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Deficits in the clearance of amyloid β-protein (Aβ) play a pivotal role in the pathogenesis of sporadic Alzheimer’s disease (AD). The roles of blood monocytes in the development of AD remain unclear. In this study, we sought to investigate the alterations in the Aβ phagocytosis function of peripheral monocytes during ageing and in AD patients. A total of 104 cognitively normal participants aged 22–89 years, 24 AD patients, 25 age- and sex-matched cognitively normal (CN) subjects, 15 Parkinson’s disease patients (PD), and 15 age- and sex-matched CN subjects were recruited. The Aβ uptake by blood monocytes was measured and its alteration during ageing and in AD patients were investigated. Aβ1-42 uptake by monocytes decreased during ageing and further decreased in AD but not in PD patients. Aβ1-42 uptake by monocytes was associated with Aβ1-42 levels in the blood. Among the Aβ uptake-related receptors and enzymes, the expression of Toll-like receptor 2 (TLR2) was reduced in monocytes from AD patients. Our findings suggest that monocytes regulate the blood levels of Aβ and might be involved in the development of AD. The recovery of the Aβ uptake function by blood monocytes represents a potential therapeutic strategy for AD.

The extracellular domain (p75ECD) of p75 neurotrophin receptor (p75NTR) antagonizes Aβ neurotoxicity and promotes Aβ clearance in Alzheimer's disease (AD). The impaired shedding of p75ECD is a key pathological process in AD, but its regulatory mechanism is largely unknown. This study was designed to investigate the presence and alterations of naturally-occurring autoantibodies against p75ECD (p75ECD-NAbs) in AD patients and their effects on AD pathology. We found that the cerebrospinal fluid (CSF) level of p75ECD-NAbs was increased in AD, and negatively associated with the CSF levels of p75ECD. Transgenic AD mice actively immunized with p75ECD showed a lower level of p75ECD and more severe AD pathology in the brain, as well as worse cognitive functions than the control groups, which were immunized with Re-p75ECD (the reverse sequence of p75ECD) and phosphate-buffered saline, respectively. These findings demonstrate the impact of p75ECD-NAbs on p75NTR/p75ECD imbalance, providing a novel insight into the role of autoimmunity and p75NTR in AD.

Background A previous study demonstrated that nearly 40%–60% of brain Aβ flows out into the peripheral system for clearance. However, where and how circulating Aβ is cleared in the periphery remains unclear. The spleen acts as a blood filter and an immune organ. The aim of the present study was to investigate the role of the spleen in the clearance of Aβ in the periphery. Methods We investigated the physiological clearance of Aβ by the spleen and established a mouse model of AD and spleen excision by removing the spleens of APP/PS1 mice to investigate the effect of splenectomy on AD mice. Results We found that Aβ levels in the splenic artery were higher than those in the splenic vein, suggesting that circulating Aβ is cleared when blood flows through the spleen. Next, we found that splenic monocytes/macrophages could take up Aβ directly in vivo and in vitro. Splenectomy aggravated behaviour deficits, brain Aβ burden and AD‐related pathologies in AD mice. Conclusion Our study reveals for the first time that the spleen exerts a physiological function of clearing circulating Aβ in the periphery. Our study also suggests that splenectomy, which is a routine treatment for splenic rupture and hypersplenism, might accelerate the development of AD., Our study reveals the physiological capacity of the spleen to clear circulating Aβ, and the splenectomy aggravates Alzheimer‐type pathogenesis in APP/PS1 transgenic mice.

Deficits in the clearance of amyloid β protein (Aβ) by the peripheral system play a critical role in the pathogenesis of sporadic Alzheimer’s disease (AD). Impaired uptake of Aβ by dysfunctional monocytes is deemed to be one of the major mechanisms underlying deficient peripheral Aβ clearance in AD. In the current study, flow cytometry and biochemical and behavioral techniques were applied to investigate the effects of polysaccharide krestin (PSK) on AD-related pathology in vitro and in vivo. We found that PSK, widely used in therapy for various cancers, has the potential to enhance Aβ uptake and intracellular processing by human monocytes in vitro. After administration of PSK by intraperitoneal injection, APP/PS1 mice performed better in behavioral tests, along with reduced Aβ deposition, neuroinflammation, neuronal loss, and tau hyperphosphorylation. These results suggest that PSK holds promise as a preventive agent for AD by strengthening the Aβ clearance by blood monocytes and alleviating AD-like pathology. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12264-021-00779-5.

Background Alzheimer’s disease (AD) is the most popular neurodegenerative disease affecting cognitive functions of the elderly population. Neuronal apoptosis is an important pathological process during the development of AD. The Bcl-2-interacting mediator of cell death (Bim) mediates Amyloid-beta (Aβ)-induced neuronal apoptosis. Naturally occurring antibodies against Bim (NAbs-Bim) exist in human blood, with their levels and functions unknown in AD. Methods This study investigated the clinical relevance of plasma NAbs-Bim to AD in 55 AD patients, 28 patients with non-AD dementia, and 70 cognitively normal subjects. Furthermore, the pathophysiological functions of NAbs-Bim were explored in APP/PS1 mice and SY5Y cell lines overexpressing human amyloid precursor protein (APP). Results We found that plasma levels of NAbs-Bim were lower in AD patients in comparison with patients with non-AD dementia and cognitively normal controls. Plasma levels of NAbs-Bim were negatively associated with brain amyloid burdens and positively associated with cognitive functions. NAbs-Bim purified from intravenous immunoglobulin rescued behavioral deficits of APP/PS1 mice. NAbs-Bim ameliorated Aβ deposition, Tau hyperphosphorylation, microgliosis and neuronal apoptosis in APP/PS1 mice. In vitro investigations demonstrated that NAbs-Bim exerted neuroprotective effects against AD through neutralizing Bim-directed neuronal apoptosis and amyloidogenic processing of amyloid precursor protein. Conclusions The decrease of NAbs-Bim might contribute to the pathogenesis of AD and immunotherapies targeting Bim may hold promise for the treatment of AD.

BackgroundThe COVID-19 pandemic is associated with common mental health problems. However, evidence for the association between fear of COVID-19 and obsessive-compulsive disorder (OCD) is limited.ObjectiveThis study aimed to examine if fear of negative events affects Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores in the context of a COVID-19–fear-invoking environment.MethodsAll participants were medical university students and voluntarily completed three surveys via smartphone or computer. Survey 1 was conducted on February 8, 2020, following a 2-week-long quarantine period without classes; survey 2 was conducted on March 25, 2020, when participants had been taking online courses for 2 weeks; and survey 3 was conducted on April 28, 2020, when no new cases had been reported for 2 weeks. The surveys comprised the Y-BOCS and the Zung Self-Rating Anxiety Scale (SAS); additional items included questions on demographics (age, gender, only child vs siblings, enrollment year, major), knowledge of COVID-19, and level of fear pertaining to COVID-19.ResultsIn survey 1, 11.3% of participants (1519/13,478) scored ≥16 on the Y-BOCS (defined as possible OCD). In surveys 2 and 3, 3.6% (305/8162) and 3.5% (305/8511) of participants had scores indicative of possible OCD, respectively. The Y-BOCS score, anxiety level, quarantine level, and intensity of fear were significantly lower at surveys 2 and 3 than at survey 1 (PConclusionsOur findings indicate that fear of COVID-19 was associated with a greater Y-BOCS score, suggesting that an environment (COVID-19 pandemic) × psychology (fear and/or anxiety) interaction might be involved in OCD and that a fear of negative events might play a role in the etiology of OCD.

BACKGROUND The COVID-19 pandemic is associated with common mental health problems. However, evidence for the association between fear of COVID-19 and obsessive-compulsive disorder (OCD) is limited. OBJECTIVE This study aimed to examine if fear of negative events affects Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores in the context of a COVID-19–fear-invoking environment. METHODS All participants were medical university students and voluntarily completed three surveys via smartphone or computer. Survey 1 was conducted on February 8, 2020, following a 2-week-long quarantine period without classes; survey 2 was conducted on March 25, 2020, when participants had been taking online courses for 2 weeks; and survey 3 was conducted on April 28, 2020, when no new cases had been reported for 2 weeks. The surveys comprised the Y-BOCS and the Zung Self-Rating Anxiety Scale (SAS); additional items included questions on demographics (age, gender, only child vs siblings, enrollment year, major), knowledge of COVID-19, and level of fear pertaining to COVID-19. RESULTS In survey 1, 11.3% of participants (1519/13,478) scored ≥16 on the Y-BOCS (defined as possible OCD). In surveys 2 and 3, 3.6% (305/8162) and 3.5% (305/8511) of participants had scores indicative of possible OCD, respectively. The Y-BOCS score, anxiety level, quarantine level, and intensity of fear were significantly lower at surveys 2 and 3 than at survey 1 (PPPr=0.74 for survey 2, Pr=0.63 for survey 3, P=.006). CONCLUSIONS Our findings indicate that fear of COVID-19 was associated with a greater Y-BOCS score, suggesting that an environment (COVID-19 pandemic) × psychology (fear and/or anxiety) interaction might be involved in OCD and that a fear of negative events might play a role in the etiology of OCD.

BackgroundDeficits in the clearance of amyloid β-protein (Aβ) play a pivotal role in the pathogenesis of sporadic Alzheimer’s disease (AD). The roles of blood monocytes, the counterpartsof microglia in the periphery, in the development of AD remain unclear. In this study, we sought to investigate the alterations in the Aβ phagocytosis function of peripheral monocytes during ageing and in AD patients. Methods:A total of104 cognitively normal participants aged 22 to 89 years old, 22 AD patients, 22 age- and sex-matched cognitively normal (CN) subjects, 15 Parkinson’s disease patients (PD) and 15 age- and sex-matched CN subjects were recruited. The Aβ uptake by blood monocytes were measured and its alteration during ageing and in AD were investigated. ResultsAβ1-42 uptake by monocytes was associated with Aβ1-42 levels in the blood. Aβ1-42 uptake by monocytes decreased during ageing, and further decreased in AD but not in PD patients. Among the Aβ uptake-related receptors and enzymes, the expression of Toll‑like receptor 2 (TLR2) was reduced in monocytes from AD patients.ConclusionOur findings suggest that monocytes regulate the blood levels of Aβ and might be involved in the development of AD. The recovery of the Aβ clearance function by blood monocytes represents a potential therapeutic strategy for AD.

Bacterial blight of rice caused by Xanthomonas oryzae pv. oryzae (Xoo) is one of high nitrogen (N) responsive diseases. Rice plants became more disease resistant with decreasing N suggesting that the crosstalk between disease resistance and N utilization pathways might exist. However, the co-regulatory components in such crosstalk have not been elucidated. Here, we comparatively analyzed the gene expression profiling of rice under Xoo inoculation, low N treatment, or a combination of both stresses, and identified the differentially-expressed genes (DEGs) in overlapping responses. These DEGs were involved in different biological processes, including innate immunity and nitrogen metabolism. The randomly-selected DEGs expression was validated by quantitative real-time PCR assays. Temporal expression of six genes from different functional categories suggested that N condition was the dominant factor when both stresses were present. These DEGs identified provide novel insights into the coordinated regulatory mechanism in biotic and abiotic stress responses in rice.