FUBP3 mediates the amyloid-β-induced neuronal NLRP3 expression

Alzheimer's disease is characterized by deposition of amyloid-β,which forms extracellular neuritic plaques,and accumulation of hyperphosphorylated tau,which aggregates to form intraneuronal neurofibrillary tangles,in the brain.The NLRP3 inflammasome may play a role in the transition from amyloid-βdeposition to tau phosphorylation and aggregation.Because NLRP3 is primarily found in brain microglia,and tau is predominantly located in neurons,it has been suggested that NLRP3 expressed by microglia indirectly triggers tau phosphorylation by upregulating the expression of pro-inflammatory cytokines.Here,we found that neurons also express NLRP3 in vitro and in vivo,and that neuronal NLRP3 regulates tau phosphorylation.Using biochemical methods,we mapped the minimal NLRP3 promoter and identified FUBP3 as a transcription factor regulating NLRP3 expression in neurons.In primary neurons and the neuroblastoma cell line Neuro2A,FUBP3 is required for endogenous NLRP3 expression and tau phosphorylation only when amyloid-βis present.In the brains of aged wild-type mice and a mouse model of Alzheimer's disease,FUBP3 expression was markedly increased in cortical neurons.Transcriptome analysis suggested that FUBP3 plays a role in neuron-mediated immune responses.We also found that FUBP3 trimmed the 5′end of DNA fragments that it bound,implying that FUBP3 functions in stress-induced responses.These findings suggest that neuronal NLRP3 may be more directly involved in the amyloid-β-to–phospho-tau transition than microglial NLRP3,and that amyloid-βfundamentally alters the regulatory mechanism of NLRP3 expression in neurons.Given that FUBP3 was only expressed at low levels in young wild-type mice and was strongly upregulated in the brains of aged mice and Alzheimer's disease mice,FUBP3 could be a safe therapeutic target for preventing Alzheimer's disease progression.

Combined application of organic fertilizer and chemical fertilizer alleviates the kernel position effect in summer maize by promoting post-silking nitrogen uptake and dry matter accumulation

Adjusting agronomic measures to alleviate the kernel position effect in maize is important for ensuring high yields.In order to clarify whether the combined application of organic fertilizer and chemical fertilizer(CAOFCF)can alleviate the kernel position effect of summer maize,field experiments were conducted during the 2019 and 2020 growing seasons,and five treatments were assessed:CF,100%chemical fertilizer;OFCF1,15%organic fertilizer+85%chemical fertilizer;OFCF2,30%organic fertilizer+70%chemical fertilizer;OFCF3,45%organic fertilizer+55%chemical fertilizer;and OFCF4,60%organic fertilizer+40%chemical fertilizer.Compared with the CF treatment,the OFCF1 and OFCF2 treatments significantly alleviated the kernel position effect by increasing the weight ratio of inferior kernels to superior kernels and reducing the weight gap between the superior and inferior kernels.These effects were largely due to the improved filling and starch accumulation of inferior kernels.However,there were no obvious differences in the kernel position effect among plants treated with CF,OFCF3,or OFCF4 in most cases.Leaf area indexes,post-silking photosynthetic rates,and net assimilation rates were higher in plants treated with OFCF1 or OFCF2 than in those treated with CF,reflecting an enhanced photosynthetic capacity and improved postsilking dry matter accumulation(DMA)in the plants treated with OFCF1 or OFCF2.Compared with the CF treatment,the OFCF1 and OFCF2 treatments increased post-silking N uptake by 66.3 and 75.5%,respectively,which was the major factor driving post-silking photosynthetic capacity and DMA.Moreover,the increases in root DMA and zeatin riboside content observed following the OFCF1 and OFCF2 treatments resulted in reduced root senescence,which is associated with an increased post-silking N uptake.Analyses showed that post-silking N uptake,DMA,and grain yield in summer maize were negatively correlated with the kernel position effect.In conclusion,the combined application of 15-30%organic fertilizer and 70-85%chemical fertilizer alleviated the kernel position effect in summer maize by improving post-silking N uptake and DMA.These results provide new insights into how CAOFCF can be used to improve maize productivity.

Perspectives on a collaborative Canada-China research program on diagnostic biomarkers for pre-dementia stages of Alzheimer’s disease

As biomarkers are important in the early diagnosis ofAlzheimer’s disease （AD）, the frst collab-orative work of recruiting early-onset familial AD （EO-FAD） families in Canada and China was initiated in 2012. The registration networks have collected hundreds of pedigrees, for which genetic screening, neuropsycholog-ical tests and amyloid and tau imaging was used to study diagnostic biomarkers for preclinical and mild cognitive impairment （MCI） stages of AD. Besides identifying ped-igrees with novel mutations in presenilins （PSENs）/amy-loid precursor protein （APP）, the program has benefted training of Chinese research fellows, AD clinical trials forprevention,the ethical concernsfor clinical fndings, and other collaborative projects with Chinese investiga-tors. Further research of the collaborative program may facilitate the testing and clinical use of novel treatments for EOFAD and late onset AD and contribute to dementia prevention strategies in Canada and China.

Advances in longitudinal studies of amnestic mild cognitive impairment and Alzheimer's disease based on multi-modal MRI techniques

Amnestic mild cognitive impairment （aMCI） is a prodromal stage of Alzheimer＇s disease （AD）, and 75%-80% of aMCI patients finally develop AD. So, early identification of patients with aMCI or AD is of great significance for prevention and intervention. According to cross-sectional studies, it is known that the hippocampus, posterior cingulate cortex, and corpus callosum are key areas in studies based on structural MRI （sMRI）, functional MRI （fMRI）, and diffusion tensor imaging （DTI） respectively. Recently, longitudinal studies using each MRI modality have demonstrated that the neuroimaging abnormalities generally involve the posterior brain regions at the very beginning and then gradually affect the anterior areas during the progression of aMCI to AD. However, it is not known whether follow-up studies based on multi-modal neuroimaging techniques （e.g., sMRI, fMRI, and DTI） can help build effective MRI models that can be directly applied to the screening and diagnosis of aMCI and AD. Thus, in the future, large-scale multi-center follow-up studies are urgently needed, not only to build an MRI diagnostic model that can be used on a single person, but also to evaluate the variability and stability of the model in the general population. In this review, we present longitudinal studies using each MRI modality separately, and then discuss the future directions in this field.

Clusterin transduces Alzheimer-risk signals to amyloidogenesis

Dear Editor,Deposition of amyloid-β(Aβ)to form neuritic plaque(NP)is the hallmark of Alzheimer’s Disease(AD).Major non-genetic risk factors such as ageing,stroke,diabetes and other conditions facilitate AD pathogenesis via unclear mechanisms.Furthermore,the mechanism underlying NP formation is unclear.Increasing Aβcauses NP in familial AD patients and in transgenic AD mice robustly expressing Aβ,but the NP formation requires long-term Aβaccumulation.

Prevention strategies for Alzheimer’s disease

Symptomatic treatment during the dementia stage of Alzheimer’s disease(AD)cannot delay or halt the progression of this disease.Therefore,prevention in the preclinical stage is likely the most effective way to decrease the incidence of this age-associated neurodegenerative condition,and its associated burden for individuals and society.Age,gender,family history,ApoE4,systolic blood pressure,body mass index,total cholesterol level and physical activity are all used as component of dementia risk score.There have been numerous challenges in conducting primary prevention trials in AD.Enrichment strategies for prevention studies include studying those subjects with more risk factors for AD,such as older age,those with a positive family history of late onset AD,and those who are ApoE4 positive.Each of these strategies is designed to increase the probability of developing AD thereby decreasing the sample size or the duration of follow up.Another strategy would be to target directly the pathophysiology of AD in its preclinical stages and use the biomarkers in prevention trial as surrogate markers.This will be done first in carriers of dominantly inherited early onset AD.As this research takes place networks of memory clinics must prepare to transfer new knowledge to persons interested in a preventive approach to AD.