory impairment. HFD exposure has a pro-inflammatory effect associated with microglial cell modifications in the hippocampus, a region involved in the working memory process. Immune tolerance can protect from inflammation in periphery induced by HFD consumption, when the immune response is desensitized in development period with lipopolysaccharide (LPS) exposure, maybe this previously state can change the course of the diseases associated to HFDs but is not known if can protect the hippocampus's inflammatory response. In the present study, male mice were injected with LPS (100 µg.kg-1 body weight) on postnatal day 3 and fed with HFD for 16 weeks after weaning. Ours results indicated that postnatal exposure to LPS in the early postnatal developmental stage combined with HFD consumption prevented glycemia, insulin, HOMA-IR, microglial process, and increased pro-inflammatory cytokines mRNA expression, without changes in body weight gain and spatial working memory with respect vehicle + HFD group. These findings suggest that HFD consumption after postnatal LPS exposure induces hippocampal immune tolerance, without prevention in spatial working memory impairment on male mice.

A role of Na+, K+ -ATPase in spatial memory deficits and inflammatory/oxidative stress after recurrent concussion in adolescent rats.

Sports-related concussions are particularly common during adolescence, and there is insufficient knowledge about how recurrent concussions in this phase of life alter the metabolism of essential structures for memory in adulthood. In this sense, our experimental data revealed that seven recurrent concussions (RC) in 35-day-old rats decreased short-term and long-term memory in the object recognition test (ORT) 30 days after injury. The RC protocol did not alter motor and anxious behavior and the immunoreactivity of brain-derived neurotrophic factor (BDNF) in the cerebral cortex. Recurrent concussions induced the inflammatory/oxidative stress characterized here by increased glial fibrillary acidic protein (GFAP), interleukin 1ß (IL 1ß), 4-hydroxynonenal (4 HNE), protein carbonyl immunoreactivity, and 2',7'-dichlorofluorescein diacetate oxidation (DCFH) levels and lower total antioxidant capacity (TAC). Inhibited Na+,K+-ATPase activity (specifically isoform α2/3) followed by Km (Michaelis-Menten constant) for increased ATP levels and decreased immunodetection of alpha subunit of this enzyme, suggesting that cognitive impairment after RC is caused by the inability of surviving neurons to maintain ionic gradients in selected targets to inflammatory/oxidative damage, such as Na,K-ATPase activity.

Morin attenuates memory deficits in a rat model of Alzheimer's disease by ameliorating oxidative stress and neuroinflammation.

This study aimed to investigate the effect of flavonoid morin on oxidative/nitrosative stress, neuroinflammation, and histological, molecular, and behavioral changes caused by amyloid-beta (Aß)1-42 in male Wistar rats (Alzheimer's disease model). Rats received morin (20 mg/kg, oral gavage) for 14 consecutive days after intrahippocampal injection of Aß1-42. Morin decreased the levels of malondialdehyde and nitric oxide, increased glutathione content, and enhanced catalase activity in the hippocampus of animals receiving Aß1-42. It also reduced the expression of tumor necrosis factor-α, interleukin-1ß, interleukin-6, nuclear factor-kappa B, and N-methyl-D-aspartate receptor subunits 2A and 2B and increased the expression of brain-derived neurotrophic factor and α7 nicotinic acetylcholine receptor in the hippocampus of Aß1-42-injected rats. Besides, morin modified neuronal loss and histological changes in the CA1 region of the hippocampus. Morin allowed Aß1-42-infused rats to swim more time in the target quadrant in the Morris water maze test. It is concluded that morin may be suitable for the prevention and treatment of Alzheimer's disease by strengthening the antioxidant system, inhibiting neuroinflammation, preventing neuronal death, and enhancing memory function.

Decreased convulsive threshold and memory loss after anti-NMDAR positive CSF injection in zebrafish.

Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis initially promotes memory deficits, behavioral changes, and epileptic seizures. We developed a new animal model of anti-NMDAR encephalitis using a single cerebroventricular injection of CSF from patients in adult zebrafish. We observed a reduction of the seizure threshold and recent memory deficits in those animals injected with CSF from patients with anti-NMDAR encephalitis. The locomotor activity was similar in the CSF and control groups. This zebrafish model consistently recapitulates symptoms seen in patients with anti-NMDAR encephalitis. It may provide a reliable, fast and cost-effective platform to investigate new therapeutic strategies to anti-NMDAR encephalitis.

Amyloidogenic, neuroinflammatory and memory dysfunction effects of HIV-1 gp120.

Human immunodeficiency virus 1 (HIV-1) infection can cause several HIV-associated neurocognitive disorders a variety of neurological impairments characterized by the loss of cortical and subcortical neurons and decreased cognitive and motor function. HIV-1 gp120, the major envelope glycoprotein on viral particles, acts as a binding protein for viral entry and is known to be an agent of neuronal cell death. To determine the mechanism of HIV-1 gp120-induced memory dysfunction, we performed mouse intracerebroventricular (i.c.v.) infusion with HIV-1 gp120 protein (300 ng per mouse) and investigated memory impairment and amyloidogenesis. Infusion of the HIV-1 gp120 protein induced memory dysfunction, which was evaluated using passive avoidance and water maze tests. Infusion of HIV-1 gp120 induced neuroinflammation, such as the release of iNOS and COX-2 and the activation of astrocytes and microglia and increased the mRNA and protein levels of IL-6, ICAM-1, M-CSF, TIM, and IL-2. In particular, we found that the infusion of HIV-1 gp120 induced the accumulation of amyloid plaques and signs of elevated amyloidogenesis, such as increased expression of amyloid precursor protein and BACE1 and increased ß-secretase activity. Therefore, these studies suggest that HIV-1 gp120 may induce memory impairment through Aß accumulation and neuroinflammation.

Sodium Houttuyfonate Ameliorates ß-amyloid1-42-Induced Memory Impairment and Neuroinflammation through Inhibiting the NLRP3/GSDMD Pathway in Alzheimer's Disease.

OBJECTIVE: Our research is designed to explore the function of sodium houttuyfonate (SH) on Alzheimer's disease (AD) and its potential molecular mechanisms. METHODS: In our study, the Morris water maze (MWM) test was used to assess the role of SH on spatial learning and memory deficiency in amyloid-ß peptide (Aß)1-42-induced AD mice. We explored the functions of SH on proinflammatory cytokines, neuron apoptosis, and damage in vivo and in vitro by using an enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR), flow cytometry, western blot, and Nissl staining. Moreover, the effect of SH on oxidative stress in vivo and in vitro was also detected. To explore the underlying molecular mechanisms of SH on AD, the expressions of proteins and mRNA involved in the NOD-like receptor pyrin domain containing-3/gasdermin D (NLRP3/GSDMD) pathway were determined using western blot, immunofluorescence staining, and qRT-PCR. RESULTS: Our data demonstrated that SH ameliorated spatial learning and memory deficiency in Aß 1-42-induced AD mice. Moreover, SH significantly improved hippocampal neuron damage and inhibited oxidative stress, neuroinflammation, and neuron apoptosis in Aß 1-42-induced AD mice and PC12 cells. The results also revealed that SH protected Aß 1-42-induced AD through inhibiting the NLRP3/GSDMD pathway. CONCLUSION: The present study demonstrated that SH could ameliorate Aß 1-42-induced memory impairment neuroinflammation and pyroptosis through inhibiting the NLRP3/GSDMD pathway in AD, suggesting that SH may be a potential candidate for AD treatment.

Mild Microglial Responses in the Cortex and Perivascular Macrophage Infiltration in Subcortical White Matter in Dogs with Age-Related Dementia Modelling Prodromal Alzheimer's Disease.

BACKGROUND: Microglia contribute to Alzheimer's disease (AD) pathogenesis by clearing amyloid-ß (Aß) and driving neuroinflammation. Domestic dogs with age-related dementia (canine cognitive dysfunction (CCD)) develop cerebral amyloidosis like humans developing AD, and studying such dogs can provide novel information about microglial response in prodromal AD. OBJECTIVE: The aim was to investigate the microglial response in the cortical grey and the subcortical white matter in dogs with CCD versus age-matched cognitively normal dogs. METHODS: Brains from aged dogs with CCD and age-matched controls without dementia were studied. Cases were defined by dementia rating score. Brain sections were stained for Aß, thioflavin S, hyperphosphorylated tau, and the microglial-macrophage ionized calcium binding adaptor molecule 1 (Iba1). Results were correlated to dementia rating score and tissue levels of Aß. RESULTS: Microglial numbers were higher in the Aß plaque-loaded deep cortical layers in CCD versus control dogs, while the coverage by microglial processes were comparable. Aß plaques were of the diffuse type and without microglial aggregation. However, a correlation was found between the %Iba1 area and insoluble Aß 42 and N-terminal pyroglutamate modified Aß(N3pE)-42. The %Iba1 area was higher in white matter, showing phosphorylation of S396 tau, versus grey matter. Perivascular macrophage infiltrates were abundant in the white matter particularly in CDD dogs. CONCLUSION: The results from this study of the microglial-macrophage response in dogs with CCD are suggestive of relatively mild microglial responses in the Aß plaque-loaded deep cortical layers and perivascular macrophage infiltrates in the subcortical white matter, in prodromal AD.

Adenosine A2A receptor agonist polydeoxyribonucleotide ameliorates short-term memory impairment by suppressing cerebral ischemia-induced inflammation via MAPK pathway.

Cerebral ischemia causes tissue death owing to occlusion of the cerebral blood vessels, and cerebral ischemia activates mitogen-activated protein kinase (MAPK) and induces secretion of pro-inflammatory cytokines. Adenosine A2A receptor agonist, polydeoxyribonucleotide (PDRN), suppresses the secretion of pro-inflammatory cytokines and exhibits anti-inflammatory effect. In the current study, the therapeutic effect of PDRN on cerebral ischemia was evaluated using gerbils. For the induction of cerebral ischemia, the common carotid arteries were exposed, and then aneurysm clips were used to occlude the common carotid arteries bilaterally for 7 minutes. In the PDRN-treated groups, the gerbils were injected intraperitoneally with 0.3 mL of saline containing 8 mg/kg PDRN, per a day for 7 days following cerebral ischemia induction. In order to confirm the participation of the adenosine A2A receptor in the effects mediated by PDRN, 8 mg/kg 7-dimethyl-1-propargylxanthine (DMPX), adenosine A2A receptor antagonist, was treated with PDRN. In the current study, induction of ischemia enhanced the levels of pro-inflammatory cytokines and increased phosphorylation of MAPK signaling factors in the hippocampus and basolateral amygdala. However, treatment with PDRN ameliorated short-term memory impairment by suppressing the production of pro-inflammatory cytokines and inactivation of MAPK signaling factors in cerebral ischemia. Furthermore, PDRN treatment enhanced the concentration of cyclic adenosine-3,5'-monophosphate (cAMP) as well as phosphorylation of cAMP response element-binding protein (p-CREB). Co-treatment of DMPX and PDRN attenuated the therapeutic effect of PDRN on cerebral ischemia. Based on these findings, PDRN may be developed as the primary treatment in cerebral ischemia.

High Mobility Group Protein 1 and Dickkopf-Related Protein 1 in Schizophrenia and Treatment-Resistant Schizophrenia: Associations With Interleukin-6, Symptom Domains, and Neurocognitive Impairments.

BACKGROUND: Schizophrenia (SCZ) and treatment-resistant schizophrenia (TRS) are associated with aberrations in immune-inflammatory pathways. Increased high mobility group protein 1 (HMGB1), an inflammatory mediator, and Dickkopf-related protein (DKK1), a Wnt/ß-catenin signaling antagonist, affect the blood-brain barrier and induce neurotoxic effects and neurocognitive deficits. AIM: The present study aims to examine HMGB1 and DDK1 in nonresponders to treatments (NRTT) with antipsychotics (n = 60), partial RTT (PRTT, n = 55), and healthy controls (n = 43) in relation to established markers of SCZ, including interleukin (IL)-6, IL-10, and CCL11 (eotaxin), and to delineate whether these proteins are associated with the SCZ symptom subdomains and neurocognitive impairments. RESULTS: HMGB1, DKK1, IL-6, and CCL11 were significantly higher in SCZ patients than in controls. DKK1 and IL-6 were significantly higher in NRTT than in PRTT and controls, while IL-10 was higher in NRTT than in controls. Binary logistic regression analysis showed that SCZ was best predicted by increased DDK1 and HMGB1, while NRTT (vs PRTT) was best predicted by increased IL-6 and CCL11 levels. A large part of the variance in psychosis, hostility, excitation, mannerism, and negative (PHEMN) symptoms and formal thought disorders was explained by HMGB1, IL-6, and CCL11, while most neurocognitive functions were predicted by HMGB1, DDK1, and CCL11. CONCLUSIONS: The neurotoxic effects of HMGB1, DKK1, IL-6, and CCL11 including the effects on the blood-brain barrier and the Wnt/ß-catenin signaling pathway may cause impairments in executive functions and working, episodic, and semantic memory and explain, in part, PHEMN symptoms and a nonresponse to treatment with antipsychotic drugs.

Inflammatory cytokines derived from peripheral blood contribute to the modified electroconvulsive therapy-induced cognitive deficits in major depressive disorder.

Little is known about the pathophysiology of memory deficits in patients with major depressive disorder (MDD) treated with modified electroconvulsive therapy (MECT). This study examined the profiles of cytokines, the memory function, and their association in MECT-treated MDD patients. Forty first-episode, drug-free MDD patients and 40 healthy controls were recruited. MECT was started with antidepressant treatment at a stable initial dose. The Wechsler Memory Scale (WMS) and Hamilton Rating Scale for Depression 17 (HRSD-17) were used to assess the cognitive function. MDD patients were divided into the memory impairment group (WMS < 50) and the non-memory impairment group (WMS ≥ 50) based on the total WMS scores after MECT. The levels of NOD-like receptor 3 (NLRP3) inflammasome, interleukin-18 (IL-18) and nuclear factor kappa-B (NF-κB) in the serum were measured. MDD patients showed significantly higher levels of NLRP3 inflammasome, IL-18 and NF-κB than that in the controls prior to MECT, and the levels also significantly increased after MECT. In MDD patients, the serum levels of these inflammatory cytokines were negatively associated with the total WMS scores and likely contributed to the scores independently. The receiver operating characteristic curve showed that the serum levels of these inflammatory cytokines may predict the cognitive impairment risk in MDD patients receiving MECT. Abnormal levels of NLRP3 inflammasome, IL-18 and NF-κB reflecting the disturbed balance of pro-inflammatory and anti-inflammatory mechanisms likely contribute to the MECT-induced cognitive deficits in MDD patients.

Cronobacter sakazakii Infection in Early Postnatal Rats Impaired Contextual-Associated Learning: a Putative Role of C5a-Mediated NF-κß and ASK1 Pathways.

This study was designed to test whether the Cronobacter sakazakii infection-impaired contextual learning and memory are mediated by the activation of the complement system; subsequent activation of inflammatory signals leads to alternations in serotonin transporter (SERT). To test this, rat pups (postnatal day, PND 15) were treated with either C. sakazakii (107 CFU) or Escherichia coli OP50 (107 CFU) or Luria bertani broth (100 µL) through oral gavage and allowed to stay with their mothers until PND 24. Experimental groups' rats were allowed to explore (PNDs 31-35) and then trained in contextual learning task (PNDs 36-43). Five days after training, individuals were tested for memory retention (PNDs 49-56). Observed behavioural data showed that C. sakazakii infection impaired contextual-associative learning and memory. Furthermore, our analysis showed that C. sakazakii infection activates complement system complement anaphylatoxin (C5a) (a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS1)) and mitogen-activated protein kinase kinase1 (MEKK1). Subsequently, MEKK1 induces pro-inflammatory signals possibly through apoptosis signal-regulating kinase-1 (ASK-1), c-Jun N-terminal kinase (JNK1/3) and protein kinase B gamma (AKT-3). In parallel, activated nuclear factor kappa-light-chain-enhancer B cells (NF-κB) induces interleukin-6 (IL-6) and IFNα-1, which may alter the level of serotonin transporter (SERT). Observed results suggest that impaired contextual learning and memory could be correlated with C5a-mediated NF-κß and ASK1 pathways.

Unexpected Transcriptional Programs Contribute to Hippocampal Memory Deficits and Neuronal Stunting after Early-Life Adversity.

Early-life adversity (ELA) is associated with lifelong memory deficits, yet the responsible mechanisms remain unclear. We impose ELA by rearing rat pups in simulated poverty, assess hippocampal memory, and probe changes in gene expression, their transcriptional regulation, and the consequent changes in hippocampal neuronal structure. ELA rats have poor hippocampal memory and stunted hippocampal pyramidal neurons associated with ~140 differentially expressed genes. Upstream regulators of the altered genes include glucocorticoid receptor and, unexpectedly, the transcription factor neuron-restrictive silencer factor (NRSF/REST). NRSF contributes critically to the memory deficits because blocking its function transiently following ELA rescues spatial memory and restores the dendritic arborization of hippocampal pyramidal neurons in ELA rats. Blocking NRSF function in vitro augments dendritic complexity of developing hippocampal neurons, suggesting that NRSF represses genes involved in neuronal maturation. These findings establish important, surprising contributions of NRSF to ELA-induced transcriptional programming that disrupts hippocampal maturation and memory function.

The effect of insomnia on development of Alzheimer's disease.

Alzheimer's disease (AD) is the most common type of dementia and a neurodegenerative disorder characterized by memory deficits especially forgetting recent information, recall ability impairment, and loss of time tracking, problem-solving, language, and recognition difficulties. AD is also a globally important health issue but despite all scientific efforts, the treatment of AD is still a challenge. Sleep has important roles in learning and memory consolidation. Studies have shown that sleep deprivation (SD) and insomnia are associated with the pathogenesis of Alzheimer's disease and may have an impact on the symptoms and development. Thus, sleep disorders have decisive effects on AD; this association deserves more attention in research, diagnostics, and treatment, and knowing this relation also can help to prevent AD through screening and proper management of sleep disorders. This study aimed to show the potential role of SD and insomnia in the pathogenesis and progression of AD.

Effects of electroconvulsive shock on neuro-immune responses: Does neuro-damage occur?

Electroconvulsive therapy (ECT) is one of the most effective treatments for treatment-resistant depression. However, this treatment may produce memory impairment. The mechanisms of the cognitive adverse effects are not known. Neuroimmune response is related to the cognitive deficits. By reviewing the available animal literature, we examined the glia activation, inflammatory cytokines, neuron oxidative stress responses, and neural morphological changes following electroconvulsive shock (ECS) treatment. The studies showed that ECS activates microglia, upregulates neuro-inflammatory cytokines, and increases oxidative stress responses. But these effects are rapid and may be transient. They normalize as ECS treatment continues, suggesting endogenous neuroprotection may be mobilized. The transient changes are well in line with the clinical observations that ECT usually does not cause significant long-lasting retrograde amnesia. The longitudinal studies will be particularly important to explore the dynamic changes of neuroplasticity following ECT (Jonckheere et al., 2018). Investigating the neuroplasticity changes in animals that suffered chronic stress may also be crucial to giving support to the translation of preclinical research.

A Novel Microglia-Specific Transcriptional Signature Correlates With Behavioral Deficits in Neuropsychiatric Lupus.

Neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE) affect over one-half of SLE patients, yet underlying mechanisms remain largely unknown. We demonstrate that SLE-prone mice (CReCOM) develop NP-SLE, including behavioral deficits prior to systemic autoimmunity, reduced brain volumes, decreased vascular integrity, and brain-infiltrating leukocytes. NP-SLE microglia exhibit numerical expansion, increased synaptic uptake, and a more metabolically active phenotype. Microglia from multiple SLE-prone models express a "NP-SLE signature" unrelated to type I interferon. Rather, the signature is associated with lipid metabolism, scavenger receptor activity and downregulation of inflammatory and chemotaxis processes, suggesting a more regulatory, anti-inflammatory profile. NP-SLE microglia also express genes associated with disease-associated microglia (DAM), a subset of microglia thought to be instrumental in neurodegenerative diseases. Further, expression of "NP-SLE" and "DAM" signatures correlate with the severity of behavioral deficits in young SLE-prone mice prior to overt systemic disease. Our data are the first to demonstrate the predictive value of our newly identified microglia-specific "NP-SLE" and "DAM" signatures as a surrogate for NP-SLE clinical outcomes and suggests that microglia-intrinsic defects precede contributions from systemic SLE for neuropsychiatric manifestations.

Microglia mediate forgetting via complement-dependent synaptic elimination.

Synapses between engram cells are believed to be substrates for memory storage, and the weakening or loss of these synapses leads to the forgetting of related memories. We found engulfment of synaptic components by microglia in the hippocampi of healthy adult mice. Depletion of microglia or inhibition of microglial phagocytosis prevented forgetting and the dissociation of engram cells. By introducing CD55 to inhibit complement pathways, specifically in engram cells, we further demonstrated that microglia regulated forgetting in a complement- and activity-dependent manner. Additionally, microglia were involved in both neurogenesis-related and neurogenesis-unrelated memory degradation. Together, our findings revealed complement-dependent synapse elimination by microglia as a mechanism underlying the forgetting of remote memories.

Targeting Cannabinoid Receptor Activation and BACE-1 Activity Counteracts TgAPP Mice Memory Impairment and Alzheimer's Disease Lymphoblast Alterations.

Alzheimer's disease (AD), the leading cause of dementia in the elderly, is a neurodegenerative disorder marked by progressive impairment of cognitive ability. Patients with AD display neuropathological lesions including senile plaques, neurofibrillary tangles, and neuronal loss. There are no disease-modifying drugs currently available. With the number of affected individuals increasing dramatically throughout the world, there is obvious urgent need for effective treatment strategy for AD. The multifactorial nature of AD encouraged the development of multifunctional compounds, able to interact with several putative targets. Here, we have evaluated the effects of two in-house designed cannabinoid receptors (CB) agonists showing inhibitory actions on ß-secretase-1 (BACE-1) (NP137) and BACE-1/butyrylcholinesterase (BuChE) (NP148), on cellular models of AD, including immortalized lymphocytes from late-onset AD patients. Furthermore, the performance of TgAPP mice in a spatial navigation task was investigated following chronic administration of NP137 and NP148. We report here that NP137 and NP148 showed neuroprotective effects in amyloid-ß-treated primary cortical neurons, and NP137 in particular rescued the cognitive deficit of TgAPP mice. The latter compound was able to blunt the abnormal cell response to serum addition or withdrawal of lymphoblasts derived from AD patients. It is suggested that NP137 could be a good drug candidate for future treatment of AD.

Immune checkpoint inhibitor induced anti-glutamic acid decarboxylase 65 (Anti-GAD 65) limbic encephalitis responsive to intravenous immunoglobulin and plasma exchange.

Immune checkpoint inhibitors have made significant advances in available cancer treatment options towards progression-free and overall survival in cancer patients by potentiating own anti-tumor immune response. Anti-programmed death (PD-1) and anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) have been increasingly associated with neurologic complications. LE is a rare complication and like many complications secondary to immunotherapy, there is no standard for evaluation and treatment. Anti-GAD65-associated LE has been associated with thymic carcinoma. We describe a patient who presented with progressive memory loss 2 weeks after her third cycle of Ipilimumab and Nivolumab with associated elevated Anti-GAD65 levels. Treatment with IVIG and PLEX led to complete resolution of her symptoms and improvement in her brain imaging and CSF findings.