Tau inhibits PKA by nuclear proteasome‐dependent PKAR2α elevation with suppressed CREB/GluA1 phosphorylation

Intraneuronal accumulation of wild‐type tau plays a key role in Alzheimer's disease, while the mechanisms underlying tauopathy and memory impairment remain unclear. Here, we report that overexpressing full‐length wild‐type human tau (hTau) in mouse hippocampus induces learning and memory deficits with remarkably reduced levels of multiple synapse‐ and memory‐associated proteins. Overexpressing hTau inhibits the activity of protein kinase A (PKA) and decreases the phosphorylation level of cAMP‐response element binding protein (CREB), GluA1, and TrkB with reduced BDNF mRNA and protein levels both in vitro and in vivo. Simultaneously, overexpressing hTau increased PKAR2α (an inhibitory subunit of PKA) in nuclear fraction and inactivated proteasome activity. With an increased association of PKAR2α with PA28γ (a nuclear proteasome activator), the formation of PA28γ‐20S proteasome complex remarkably decreased in the nuclear fraction, followed by a reduced interaction of PKAR2α with 20S proteasome. Both downregulating PKAR2α by shRNA and upregulating proteasome by expressing PA28γ rescued hTau‐induced PKA inhibition and CREB dephosphorylation, and upregulating PKA improved hTau‐induced cognitive deficits in mice. Together, these data reveal that intracellular tau accumulation induces synapse and memory impairments by inhibiting PKA/CREB/BDNF/TrkB and PKA/GluA1 signaling, and deficit of PA28γ‐20S proteasome complex formation contributes to PKAR2α elevation and PKA inhibition.     

Cytoskeleton stiffness regulates cellular senescence and innate immune response in Hutchinson–Gilford Progeria Syndrome

Hutchinson–Gilford progeria syndrome (HGPS) is caused by the accumulation of mutant prelamin A (progerin) in the nuclear lamina, resulting in increased nuclear stiffness and abnormal nuclear architecture. Nuclear mechanics are tightly coupled to cytoskeletal mechanics via lamin A/C. However, the role of cytoskeletal/nuclear mechanical properties in mediating cellular senescence and the relationship between cytoskeletal stiffness, nuclear abnormalities, and senescent phenotypes remain largely unknown. Here, using muscle‐derived mesenchymal stromal/stem cells (MSCs) from the Zmpste24^?/? (Z24^?/?) mouse (a model for HGPS) and human HGPS fibroblasts, we investigated the mechanical mechanism of progerin‐induced cellular senescence, involving the role and interaction of mechanical sensors RhoA and Sun1/2 in regulating F‐actin cytoskeleton stiffness, nuclear blebbing, micronuclei formation, and the innate immune response. We observed that increased cytoskeletal stiffness and RhoA activation in progeria cells were directly coupled with increased nuclear blebbing, Sun2 expression, and micronuclei‐induced cGAS‐Sting activation, part of the innate immune response. Expression of constitutively active RhoA promoted, while the inhibition of RhoA/ROCK reduced cytoskeletal stiffness, Sun2 expression, the innate immune response, and cellular senescence. Silencing of Sun2 expression by siRNA also repressed RhoA activation, cytoskeletal stiffness and cellular senescence. Treatment of Zmpste24^?/? mice with a RhoA inhibitor repressed cellular senescence and improved muscle regeneration. These results reveal novel mechanical roles and correlation of cytoskeletal/nuclear stiffness, RhoA, Sun2, and the innate immune response in promoting aging and cellular senescence in HGPS progeria.     

Age attenuates the T‐type CaV3.2‐RyR axis in vascular smooth muscle

Caveolae position Ca_V3.2 (T‐type Ca²⁺ channel encoded by the α‐3.2 subunit) sufficiently close to RyR (ryanodine receptors) for extracellular Ca²⁺ influx to trigger Ca²⁺ sparks and large‐conductance Ca²⁺‐activated K⁺ channel feedback in vascular smooth muscle. We hypothesize that this mechanism of Ca²⁺ spark generation is affected by age. Using smooth muscle cells (VSMCs) from mouse mesenteric arteries, we found that both Ca_v3.2 channel inhibition by Ni²⁺ (50 µM) and caveolae disruption by methyl‐ß‐cyclodextrin or genetic abolition of Eps15 homology domain‐containing protein (EHD2) inhibited Ca²⁺ sparks in cells from young (4 months) but not old (12 months) mice. In accordance, expression of Ca_v3.2 channel was higher in mesenteric arteries from young than old mice. Similar effects were observed for caveolae density. Using SMAKO Ca_v1.2^?/? mice, caffeine (RyR activator) and thapsigargin (Ca²⁺ transport ATPase inhibitor), we found that sufficient SR Ca²⁺ load is a prerequisite for the Ca_V3.2‐RyR axis to generate Ca²⁺ sparks. We identified a fraction of Ca²⁺ sparks in aged VSMCs, which is sensitive to the TRP channel blocker Gd³⁺ (100 µM), but insensitive to Ca_V1.2 and Ca_V3.2 channel blockade. Our data demonstrate that the VSMC Ca_V3.2‐RyR axis is down‐regulated by aging. This defective Ca_V3.2‐RyR coupling is counterbalanced by a Gd³⁺ sensitive Ca²⁺ pathway providing compensatory Ca²⁺ influx for triggering Ca²⁺ sparks in aged VSMCs.     

Psoralen attenuates bleomycin‐induced pulmonary fibrosis in mice through inhibiting myofibroblast activation and collagen deposition

Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by excessive deposition of extracellular matrix (ECM) and chronic inflammation with limited therapeutic options. Psoralen, a major active component extracted from Psoralea corylifolia L. seed, has several biological effects. However, the role of psoralen in IPF is still unclear. Here, we hypothesized that psoralen played an essential role in IPF in the inhibition of fibroblast proliferation and inflammatory response. A murine model of IPF was established by injecting bleomycin (BLM) intratracheally, and psoralen was administered for 14 days from the 7^th to 21^st day after BLM injection. Our results demonstrated that psoralen treatment reduced body weight loss and improved the survival rate of mice with IPF. Histological and immunofluorescent examination showed that psoralen alleviated BLM‐induced lung parenchymal inflammatory and fibrotic alteration. Furthermore, psoralen inhibited proliferation and collagen synthesis of mouse fibroblasts and partially reversed BLM‐induced expression of α‐smooth muscle actin at both the tissue and cell level. Moreover, psoralen decreased the expression of transforming growth factor‐β1, interleukin‐1β, and tumor necrosis factor‐α in the lungs of BLM‐stimulated mice. Our results reveale for the first time that psoralen exerts therapeutic effects against IPF in a BLM‐induced murine model.     

The asymmetric relationships of the distribution of conspecific saplings and adults in forest fragments

随着土地利用方式变化的加剧,生境片段化已成为影响植物多样性的主要因子之一。通常,当成年树个体的密度越高,其周边同种幼树个体的存活率可能会下降,从而为其它物种提供了空间和资源,进而可以维持较高的局域物种多样性。因此,同种成年树和幼树个体的空间分布格局关系和作用强度可以调节植物多样性。然而,对于在片段化森林中,同种成年树和幼树个体空间分布关系的研究却很少报道,迄今尚不清楚片段化景观中同种个体的空间分布关系与物种多样性之间的联系。本研究选择千岛湖陆桥岛屿系统中的27个岛屿,基于岛屿上幼树和成年树个体的空间分布数据,利用混合效应模型分析它们之间的作用强度。同种幼树和成年树个体的空间作用强度越大,说明它们之间的负相互作用越强,即幼树和成年树个体空间分布越分散。此外,本研究分析了岛屿属性(岛屿面积、与大陆的距离和与最近岛屿的距离)与同种个体空间作用强度及物种多样性之间的关系。结果表明,同种个体的空间作用强度随着与最近岛屿距离的增加而增加。同时,物种多样性随着同种个体的空间作用强度的增加而显著增加,且岛屿面积和同种个体的空间作用强度分别解释了岛屿间物种多样性差异的26%和6%,共同解释了8%。耐阴种和非常见种比非耐阴种和常见种的同种幼树和成年树的空间分布更为分散。本研究表明,同种个体的空间分布可能会影响多度较低物种在片段化森林中的生存,反映了生物相互作用对于维持片段化森林中的植物多样性具有重要作用。 本研究也强调在检验同种密度制约时应考虑森林之间的连接度。     

新疆吉木萨尔县蝴蝶群落多样性

蝴蝶作为指示生物, 被广泛地应用于生物多样性监测及环境质量评估。探究新疆吉木萨尔县蝴蝶群落多样性, 可为当地蝴蝶多样性的保护及环境监测提供基础数据。本研究采用样线法在新疆吉木萨尔县选取山前荒漠、农田、山地草原、山地森林、亚高山草甸5种不同的生境类型, 对蝴蝶种类和群落多样性进行调查。共记录蝴蝶4,401号, 隶属于7科26属38种。其中蛱蝶科有9属12种, 为优势科; 粉蝶科的个体数最多, 占比55.01%; 绢蝶科、凤蝶科和弄蝶科的种类数和个体数最少, 均为单科种, 是该地区的稀有类群。对不同生境蝴蝶群落多样性和相似度分析比较的结果显示: 5种生境中多样性指数从高到低依次为亚高山草甸、山地森林、山地草原、农田及山前荒漠, 其中山地森林和亚高山草甸的相似性系数较高, 达到0.77, 山前荒漠和山地草原的相似性系数最低, 为0.37。蝴蝶物种数及多样性指数随海拔的增加呈上升趋势。蝴蝶群落随月份发生变化, 蝴蝶种类和数量在5月发生、7月达到峰值。蝶类个体数在3年内呈下降趋势。研究结果表明, 蝴蝶物种的组成和多样性与生境类型具有密切联系, 保护生态环境, 维持该地区植物群落的多样性、降低人为干扰程度是保护蝶类多样性的关键。