What do we know from clinical trials on exercise and Alzheimer's disease?

Alzheimer's disease(AD) is the most common form of dementia in elderly with major symptoms of a general term for memory loss and other intellectual abilities impairment which are serious enough to interfere with daily life.While there is no treatment can prevent and revise the cognitive function impairment in AD,physical activity becomes a potential beneficia intervention for AD.Multiple evidences suggested that exercise in general plays beneficia roles in improving brain function.Most common mechanisms of exercise-induced enhancement of brain function are including alteration of neurogenesis,neuron plasticity,neuronal signaling and receptors,as well as neuronal networks.This mini review includes most recent clinical studies and focuses on the effects of physical exercise,cognitive stimulation,and combination of both physical and cognitive training on protection and rescue cognitive decline in people with AD.

Nanoscale Reorganization of Glutamate Receptors Underlies Synaptic Plasticity and Pathology

Excitatory synapses serve as the primary sites for information transmission between neurons in the brain.Seminal work over the past decades has identified and revealed multiple compositions and functions of the synaptic proteome in the postsynaptic density(PSD),including receptors,scaffold proteins,and signaling molecules,which work together to ensure stable and effective synaptic transmission.

Now and future:Strategies for diagnosis,prevention and therapies for Alzheimer’s disease

After a number of failed drug studies on Alzheimer’s disease(AD)over the past decade,clinical trials of AD started to show encouraging results and were approved or pending approval for clinical use.However,controversies on the clinically meaningful benefits and risks of brain edema and microhemorrhages have reminded us to think further about monitoring treatment and developing new drug targets.The goal of this review is to find insights from clinical trials that aimed at two key pathological features of AD,i.e.,amyloid-β(Aβ)and tau protein,and to explore other targets such as anti-inflammation in AD.The complex pathophysiology of AD may require combination therapies rather than monotherapy.Throughout the course of AD,multiple pathways are disrupted,presenting a multitude of possible therapeutic targets for designing prevention and intervention for AD.

阿尔茨海默病的血液生物标志物:一项基于中国多中心的横断面和纵向研究

阿尔茨海默病(AD)的生物标志物在血液中含量可能因种族、老年性疾病与各种环境风险因素等不同而存在差异,尚缺乏系统性的研究来评估AD生物标志物在中国老年及AD患者人群中的变化以及是否具有准确预测脑内淀粉样蛋白沉积的能力.本工作为一项多中心纵向队列研究,共纳入来自全国各地6个不同临床中心的817个血液样本.研究测量了多个国际上通用的AD生物标志物,包括β-淀粉样蛋白40与42、磷酸化Tau(pTau)蛋白、总Tau蛋白、神经纤维丝轻链(NFL)和胶质纤维酸性蛋白(GFAP),并使用淀粉样斑块PET示踪剂和核磁结构影像对受试者进行综合评估.研究发现,APOE基因型与血浆pTau或血清GFAP组合的预测模型对脑内淀粉样斑块的沉积状态具有较好的区分能力.此外,研究还发现GFAP基线水平越高的患者其神经退行性变的速度越快.本研究结果基于多中心数据,论证了AD血液生物标志物在中国汉族人群中的实用性和应用前景,提示了血液pTau和GFAP是检测AD早期症状的有效指标,为我国AD的早期诊断和治疗提供了参考.

Generation of nonhuman primate retinitis pigmentosa model by in situ knockout of RHO in rhesus macaque retina

Retinitis pigmentosa(RP)is a form of inherited retinal degenerative diseases that ultimately involves the macula,which is present in primates but not in the rodents.Therefore,creating nonhuman primate(NHP)models of RP is of critical importance to study its mechanism of pathogenesis and to evaluate potential therapeutic options in the future.Here we applied adeno-associated virus(AAV)-delivered CRISPR/SaCas9 technology to knockout the RHO gene in the retinae of the adult rhesus macaque(Macaca mulatta)to investigate the hypothesis whether non-germline mutation of the RHO gene is sufficient to recapitulate RP.Through a series of studies,we were able to demonstrate successful somatic editing of the RHO gene and reduced RHO protein expression.More importantly,the mutant macaque retinae displayed clinical RP phenotypes,including photoreceptor degeneration,retinal thinning,abnormal rod subcellular structures,and reduced photoresponse.Therefore,we suggest somatic editing of the RHO gene is able to phenocopy RP,and the reduced time span in generating NHP mutant accelerates RP research and expands the utility of NHP model for human disease study.

Receptor expression-enhancing protein 1 gene （SPG31） mutations are rare in Chinese Han patients with hereditary spastic paraplegia

Hereditary spastic paraplegia （HSP）, also known as familial spastic paraparesis or Stumpell-Lorrain disease, is a large group of inherited, heterogeneous neurologic disorders caused by the degeneration of corticospinal axons. The prevalence is estimated at 3-10 cases per 100000 people in Europe, and is uncertain in other continents. Most patients have the same core features, which are characterized by spastic gait, lower limb hypertonicity, hyperreflexia, extensor-plantar responses, muscle weakness, and occasionally decreased vibration sense at the ankles, bladder dysfunction, pes cavus, or scoliosis.

Single-cell profiling reveals Müller glia coordinate retinal intercellular communication during light/dark adaptation via thyroid hormone signaling

Light adaptation enables the vertebrate visual system to operate over a wide range of ambient illumination.Regulation of phototransduction in photoreceptors is considered a major mechanism underlying light adaptation.However,various types of neurons and glial cells exist in the retina,and whether and how all retinal cells interact to adapt to light/dark conditions at the cellular and molecular levels requires systematic investigation.Therefore,we utilized single-cell RNA sequencing to dissect retinal cell-type-specific transcriptomes during light/dark adaptation in mice.The results demonstrated that,in addition to photoreceptors,other retinal cell types also showed dynamic molecular changes and specifically enriched signaling pathways under light/dark adaptation.Importantly,Müller glial cells(MGs)were identified as hub cells for intercellular interactions,displaying complex cell‒cell communication with other retinal cells.Furthermore,light increased the transcription of the deiodinase Dio2 in MGs,which converted thyroxine(T4)to active triiodothyronine(T3).Subsequently,light increased T3 levels and regulated mitochondrial respiration in retinal cells in response to light conditions.As cones specifically express the thyroid hormone receptor Thrb,they responded to the increase in T3 by adjusting light responsiveness.Loss of the expression of Dio2 specifically in MGs decreased the light responsive ability of cones.These results suggest that retinal cells display global transcriptional changes under light/dark adaptation and that MGs coordinate intercellular communication during light/dark adaptation via thyroid hormone signaling.

Single-dose AAV-based vaccine induces a high level of neutralizing antibodies against SARS-CoV-2 in rhesus macaques

Dear Editor,Coronavirus disease 2019(COVID-19)is a highly infectious respiratory disease that continues to pose a serious global public health emergency.The disease shows a high infection rate,long incubation period,and rapidly emerging variants,which have led to its rapid spread worldwide(Krammer 2020).Many vaccines have been developed for the control of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the virus responsible for COVID-19,including vaccines based on messenger RNA(mRNA)(Polack et al.2020),viral vectors(Zhu et al.2020),recombinant proteins(Yang et al.2020),and inactivated SARS-CoV-2(Zhang et al.2021).

The landscape of aging

Aging is characterized by a progressive deterioration of physiological integrity,leading to impaired functional ability and ultimately increased susceptibility to death.It is a major risk factor for chronic human diseases,including cardiovascular disease,diabetes,neurological degeneration,and cancer.Therefore,the growing emphasis on “healthy aging” raises a series of important questions in life and social sciences.In recent years,there has been unprecedented progress in aging research,particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes.In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases,we review the descriptive,conceptual,and interventive aspects of the landscape of aging composed of a number of layers at the cellular,tissue,organ,organ system,and organismal levels.

Epigenomic profiling identifies the role of Nr5a2 and CYP1B1 in hepatocellular carcinoma stemness maintenance

Cancer stem cells (CSCs) are largely responsible for the formation of tumor heterogeneity and tumor’s resistance to traditional treatments such as chemotherapy due to its self-renew capability and multi-lineage differentiation potential (1)However, it remains elusive how the CSCs maintain their stemness, thus restricting the development of therapeutic treatments specifically targeting the CSCs.

Multilayer core-shell nanostructures for enhanced 808 nm responsive upconversion

The construction of core-shell structure is an effective strategy for promoting the emission efficiency of upconversion nanocrystals(UCNCs). In this work, the UCNCs based on Nd-doping with a multilayer coreshell nanostructure are fabricated toward achieving efficient upconversion for 808 nm excitation, which have great potential for optical applications, especially photobiological applications.

散发性早发阿尔茨海默病中磷酸化tau蛋白的高负荷和特异性楔前叶萎缩:一项前瞻性队列研究

早发性阿尔茨海默病(EOAD)是阿尔茨海默病(AD)的罕见且严重的亚型,于65岁之前发病,占所有AD病例的5%~10%.以往关于EOAD的研究主要集中在家族性遗传人群,而对于占EOAD病例85%~90%的散发性EOAD(sEOAD)的研究则较为有限.在这项前瞻性队列研究中,共纳入sEOAD110例,晚发性AD(LOAD)89例,年龄匹配对照组75例.研究对象排除了家族性EOAD患者,所有纳入AD患者均符合基于ATN框架下的生物标志物证据的诊断标准.对纳入患者进行了患病危险因素分析、多维度认知功能评估、多模态分子影像学评估及脑脊液/外周血生物标记物检测.结果显示,与LOAD患者相比,sEOAD患者没有表现出特定的危险因素,但表现出更严重的执行功能损害和双侧楔前叶萎缩.在sEOAD患者中的脑脊液和血浆中磷酸化tau181(P-tau181)水平较LOAD组显著升高.本研究探讨了散发性EOAD人群的临床特征,发现了tau蛋白磷酸化在sEOAD发生和进展中的重要性,有助于全面了解AD的病因、发病年龄决定因素和疾病进展,并为潜在的治疗策略提供了重要思路.

TAF15 Overexpression Impairs Memory in Mice by Inhibiting the Transcription of Npas4

Dear Editor,Learning-induced expression of activity-dependent genes,especially immediate-early genes(IEGs),is required for the conversion of experience-induced neuronal activity into long-term memory[1].Neuronal Per-Arnt-Sim domain protein 4(Npas4)is one of the most rapidly induced IEGs,functioning as a transcription factor to regulate the activity-dependent expression of other IEGs,such as activityregulated cytoskeleton associated protein(Arc),Fos protooncogene,and early growth response 1(Egrl)[1].