Intestinal dysbiosis mediates cognitive impairment via the intestine and brain NLRP3 inflammasome activation in chronic sleep deprivation.

Growing evidence suggests the involvement of the microbiota-gut-brain axis in cognitive impairment induced by sleep deprivation (SD), however how the microbiota-gut-brain axis work remains elusive. Here, we discovered that chronic SD induced intestinal dysbiosis, activated NLRP3 inflammasome in the colon and brain, destructed intestinal/blood-brain barrier, and impaired cognitive function in mice. Transplantation of "SD microbiota" could almost mimic the pathological and behavioral changes caused by chronic SD. Furthermore, all the behavioral and pathological abnormalities were practically reversed in chronic sleep-deprived NLRP3-/- mice. Regional knockdown NLRP3 expression in the gut and hippocampus, respectively. We observed that down-regulation of NLRP3 in the hippocampus inhibited neuroinflammation, and ameliorated synaptic dysfunction and cognitive impairment induced by chronic SD. More intriguingly, the down-regulation of NLRP3 in the gut protected the intestinal barrier, attenuated the levels of peripheral inflammatory factors, down-regulated the expression of NLRP3 in the brain, and improved cognitive function in chronic SD mice. Our results identified gut microbiota as a driver in chronic SD and highlighted the NLRP3 inflammasome as a key regulator within the microbiota-gut-brain axis.

Activation of GSK-3 disrupts cholinergic homoeostasis in nucleus basalis of Meynert and frontal cortex of rats.

The cholinergic impairment is an early marker in Alzheimer's disease (AD), while the mechanisms are not fully understood. We investigated here the effects of glycogen synthase kinse-3 (GSK-3) activation on the cholinergic homoeostasis in nucleus basalis of Meynert (NBM) and frontal cortex, the cholinergic enriched regions. We activated GSK-3 by lateral ventricular infusion of wortmannin (WT) and GF-109203X (GFX), the inhibitors of phosphoinositol-3 kinase (PI3-K) and protein kinase C (PKC), respectively, and significantly decreased the acetylcholine (ACh) level via inhibiting choline acetyl transferase (ChAT) rather than regulating acetylcholinesterase (AChE). Neuronal axonal transport was disrupted and ChAT accumulation occurred in NBM and frontal cortex accompanied with hyperphosphorylation of tau and neurofilaments. Moreover, ChAT expression decreased in NBM attributing to cleavage of nuclear factor-κB/p100 into p52 for translocation into nucleus to lower ChAT mRNA level. The cholinergic dysfunction could be mimicked by overexpression of GSK-3 and rescued by simultaneous administration of LiCl or SB216763, inhibitors of GSK-3. Our data reveal the molecular mechanism that may underlie the cholinergic impairments in AD patients.

Low plasma BDNF is not a biomarker for cognitive dysfunction in elderly T2DM patients.

Type 2 diabetes mellitus (T2DM) is a known cause of cognitive dysfunction, and brain-derived neurotrophic factor (BDNF) is a key protein in promoting memory growth and survival of neurons. However, the relationship between plasma BDNF and diabetic cognitive dysfunction is still elusive. A total of 89 patients over 60 years with T2DM and 40 well-matched health controls were enrolled. All participants received a set of multi-dimensional neuropsychological tests for the cognitive assessment. The subjects were divided into amnesic mild cognitive impairment (aMCI) and non-aMCI groups. An enzyme-linked immunosorbent assay (ELISA) was used to measure plasma BDNF concentrations for all subjects. No significant difference was found between T2DM patients and healthy control in MMSE scores. The T2DM patients performed significantly worse in four cognitive domains (including episodic memory, executive function, visuospatial function, and information processing speed) compared with the controls (all p < 0.05). The prevalence of aMCI in T2DM population was higher [OR = 4.032 (1.536~10.582), 37/89-6/40]. Additionally, the plasma concentration of BDNF in T2DM patients was significantly lower than that in controls (p < 0.01). However, no significant correlation was found between plasma BDNF and cognitive function in T2DM. Our results suggested that T2DM have a higher prevalence of cognitive impairment. The plasma BDNF concentration in T2DM patients was significantly lower than that in controls, but low BDNF was not a biomarker for cognitive dysfunction in T2DM patients.

Glycogen synthase kinase-3 regulates production of amyloid-ß peptides and tau phosphorylation in diabetic rat brain.

The pathogenesis of diabetic neurological complications is not fully understood. Diabetes mellitus (DM) and Alzheimer's disease (AD) are characterized by amyloid deposits. Glycogen synthase kinase-3 (GSK-3) plays an important role in the pathogenesis of AD and DM. Here we tried to investigate the production of amyloid-ß peptides (A ß) and phosphorylation of microtubule-associated protein tau in DM rats and elucidate the role of GSK-3 and Akt (protein kinase B, PKB) in these processes. Streptozotocin injection-induced DM rats displayed an increased GSK-3 activity, decreased activity and expression of Akt. And A ß 40 and A ß 42 were found overproduced and the microtubule-associated protein tau was hyperphosphorylated in the hippocampus. Furthermore, selective inhibition of GSK-3 by lithium could attenuate the conditions of A ß overproduction and tau hyperphosphorylation. Taken together, our studies suggest that GSK-3 regulates both the production of A ß and the phosphorylation of tau in rat brain and may therefore contribute to DM caused AD-like neurological defects.

Phospho-Rb mediating cell cycle reentry induces early apoptosis following oxygen-glucose deprivation in rat cortical neurons.

The aim of this study was to investigate the relationship between cell cycle reentry and apoptosis in cultured cortical neurons following oxygen-glucose deprivation (OGD). We found that the percentage of neurons with BrdU uptake, TUNEL staining, and colocalized BrdU uptake and TUNEL staining was increased relative to control 6, 12 and 24 h after 1 h of OGD. The number of neurons with colocalized BrdU and TUNEL staining was decreased relative to the number of TUNEL-positive neurons at 24 h. The expression of phosphorylated retinoblastoma protein (phospho-Rb) was significantly increased 6, 12 and 24 h after OGD, parallel with the changes in BrdU uptake. Phospho-Rb and TUNEL staining were colocalized in neurons 6 and 12 h after OGD. This colocalization was strikingly decreased 24 h after OGD. Treatment with the cyclin-dependent kinase inhibitor roscovitine (100 µM) decreased the expression of phospho-Rb and reduced neuronal apoptosis in vitro. These results demonstrated that attempted cell cycle reentry with phosphorylation of Rb induce early apoptosis in neurons after OGD and there must be other mechanisms involved in the later stages of neuronal apoptosis besides cell cycle reentry. Phosphoralated Rb may be an important factor which closely associates aberrant cell cycle reentry with the early stages of neuronal apoptosis following ischemia/hypoxia in vitro, and pharmacological interventions for neuroprotection may be useful directed at this keypoint.

DI-3-n-butylphthalide mitigates stress-induced cognitive deficits in mice through inhibition of NLRP3-Mediated neuroinflammation.

Our previous study has demonstrated that chronic stress could cause cognitive deficits and tau pathology. However, the underlying mechanism and whether/how DI-3-n-Butylphthalide (NBP) ameliorates these effects are still unclear. Here, Wild-type mice were subjected to chronic unpredictable and mild stress (CUMS) for 8 weeks. Following the initial 4 weeks, the stressed animals were separated into susceptible (depressive) and unsusceptible (resilient) groups based on behavioral tests. Then, NBP (30 mg/kg i.g) was administered for 4 weeks. Morris water maze (MWM), Western-blot, Golgi staining, immunofluorescence staining and ELISA were used to examine behavioral, biochemical, and pathological changes. The results showed that both depressive and resilient mice displayed spatial memory deficits and an accumulation of tau in the hippocampus. Activated microglia and NLRP3 inflammasome were found after 8-week chronic stress. We also found a decreased level of postsynaptic density (PSD) related proteins (PSD93 and PSD95) and decreased the number of dendritic spines in the hippocampus. Interestingly, almost all the pathological changes in depressive and resilient mice previously mentioned could be reversed by NBP treatment. To further investigate the role of NLRP3 inflammasome in chronic stress-induced cognitive deficits, NLRP3 KO mice were also exposed to chronic stress. And these changes induced by chronic stress could not be found in NLRP3 KO mice. These results show an important role for the NLRP3/caspase-1/IL-1ß axis in chronic stress-induced cognitive deficits and NBP meliorates cognitive impairments and selectively attenuates phosphorylated tau accumulation in stressed mice through regulation of NLRP3 inflammatory signaling pathway.

Submucosal esophageal abscess evolving into intramural submucosal dissection: A case report.

BACKGROUND: Here we report a rare case of submucosal esophageal abscess evolving into intramural submucosal dissection. CASE SUMMARY: An 80-year-old woman was admitted to our emergency department with a chief complaint of dysphagia and fever. Laboratory tests showed mild leukocytosis and elevated C-reactive protein level. Computed tomography showed thickening of the esophageal wall. Upper endoscopy showed a laceration of the esophageal mucosa and a submucosal mass. Spontaneous drainage occurred, and we could see purulent exudate from the crevasse. We closed the laceration with endoscopic clips. The patient did not remember swallowing a foreign body; however, she ate crabs before the symptoms occurred. We prescribed the patient with antibiotic, and the symptoms were gradually relieved. Two months later, upper endoscopy showed that the laceration was healed, and the submucosal abscess disappeared. However, intramural esophageal dissection was formed. We performed endoscopic incision of the septum using dual-knife effectively. CONCLUSION: In conclusion, we are the first to report the case of esophageal submucosal abscess evolving into intramural esophageal dissection. The significance of this case lies in clear presentation of the evolution process between two disorders. In addition, we recommend that endoscopic incision be considered as one of the routine therapeutic modalities of intramural esophageal dissection.

Escitalopram Alleviates Alzheimer's Disease-Type Tau Pathologies in the Aged P301L Tau Transgenic Mice.

BACKGROUND: The inhibition of tau hyperphosphorylation is one of the most promising therapeutic targets for the development of Alzheimer's disease (AD) modifying drugs. Escitalopram, a kind of selective serotonin reuptake inhibitor antidepressant, has been previously reported to ameliorate tau hyperphosphorylation in vitro. OBJECTIVE: In this study, we determined whether escitalopram alleviates tau pathologies in the aged P301L mouse. METHODS: Mice were intraperitoneal injected with either escitalopram or saline for 4 weeks, and a battery of behavioral tests were conducted before tissue collection and biochemical analyses of brain tissue with western blot and immunohistochemistry. RESULTS: Wild-type (Wt) mice statistically outperformed the aged pR5 mice in the Morris water maze, while escitalopram treatment did not significantly rescue learning and memory deficits of aged pR5 mice. Tau phosphorylation at different phosphorylation sites were enhanced in the hippocampus of aged pR5 mice, while escitalopram treatment significantly decreased tau phosphorylation. The levels of phosphorylated GSK-3ß and phosphorylated Akt were significantly decreased in the hippocampus of aged pR5 mice, while escitalopram administration markedly increased the expression level. The aged pR5 mice showed significant decreases in PSD95 and PSD93, while the administration of escitalopram significantly increased PSD95 and PSD93 to levels comparable with the Wt mice. CONCLUSION: The protective effects of escitalopram exposure during advanced AD are mainly associated with significant decrease in tau hyperphosphorylation, increased numbers of neurons, and increased synaptic protein levels, which may via activation of the Akt/GSK-3ß signaling pathway.

Characterization of proteasome inhibition on astrocytes cell cycle.

Increasing evidence indicates that proteasome inhibition occurs in multiple central nervous system (CNS) disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). Compared with the extensive studies on neurons, little attention is paid on the proteasome inhibition in astrocytes. Here, we demonstrated that lactacystin inhibited proteasome dose-dependently in cultured astrocytes. Simultaneously, lactacystin suppressed the expression of cell cycle proteins in astrocytes and caused the proliferating astrocytes arrested at G1/S checkpoint. Western blots showed that proteasome inhibition led to a decrease in cdk-2, cdk-4, cyclin D1 expression accompanied with an increase in p21waf1/cip1 expression. The effect of chronic low-level proteasome inhibition on astrocytes was consistent with that in acute proteasome inhibition. Furthermore, increased levels of interleukin-6 (IL-6) secretion, STAT-3 and phospho-STAT-3 expression were found, suggesting that proteasome inhibition in astrocytes could stabilize signals of grow arrest through the JAK/STAT signaling cascade.

Lactacystin stimulates stellation of cultured rat cortical astrocytes.

Proteasome inhibition has been observed in many neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Here, the effect of proteasome inhibition on the morphology of cultured rat cortical astrocytes was investigated. Increasing evidence suggests that the function of astrocytes is related closely to its morphology. Lactacystin, a specific inhibitor of the 20S proteasome, can induce astrocytes stellation in a dose dependent manner and reorganize the cytoskeleton of astrocytes. Furthermore, decreased levels of expression of Rho A, total Akt, and Phospho-Akt were found in the process of astrocytes stellation and lysophosphatidic acid, an activator of Rho A, can largely reverse the astrocytes stellation caused by lactacystin. This suggests that proteasome inhibition in astrocytes could stabilize signals of morphological changes that might be processed through Rho and Akt signaling cascade. Our results suggest that proteasome inhibition might function as a factor regulating astrocytes morphology in some pathophysiological conditions.

The involvement of upregulation and translocation of phospho-Rb in early neuronal apoptosis following focal cerebral ischemia in rats.

The aim of this study was to investigate the temporal and spatial relationship between phospho-Rb (ser 795) and neuronal apoptotic death in rats subjected to transient focal cerebral ischemia. We found increased phosphorylation of Rb and translocation from neuronal nucleus to cytoplasm in the penumbra zone at 12 h, 1 day, 3 days and 7 days after middle cerebral artery occlusion (MCAO)/reperfusion, compared with sham-operated controls. At 12 h and 1 day, phospho-Rb appeared to be colocalizated with TUNEL staining in neurons, but staining was not colocalizated at 3 days and 7 days. These results demonstrated that cytoplasmic translocation of phospho-Rb from nucleus of neurons occurs in potential apoptotic neurons in the early stages of ischemia/reperfusion, suggesting that the Rb pathway may only be involved in early neuronal apoptosis and may be not an apoptotic signal in the late stages of transient cerebral ischemia.

Spatial Training Ameliorates Long-Term Alzheimer's Disease-Like Pathological Deficits by Reducing NLRP3 Inflammasomes in PR5 Mice.

Recent studies have suggested that cognitive training could delay memory loss in Alzheimer's disease (AD). However, whether and how cognitive training produces long-term benefits remains unclear. Here, 10-month-old PR5 mice were spatially trained in a water maze for 4 consecutive weeks. The novel object recognition test (NORT), Western blots, Golgi staining, and ELISA were used to examine behavioral, biochemical, and pathological measures immediately after training and 3 months later. Immediately after training, we found that spatial training significantly improved cognitive performance; reduced tau neuropathology; increased the expression level of synaptophysin, PSD93, and PSD95 in the hippocampus; and increased the number of dendritic spines in PR5 mice. The expression levels of NLRP3, caspase-1, and interleukin (IL)-1ß, which were significantly elevated in PR5 mice, were reversed by spatial training. Interestingly, these effects persisted 3 months later. To further detect the role of NLRP3 in spatial training, PR5/NLRP3-/- mice and PR5/NLRP3+/- mice were also used in our study. PR5/NLRP3-/- mice showed better cognitive performance than PR5 mice. After 1 week of spatial training, these changes (including those in expression levels of synaptophysin, PSD93, and PSD95; the number of dendritic spines; and caspase-1 and IL-1ß content in PR5 mice) could be totally reversed in PR5/NLRP3-/- and PR5/NLRP3+/- mice. In addition, there was a positive correlation between NLRP3 content and the expression levels of caspase-1 and IL-1ß. These results show an important role for the NLRP3/caspase-1/IL-1ß axis in ameliorating the effect of spatial training on cognitive impairment in PR5 mice.

Escitalopram alleviates stress-induced Alzheimer's disease-like tau pathologies and cognitive deficits by reducing hypothalamic-pituitary-adrenal axis reactivity and insulin/GSK-3ß signal pathway activity.

Chronic stress, a causal factor for depression, can also cause cognitive impairments and tau pathology. However, whether and how the selective serotonin reuptake inhibitor antidepressant escitalopram ameliorates these effects are still unclear. In the present study, rats were subjected to chronic mild unpredictable stress for 8 weeks. Following the initial 4 weeks, the stressed animals were separated into susceptible (depressive) and unsusceptible (resistant) groups based on behavioral tests. Then, escitalopram (10 mg/kg i.p.) was administered for 28 days. Pathophysiological changes were assessed by performing behavioral and biochemical analyses. The results showed that both depressive and resistant rats displayed spatial memory deficits and an accumulation of tau in the hippocampus. Increased levels of corticosterone and insulin and a decreased level of glucocorticoid receptor were found in both depressive and resistant rats. We also found that activity-dependent phosphorylated insulin receptor substrate and glycogen synthase kinase-3ß (Ser9 site) were significantly decreased in both depressive and resistant rats. However, other important kinases, such as cyclin-dependent kinase 5 and mitogen-activated protein kinase kinase-1/2, did not change in our study. Furthermore, we found that the mRNA expression of tau was increased in depressive and resistant rats. No significant change in LC3B expression was found. Interestingly, almost all the pathological changes in depressive and resistant rats previously mentioned could be reversed by escitalopram. Our results suggested that escitalopram ameliorates cognitive impairments and selectively attenuates phosphorylated tau accumulation in stressed rats through the regulation of hypothalamic-pituitary-adrenal axis activity and the insulin receptor substrate/glycogen synthase kinase-3ß signaling pathway.

LINGO-1 antibody ameliorates myelin impairment and spatial memory deficits in the early stage of 5XFAD mice.

AIMS: Multiple evidence has indicated that myelin injury is common in Alzheimer's disease (AD). However, whether myelin injury is an early event in AD and the relationship between it and cognitive function is still elusive. METHODS: Spatial memory of 5XFAD mice was determined by Morris water maze at 1 and 3 months old. Meanwhile, the deposition of Aß, the expression of myelin basic protein (MBP), LINGO-1, NgR, and myelin ultrastructure in many memory-associated brain regions were detected in one-month-old and three-month-old mice (before and after LINGO-1 antibody administration) using immunostaining, Western blot (WB), and transmission electron microscopy (TEM), respectively. RESULTS: No abnormal Aß deposition was found in one-month-old 5XFAD mice. However, spatial memory deficits were proved in accordance with an obvious demyelination in memory-associated brain regions in one-month-old mice and both deteriorated with age. Administration of LINGO-1 antibody could obviously restore the myelin impairments in CA1 and DG region and partially ameliorate spatial memory deficits. CONCLUSIONS: Our results demonstrated that myelin injury was an early event in 5XFAD mice even prior to emergence of deposition of Aß. Intervention with the LINGO-1 antibody could attenuate impaired spatial memory deficits by remyelination, which suggested that myelin injury was involved in spatial memory deficits and remyelination may be a potential therapeutic strategy in early stage of AD or mild cognitive impairments.

Effects of tau phosphorylation on proteasome activity.

Dysfunction of proteasome contributes to the accumulation of the abnormally hyperphosphorylated tau in Alzheimer's disease. However, whether tau hyperphosphorylation and accumulation affect the activity of proteasome is elusive. Here we found that a moderate tau phosphorylation activated the trypsin-like activity of proteasome, whereas further phosphorylation of tau inhibited the activity of the protease in HEK293 cells stably expressing tau441. Furthermore, tau hyperphosphorylation could partially reverse lactacystin-induced inhibition of proteasome. These results suggest that phosphorylation of tau plays a dual role in modulating the activity of proteasome.

Citalopram Ameliorates Synaptic Plasticity Deficits in Different Cognition-Associated Brain Regions Induced by Social Isolation in Middle-Aged Rats.

Our previous experiments demonstrated that social isolation (SI) caused AD-like tau hyperphosphorylation and spatial memory deficits in middle-aged rats. However, the underlying mechanisms of SI-induced spatial memory deficits remain elusive. Middle-aged rats (10 months) were group or isolation reared for 8 weeks. Following the initial 4-week period of rearing, citalopram (10 mg/kg i.p.) was administered for 28 days. Then, pathophysiological changes were assessed by performing behavioral, biochemical, and pathological analyses. We found that SI could cause cognitive dysfunction and decrease synaptic protein (synaptophysin or PSD93) expression in different brain regions associated with cognition, such as the prefrontal cortex, dorsal hippocampus, ventral hippocampus, amygdala, and caudal putamen, but not in the entorhinal cortex or posterior cingulate. Citalopram could significantly improve learning and memory and partially restore synaptophysin or PSD93 expression in the prefrontal cortex, hippocampus, and amygdala in SI rats. Moreover, SI decreased the number of dendritic spines in the prefrontal cortex, dorsal hippocampus, and ventral hippocampus, which could be reversed by citalopram. Furthermore, SI reduced the levels of BDNF, serine-473-phosphorylated Akt (active form), and serine-9-phosphorylated GSK-3ß (inactive form) with no significant changes in the levels of total GSK-3ß and Akt in the dorsal hippocampus, but not in the posterior cingulate. Our results suggest that decreased synaptic plasticity in cognition-associated regions might contribute to SI-induced cognitive deficits, and citalopram could ameliorate these deficits by promoting synaptic plasticity mainly in the prefrontal cortex, dorsal hippocampus, and ventral hippocampus. The BDNF/Akt/GSK-3ß pathway plays an important role in regulating synaptic plasticity in SI rats.

The involvement of glycogen synthase kinase-3 and protein phosphatase-2A in lactacystin-induced tau accumulation.

Here, we demonstrated that lactacystin inhibited proteasome dose-dependently in HEK293 cells stably expressing tau. Simultaneously, it induces accumulation of both non-phosphorylated and hyperphosphorylated tau and decreases the binding of tau to the taxol-stabilized microtubules. Lactacystin activates glycogen synthase kinsase-3 (GSK-3) and decreases the phosphorylation of GSK-3 at serine-9. LiCl inhibits GSK-3 and thus reverses the lactacystin-induced accumulation of the phosphorylated tau. Lactacystin also inhibits protein phosphase-2A (PP-2A) and it significantly increases the level of inhibitor 1 of PP-2A. These results suggest that inhibition of proteasome by lactacystin induces tau accumulation and activation of GSK-3 and inhibition of PP-2A are involved.

Escitalopram attenuates ß-amyloid-induced tau hyperphosphorylation in primary hippocampal neurons through the 5-HT1A receptor mediated Akt/GSK-3ß pathway.

Tau hyperphosphorylation is an important pathological feature of Alzheimer's disease (AD). To investigate whether escitalopram could inhibit amyloid-ß (Aß)-induced tau hyperphosphorylation and the underlying mechanisms, we treated the rat primary hippocampal neurons with Aß1-42 and examined the effect of escitalopram on tau hyperphosphorylation. Results showed that escitalopram decreased Aß1-42-induced tau hyperphosphorylation. In addition, escitalopram activated the Akt/GSK-3ß pathway, and the PI3K inhibitor LY294002 blocked the attenuation of tau hyperphosphorylation induced by escitalopram. Moreover, the 5-HT1A receptor agonist 8-OH-DPAT also activated the Akt/GSK-3ß pathway and decreased Aß1-42-induced tau hyperphosphorylation. Furthermore, the 5-HT1A receptor antagonist WAY-100635 blocked the activation of Akt/GSK-3ß pathway and the attenuation of tau hyperphosphorylation induced by escitalopram. Finally, escitalopram improved Aß1-42 induced impairment of neurite outgrowth and spine density, and reversed Aß1-42 induced reduction of synaptic proteins. Our results demonstrated that escitalopram attenuated Aß1-42-induced tau hyperphosphorylation in primary hippocampal neurons through the 5-HT1A receptor mediated Akt/GSK-3ß pathway.

Spatial learning and memory impairments are associated with increased neuronal activity in 5XFAD mouse as measured by manganese-enhanced magnetic resonance imaging.

Dysfunction of neuronal activity is a major and early contributor to cognitive impairment in Alzheimer's disease (AD). To investigate neuronal activity alterations at early stage of AD, we encompassed behavioral testing and in vivo manganese-enhanced magnetic resonance imaging (MEMRI) in 5XFAD mice at early ages (1-, 2-, 3- and 5-month). The 5XFAD model over-express human amyloid precursor protein (APP) and presenilin 1 (PS1) harboring five familial AD mutations, which have a high APP expression correlating with a high burden and an accelerated accumulation of the 42 amino acid species of amyloid-ß. In the Morris water maze, 5XFAD mice showed longer escape latency and poorer memory retention. In the MEMRI, 5XFAD mice showed increased signal intensity in the brain regions involved in spatial cognition, including the entorhinal cortex, the hippocampus, the retrosplenial cortex and the caudate putamen. Of note, the observed alterations in spatial cognition were associated with increased MEMRI signal intensity. These findings indicate that aberrant increased basal neuronal activity may contribute to the spatial cognitive function impairment at early stage of AD, and may further suggest the potential use of MEMRI to predict cognitive impairments. Early intervention that targets aberrant neuronal activity may be crucial to prevent cognitive impairment.

LINGO-1 antibody ameliorates myelin impairment and spatial memory deficits in experimental autoimmune encephalomyelitis mice.

More than 50% of multiple sclerosis patients develop cognitive impairment. However, the underlying mechanisms are still unclear, and there is no effective treatment. LINGO-1 (LRR and Ig domain containing NOGO receptor interacting protein 1) has been identified as an inhibitor of oligodendrocyte differentiation and myelination. Using the experimental autoimmune encephalomyelitis (EAE) mouse model, we assessed cognitive function at early and late stages of EAE, determined brain expression of myelin basic protein (MBP) and investigated whether the LINGO-1 antibody could restore deficits in learning and memory and ameliorate any loss of MBP. We found that deficits in learning and memory occurred in late EAE and identified decreased expression of MBP in the parahippocampal cortex (PHC) and fimbria-fornix. Moreover, the LINGO-1 antibody significantly improved learning and memory in EAE and partially restored MBP in PHC. Furthermore, the LINGO-1 antibody activated the AKT/mTOR signaling pathway regulating myelin growth. Our results suggest that demyelination in the PHC and fimbria-fornix might contribute to cognitive deficits and the LINGO-1 antibody could ameliorate these deficits by promoting myelin growth in the PHC. Our research demonstrates that LINGO-1 antagonism may be an effective approach to the treatment of the cognitive impairment of multiple sclerosis patients.