BACKGROUND & AIMS: Cerebrospinal fluid tau (CSF-tau) levels were quantified in 8 patients with frontotemporal dementia (FTD), 6 patients with progressive supranuclear palsy (PSP), 3 patients with corticobasal degeneration (CBD), and 6 patients with dementia with Lewy bodies (DLB). The CSF-tau levels were significantly increased in FTD and DLB, but not in PSP and CBD, compared to that previously reported in normal controls. Notably, the CSF-tau level in DLB was as high as that in Alzheimer's disease (AD). Our study suggests that tau may accumulate in the CSF of patients with certain neurodegenerative diseases other than AD and that measurement of CSF-tau may not distinguish AD from DLB.

背景与目标： 对8例额颞叶痴呆 (FTD)，6例进行性核上性麻痹 (PSP)，3例皮质基底变性 (CBD) 和6例路易体痴呆 (DLB) 患者的脑脊液tau (CSF-tau) 水平进行了定量。与以前在正常对照组中报道的相比，FTD和DLB中的CSF-tau水平显着增加，但PSP和CBD中没有。值得注意的是，DLB中的CSF-tau水平与阿尔茨海默氏病 (AD) 一样高。我们的研究表明，tau可能会在患有AD以外的某些神经退行性疾病的患者的CSF中积累，并且CSF-tau的测量可能无法将AD与DLB区分开。

BACKGROUND & AIMS: :Overexpressing Tau counteracts apoptosis and increases dephosphorylated β-catenin levels, but the underlying mechanisms are elusive. Here, we show that Tau can directly and robustly acetylate β-catenin at K49 in a concentration-, time-, and pH-dependent manner. β-catenin K49 acetylation inhibits its phosphorylation and its ubiquitination-associated proteolysis, thus increasing β-catenin protein levels. K49 acetylation further promotes nuclear translocation and the transcriptional activity of β-catenin, and increases the expression of survival-promoting genes (bcl2 and survivin), counteracting apoptosis. Mutation of Tau's acetyltransferase domain or co-expressing non-acetylatable β-catenin-K49R prevents increased β-catenin signaling and abolishes the anti-apoptotic function of Tau. Our data reveal that Tau preserves β-catenin by acetylating K49, and upregulated β-catenin/survival signaling in turn mediates the anti-apoptotic effect of Tau.

背景与目标： : 过表达的Tau可抵消细胞凋亡并增加去磷酸化的 β-catenin水平，但潜在的机制难以捉摸。在这里，我们显示Tau可以在K49以浓度，时间和pH依赖性的方式直接有效地乙酰化 β-catenin。Β-catenin K49乙酰化抑制其磷酸化及其泛素化相关蛋白水解，从而增加 β-catenin蛋白水平。K49乙酰化进一步促进核易位和 β-catenin的转录活性，并增加存活促进基因 (bcl2和survivin) 的表达，从而抵消细胞凋亡。Tau的乙酰基转移酶结构域的突变或共表达非乙酰化的 β-catenin-k49r可防止 β-catenin信号传导增加并消除Tau的抗凋亡功能。我们的数据表明，Tau通过乙酰化K49来保留 β-catenin，而上调的 β-catenin/存活信号又介导了Tau的抗凋亡作用。

BACKGROUND & AIMS: :We report a case of familial frontotemporal dementia and parkinsonism characterized by early onset with mental retardation. The patient died at the age of 54; neuronal loss was severe in the frontal and temporal cortices, globus pallidus, substantia nigra, red nucleus and dentate nucleus. Anti-tau-positive fibrillary changes were observed in neurons and glia in these regions. Although the patient had 2 novel point mutations of the tau gene, P301P (CCG to CCA) and an intron 10+11-splice site (T to C), exon trapping analysis indicated that the latter was pathogenic.

背景与目标： : 我们报告了一例家族性额颞叶痴呆和帕金森病，其特征是早发性智力低下。患者死亡，享年54岁; 额叶和颞叶皮质，苍白球，黑质，红核和齿状核的神经元丢失严重。在这些区域的神经元和神经胶质细胞中观察到抗tau阳性纤维改变。尽管患者有2个新的tau基因点突变，P301P (CCG至CCA) 和一个内含子10 11剪接位点 (T至C)，但外显子捕获分析表明后者具有致病性。

BACKGROUND & AIMS: :Microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in brains with Alzheimer's disease. The phosphorylation sites of tau are mainly localized in the proline-rich (residues 172-251) and C-terminal tail (residues 368-441) regions, which flank the microtubule-binding repeats. Here, we investigated the effects of tau phosphorylation at these distinct sites/regions on its activity of stimulating microtubule assembly and its self-aggregation. We found that tau phosphorylation at the proline-rich region by dual-specificity tyrosine-phosphorylated and -regulated kinase 1A inhibited its microtubule assembly activity moderately and promoted its self-aggregation slightly. Tau phosphorylation at the C-terminal tail region by glycogen synthase kinase-3beta increased its activity and promoted its self-aggregation markedly. Tau phosphorylation at both regions plus the microtubule-binding region by cAMP-dependent protein kinase diminished its activity (approximately 70% inhibition) and disrupted microtubules. These studies reveal the differential regulation of tau's biological activity and self-aggregation by phosphorylation at various sites/regions.

背景与目标： : 微管相关蛋白tau异常过度磷酸化，聚集成阿尔茨海默氏病大脑中的神经原纤维缠结。tau的磷酸化位点主要位于富含脯氨酸 (残基172-251) 和C末端尾部 (残基368-441) 区域，这些区域位于微管结合重复序列的侧面。在这里，我们研究了在这些不同位点/区域的tau磷酸化对其刺激微管组装及其自聚集的活性的影响。我们发现，双特异性酪氨酸磷酸化和调节激酶1A在富含脯氨酸的区域的tau磷酸化适度抑制了其微管组装活性，并略微促进了其自身聚集。糖原合酶kinase-3beta在C末端尾部区域的Tau磷酸化增加了其活性并显着促进了其自聚集。cAMP依赖性蛋白激酶在两个区域加上微管结合区域的Tau磷酸化降低了其活性 (约70% 抑制) 并破坏了微管。这些研究揭示了tau的生物活性和通过在各个位置/区域的磷酸化而产生的自聚集的差异调节。

BACKGROUND & AIMS: :Interferon-tau (IFN-tau) is a type I IFN originally discovered for its role as a pregnancy recognition hormone in ruminant animals such as sheep and cows. IFN-tau possesses all of the biological properties ascribed to the other type I IFNs including antiviral, antiproliferative and immunomodulatory activities. However, IFN-tau differs in that it is relatively nontoxic to cells at high concentrations as compared to the toxicity normally associated with IFNs-alpha and -beta and the type II IFN, IFN-gamma. IFN-tau was examined for its ability to prevent the development of experimental allergic encephalomyelitis (EAE), an animal model for multiple sclerosis (MS), in humans. IFN-tau prevents development of EAE as effectively as IFN-beta, a type I IFN currently being used for the treatment of MS. Unlike IFN-beta, however, IFN-tau treated mice did not develop leucopenia or experience bodyweight loss indicative of toxicity. Superantigens can induce relapses in EAE, similar to those that are observed in patients with relapsing-remitting MS; IFN-tau blocks superantigen reactivation of EAE. The inhibitory effect of IFN-tau on induction of EAE and reactivation by superantigen involves suppression of myelin basic protein and superantigen activation of T cells as well as suppressed induction of inflammatory cytokines such as tumour necrosis factor-alpha. In addition, IFN-tau has been shown to reduce immunologically mediated spontaneous fetal resorption. Thus, IFN-tau has considerable potential for treatment of autoimmune and immunologically mediated disorders, including MS.

背景与目标： : 干扰素-tau (IFN-tau) 是一种I型IFN，最初因其在反刍动物 (如绵羊和牛) 中作为妊娠识别激素而被发现。IFN-tau具有归因于其他I型IFN的所有生物学特性，包括抗病毒，抗增殖和免疫调节活性。然而，IFN-tau的不同之处在于，与通常与IFNs-α 和-β 以及II型IFN，IFN-γ 相关的毒性相比，它对高浓度的细胞相对无毒。检查了IFN-tau预防人类实验性过敏性脑脊髓炎 (EAE) (一种多发性硬化症 (MS) 的动物模型) 发展的能力。IFN-tau与IFN-β 一样有效地防止EAE的发展，IFN-β 是目前用于治疗MS的I型IFN。然而，与IFN-β 不同，IFN-tau处理的小鼠不会出现白细胞减少症或出现表明毒性的体重下降。超抗原可以诱导EAE的复发，类似于在复发缓解型MS患者中观察到的复发; IFN-tau阻断EAE的超抗原再激活。IFN-tau对EAE诱导和超抗原再激活的抑制作用涉及抑制髓磷脂碱性蛋白和T细胞的超抗原激活，以及抑制炎性细胞因子 (例如肿瘤坏死因子-α) 的诱导。此外，已显示IFN-tau可减少免疫介导的胎儿自发吸收。因此，IFN-tau在治疗自身免疫和免疫介导的疾病 (包括MS) 方面具有相当大的潜力。

BACKGROUND & AIMS: OBJECT:To develop an improved short tau inversion recovery (iSTIR) technique with simultaneous suppression of fat, blood vessels and fluid to increase tumor conspicuity in the abdomen for cancer screening. MATERIALS AND METHODS:An adiabatic spectrally selective inversion pulse was used for fat suppression to overcome the reduced signal to noise ratio associated with chemically non-selective inversion pulse of STIR. A motion-sensitizing driven equilibrium was used for blood vessel suppression and a dual-echo single-shot fast spin echo acquisition was used for fluid suppression. The technique was optimized on four normal subjects and later tested on five patients referred for metastatic tumor evaluation. RESULTS:A velocity encoding of 2 cm/s achieved effective blood suppression even in small vessels. Subtraction of two images (one with 60 ms and the other with 280 ms echo time) acquired in the same echo train achieved excellent fluid suppression (>70% reduction). Simultaneous suppression of fat, blood vessels and fluid improved the tumor conspicuity compared to corresponding fat-suppressed (STIR) image. CONCLUSION:This technique generated two complementary images from a single scan: one that is equivalent to a STIR image and the other that qualitatively resembles a diffusion-weighted image and may have potential for magnetic resonance imaging cancer screening.

背景与目标：

BACKGROUND & AIMS: :To investigate the possible role of cyclin-dependent kinase 5 (cdk5) in the formation of paired helical filaments (PHFs) in muscle of patients with inclusion-body myositis (IBM), we immunolocalized cdk5, by light- and electron- microscopy, in muscle biopsies of six IBM patients. Approximately 80-90% of IBM vacuolated muscle fibers, and 10-15% of nonvacuolated fibers, contained well defined cdk5-immunoreactive inclusions that colocalized with phosphorylated tau in 70-80% of those fibers. Immunoelectronmicroscopy revealed the association of cdk5 with tau-immunoreactive PHFs. In all biopsies that contained them, regenerating muscle fibers had diffuse, moderate to strong cdk5 immunoreactivity. At all neuromuscular junctions, there was strong cdk5 immunoreactivity postsynaptically. Our study suggests that cdk5: (1) plays a role in IBM pathogenesis, possibly mediating phosphorylation of PHF-related tau; (2) is involved in muscle regeneration; and (3) has a novel function at normal neuromuscular junctions.

背景与目标： : 为了研究细胞周期蛋白依赖性激酶5 (cdk5) 在包涵体肌炎 (IBM) 患者肌肉中成对螺旋细丝 (PHFs) 形成中的可能作用，我们通过光学和电子显微镜对cdk5进行了免疫定位。6名IBM患者的肌肉活检。大约80-90% 的IBM空泡肌肉纤维和10-15% 的非空泡纤维含有明确定义的cdk5-immunoreactive夹杂物，这些夹杂物与磷酸化的tau共定位在70-80% 的这些纤维中。免疫电镜显示cdk5与tau免疫反应性PHFs相关。在包含它们的所有活检中，再生肌纤维具有弥漫性，中度至强烈的cdk5免疫反应性。在所有神经肌肉连接处，突触后都有很强的cdk5免疫反应性。我们的研究表明cdk5 :( 1) 在IBM发病机理中起作用，可能介导PHF相关tau的磷酸化; (2) 参与肌肉再生; (3) 在正常神经肌肉连接处具有新的功能。

BACKGROUND & AIMS: BACKGROUND:Tau pathology in AD spreads in a hierarchical pattern, whereby it first appears in the entorhinal cortex, then spreads to the hippocampus and later to the surrounding areas. Based on this sequential appearance, AD can be classified into six stages ("Braak stages"). The mechanisms and agents underlying the progression of Tau pathology are a matter of debate. Emerging evidence indicates that the propagation of Tau pathology may be due to the transmission of Tau protein, but the underlying pathways and Tau species are not well understood. In this study we investigated the question of Tau spreading via small extracellular vesicles called exosomes. METHODS:Exosomes from different sources were analyzed by biochemical methods and electron microscopy (EM) and cryo-EM. Microfluidic devices that allow the culture of cell populations in different compartments were used to investigate the spreading of Tau. RESULTS:We show that Tau protein is released by cultured primary neurons or by N2a cells overexpressing different Tau constructs via exosomes. Neuron-derived exosomal Tau is hypo-phosphorylated, compared with cytosolic Tau. Depolarization of neurons promotes release of Tau-containing exosomes, highlighting the importance of neuronal activity. Using microfluidic devices we show that exosomes mediate trans-neuronal transfer of Tau depending on synaptic connectivity. Tau spreading is achieved by direct transmission of exosomes between neurons. In organotypic hippocampal slices, Tau-containing exosomes in conditioned medium are taken up by neurons and microglia, not astrocytes. In N2a cells, Tau assemblies are released via exosomes. They can induce inclusions of other Tau molecules in N2a cells expressing mutant human Tau. We also studied exosomes from cerebrospinal fluid in AD and control subjects containing monomeric and oligomeric Tau. Split-luciferase complementation reveals that exosomes from CSF can promote Tau aggregation in cultured cells. CONCLUSION:Our study demonstrates that exosomes contribute to trans-synaptic Tau transmission, and thus offer new approches to control the spreading of pathology in AD and other tauopathies.

背景与目标：

BACKGROUND & AIMS: :We recently reported that Alzheimer's disease (AD) with amygdala Lewy bodies (ALB) is a distinct form of alpha-synucleinopathy that occurs in advanced AD. In AD/ALB the alpha-synuclein pathology correlated with tau pathology, but not amyloid plaques, and there was often co-localization of tau and alpha-synuclein in the same neuron. Given the anatomical connectivity of the anterior olfactory nucleus and the amygdala, which receives axonal projections from the olfactory bulb, we hypothesized that there might be a relationship between tau and alpha-synuclein pathology in the olfactory bulb and the amygdala in AD. We screened for alpha-synuclein pathology in the olfactory bulb in AD with and without ALB, and investigated its relationship with tau pathology. In 38 of 41 (93%) AD/ALB cases and 4 of 21 (19%) AD cases without ALB (AD/non-ALB), alpha-synuclein pathology was detected in the olfactory bulb. Double immunolabeling at the light and electron microscopic levels revealed co-localization of tau and alpha-synuclein in the olfactory bulb neurons and neurites. The severity of tau pathology correlated with alpha-synuclein pathology in the olfactory bulb. In addition, alpha-synuclein pathology in the olfactory bulb correlated with alpha-synuclein pathology in amygdala. Tau pathology was greater in both the olfactory bulb and amygdala in AD/ALB than in AD/non-ALB, but there was no difference in tau pathology between the two groups in other brain regions assessed. The present study shows that in AD/ALB, the olfactory bulb is nearly equally vulnerable to tau and alpha-synuclein pathology as the amygdala and suggests that neurodegeneration in these two anatomical regions is linked.

背景与目标： : 我们最近报道了患有杏仁核路易体 (ALB) 的阿尔茨海默氏病 (AD) 是发生在晚期AD中的一种独特形式的 α 突触核蛋白病。在AD/ALB中，α-突触核蛋白病理与tau病理相关，但与淀粉样斑块无关，并且tau和 α-突触核蛋白经常在同一神经元中共同定位。考虑到前嗅神经核和杏仁核的解剖连接，杏仁核从嗅球接收轴突投射，我们假设嗅球和AD杏仁核中的tau和 α-突触核蛋白病理之间可能存在关系。我们在有或没有ALB的AD嗅球中筛选了 α-突触核蛋白病理学，并研究了其与tau病理学的关系。在41例 (93% 例) AD/ALB病例中的38例和无ALB (AD/非ALB) 的21例 (19% 例) AD病例中的4例中，在嗅球中检测到 α-突触核蛋白病理。光镜和电子显微镜下的双重免疫标记显示tau和 α-突触核蛋白在嗅球神经元和神经突中的共定位。tau病理的严重程度与嗅球中的 α-突触核蛋白病理相关。此外，嗅球中的 α-突触核蛋白病理与杏仁核中的 α-突触核蛋白病理相关。AD/ALB中嗅球和杏仁核的Tau病理学均高于AD/非ALB，但在评估的其他大脑区域中，两组之间的tau病理学没有差异。本研究表明，在AD/ALB中，嗅球与杏仁核几乎同样容易受到tau和 α-突触核蛋白病理学的影响，并表明这两个解剖区域的神经变性是相关的。

BACKGROUND & AIMS: :It is unclear how tau gene mutations cause frontotemporal dementia (FTD) with parkinsonism linked to chromosome 17 (FTDP-17), but those in exon 10 (E10) or the following intron may be pathogenic by altering E10 splicing, perturbing the normal 1:1 ratio of four versus three microtubule-binding repeat tau (4R:3R tau ratio) and forming tau inclusions. We report on a 55-year old woman with frontotemporal dementia and a family history of FTDP-17 in whom we found a novel E12 (Glu342Val) tau gene mutation, prominent frontotemporal neuron loss, intracytoplasmic tau aggregates, paired helical tau filaments, increased 4R tau messenger RNA, increased 4R tau without E2 or E3 inserts, decreased 4R tau with these inserts, and a 4R:3R tau ratio greater than 1 in gray and white matter. Thus, this novel Glu342Val mutation may cause FTDP-17 by unprecedented mechanisms that alter splicing of E2, E3, and E10 to preferentially increase 4R tau without amino terminal inserts and promote aggregation of tau filaments into cytopathic inclusions.

背景与目标： : 目前尚不清楚tau基因突变如何导致与17号染色体 (FTDP-17) 相关的帕金森综合征的额颞叶痴呆 (FTD)，但外显子10 (E10) 或以下内含子中的突变可能通过改变E10剪接而致病，扰动四个与三个微管结合重复重复tau的正常1:1比 (4R:3R tau比) 并形成tau内含物。我们报道了一名55岁的患有额颞叶痴呆和FTDP-17家族史的女性，我们发现了新的E12 (Glu342Val) tau基因突变，突出的额颞叶神经元丢失，胞浆内tau聚集体，成对的螺旋tau细丝，增加的4R tau信使RNA，没有E2或E3插入物的4R tau增加，使用这些插入物的4R tau降低，灰色和白色物质的4R:3R tau比大于1。因此，这种新的Glu342Val突变可能通过前所未有的机制引起FTDP-17，这些机制改变E2、E3和E10的剪接，以优先增加没有氨基末端插入物的4rtau，并促进tau丝聚集到细胞病变内含物中。

BACKGROUND & AIMS: :The microtubule-associated protein tau is expressed throughout the nervous system, most highly in neurons but also in glial cells. Its functions in adult and aging mammals remain to be defined. Previous studies in mouse models found either protective or detrimental effects of genetic tau ablation. Though tau ablation prevented synaptic, network, and cognitive dysfunctions in several models of Alzheimer's disease and made mice more resistant to epileptic seizures, a recent study described a parkinsonian phenotype in aging Tau knockout mice. Here we tested cognition and motor functions in Tau(+/+), Tau(+/-), and Tau(-/-) mice at approximately 1 and 2 years of age. Tau ablation did not impair cognition and caused only minor motor deficits that were much more subtle than those associated with the aging process. Tau ablation caused a mild increase in body weight, which correlated with and might have contributed to some of the motor deficits. However, tau ablation did not cause significant dopaminergic impairments, and dopamine treatment did not improve the motor deficits, suggesting that they do not reflect extrapyramidal dysfunction.

背景与目标： : 微管相关蛋白tau在整个神经系统中表达，在神经元中表达最高，在神经胶质细胞中也表达最高。它在成年和衰老哺乳动物中的功能尚待确定。先前在小鼠模型中的研究发现了遗传tau消融的保护或有害作用。尽管tau消融在几种阿尔茨海默氏病模型中预防了突触，网络和认知功能障碍，并使小鼠对癫痫发作更具抵抗力，但最近的一项研究描述了衰老的Tau基因敲除小鼠的帕金森病表型。在这里，我们测试了大约1岁和2岁的Tau (/)，Tau (/-) 和Tau(-/-) 小鼠的认知和运动功能。Tau消融不会损害认知能力，仅引起较小的运动缺陷，比与衰老过程相关的运动缺陷要微妙得多。Tau消融导致体重轻度增加，这与某些运动缺陷相关，并可能导致某些运动缺陷。然而，tau消融并未引起明显的多巴胺能损伤，并且多巴胺治疗并未改善运动缺陷，这表明它们不能反映锥体外系功能障碍。

BACKGROUND & AIMS: :Phosphorylation of tau protein is regulated by several kinases, especially glycogen synthase kinase 3beta (GSK-3beta), cyclin-dependent protein kinase 5 (cdk5) and cAMP-dependent protein kinase (PKA). Phosphorylation of tau by PKA primes it for phosphorylation by GSK-3beta, but the site-specific modulation of GSK-3beta-catalyzed tau phosphorylation by the prephosphorylation has not been well investigated. Here, we found that prephosphorylation by PKA promotes GSK-3beta-catalyzed tau phosphorylation at Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422, but inhibits its phosphorylation at Thr212 and Ser404. In contrast, the prephosphorylation had no significant effect on its subsequent phosphorylation by cdk5 at Thr181, Ser199, Thr205, Thr231 and Ser422; inhibited it at Ser202, Thr212, Thr217 and Ser404; and slightly promoted it at Ser396. These studies reveal the nature of the inter-regulation of tau phosphorylation by the three major tau kinases.

背景与目标： : tau蛋白的磷酸化受几种激酶调节，尤其是糖原合酶激酶3β (GSK-3beta)，细胞周期蛋白依赖性蛋白激酶5 (cdk5) 和cAMP依赖性蛋白激酶 (PKA)。PKA对tau的磷酸化使其被GSK-3beta磷酸化，但是尚未很好地研究通过预磷酸化对GSK-3beta-catalyzed tau磷酸化的位点特异性调节。在这里，我们发现PKA的预磷酸化促进了Thr181，Ser199，Ser202，Thr205，Thr217，Thr231，Ser396和Ser422的GSK-3beta-catalyzed tau磷酸化，但抑制了Thr212和ser404的磷酸化。相反，预磷酸化对其随后在Thr181，Ser199，Thr205，Thr231和Ser422处被cdk5磷酸化没有显着影响; 在Ser202，Thr212，Thr217和Ser404处抑制它; 并在ser396处略微促进它。这些研究揭示了三种主要tau激酶对tau磷酸化的相互调节的性质。

BACKGROUND & AIMS: :Bisphenol A (BPA) is a well-known endocrine disruptor used to manufacture polycarbonate plastics and epoxy resins. BPA exposure especially occupational perinatal exposure to has been linked to numerous adverse effects for the offspring. Available data have shown that perinatal exposure to BPA contributes to neurodegenerative pathological changes; however, the potential mechanisms remain unclear. This study attempted to investigate the long-term consequences of perinatal exposure to BPA on the offspring mouse brain. The pregnant mice were given either a vehicle control or BPA (2, 10, 100 μg/kg/d) from day 6 of gestation until weaning (P6-PND21, foetal and neonatal exposure). At 3, 6 and 9 months of age, the neurotoxic effects in the offspring in each group were investigated. We found that the spine density but not the dendritic branches in the hippocampus were noticeably reduced at 6 and 9 months of age. Meanwhile, p-Tau, the characteristic protein for tauopathy, was dramatically increased in both the hippocampus and cortex at 3-9 months of age. Mechanically, the balance of kinase and protein phosphatase, which plays critical roles in p-Tau regulation, was disturbed. It indicated that GSK3β and CDK5, two critical kinases, were activated in most of the BPA perinatal exposure group, while protein phosphatase 2A (PP2A), one of the important phosphatases, regulated p-Tau expression through its demethylation, methylation and phosphorylation. Taken together, the present study may be translatable to the human occupational BPA exposure due to a similar exposure level. BPA perinatal exposure causes long-term adverse effects on the mouse brain and may be a risk factor for tauopathies, and the CDK5/GSK3β/PP2A axis might be a promising therapeutic target for BPA-induced neurodegenerative pathological changes.

背景与目标： : 双酚a (BPA) 是一种众所周知的内分泌干扰物，用于制造聚碳酸酯塑料和环氧树脂。BPA暴露，尤其是职业性围产期暴露，与后代的许多不良反应有关。现有数据表明，围产期暴露于BPA会导致神经退行性病理变化; 但是，潜在的机制尚不清楚。这项研究试图调查围产期暴露于BPA对后代小鼠大脑的长期影响。从妊娠的第6天至断奶 (P6-PND21，胎儿和新生儿暴露)，给予怀孕的小鼠媒介物对照或BPA (2,10，100 μ g/kg/d)。在3、6和9个月大时，研究了每组后代的神经毒性作用。我们发现，在6个月和9个月大时，海马中的脊柱密度显着降低，但树突状分支却没有显着降低。同时，在3-9个月大时，海马和皮质中的p-Tau是Tau病的特征性蛋白。从机械上讲，在p-Tau调节中起关键作用的激酶和蛋白磷酸酶的平衡受到干扰。结果表明，在大多数BPA围产期暴露组中，两种关键激酶GSK3β 和CDK5被激活，而重要的磷酸酶之一蛋白磷酸酶2A (PP2A) 通过其去甲基化，甲基化和磷酸化来调节p-Tau的表达。总而言之，由于相似的暴露水平，本研究可能可以转化为人类职业性BPA暴露。BPA围产期暴露会对小鼠大脑造成长期不良影响，并可能是taut病的危险因素，CDK5/GSK3β/PP2A轴可能是BPA诱导的神经退行性病变的有希望的治疗靶标。

BACKGROUND & AIMS: :Hyperphosphorylation and aggregation of the microtubule-binding protein tau characterize a diverse array of neurodegenerative disorders. Most of these lack mutations in the encoding MAPT gene, and the role of tau in disease pathogenesis remains controversial. Among these tauopathies is Niemann-Pick type C disease (NPC), a lysosomal storage disorder characterized by progressive neurodegeneration and premature death, most often caused by an inherited deficiency in the intracellular lipid trafficking protein NPC1. To determine the extent to which tau affects NPC pathogenesis, we generated Npc1-/- mice deficient in tau. Unexpectedly, NPC1/tau double null mutants are generated in markedly smaller litters, exhibit an enhanced systemic phenotype and die significantly earlier than NPC1 single null mutants. As autophagy is up-regulated in NPC and protein degradation through this pathway depends on movement along microtubules, we knocked down MAPT expression in NPC1-deficient human fibroblasts and examined effects on this pathway. We show that an acute reduction of tau expression in a cellular model of NPC decreases induction and flux through the autophagic pathway. Our data establish that MAPT deletion exacerbates the NPC phenotype through a mechanism independent of tau protein aggregation and identifies a critical role for tau in the regulation of autophagy in NPC1-deficient cells.

背景与目标： : 微管结合蛋白tau的过度磷酸化和聚集表征了多种神经退行性疾病。其中大多数缺乏编码MAPT基因的突变，tau在疾病发病机制中的作用仍存在争议。在这些tau病中，有尼曼-皮克C型疾病 (NPC)，这是一种溶酶体贮积障碍，其特征是进行性神经变性和过早死亡，通常是由细胞内脂质运输蛋白npc1的遗传缺陷引起的。为了确定tau对NPC发病机理的影响程度，我们生成了缺乏tau的Npc1-/-小鼠。出乎意料的是，NPC1/tau双空突变体在明显较小的凋零中生成，表现出增强的系统表型，并且比NPC1单个空突变体明显更早死亡。由于自噬在NPC中被上调，并且通过该途径的蛋白质降解取决于沿微管的运动，因此我们下调了NPC1-deficient人成纤维细胞中的MAPT表达，并检查了对该途径的影响。我们显示，NPC细胞模型中tau表达的急剧降低会降低自噬途径的诱导和通量。我们的数据表明，MAPT缺失通过独立于tau蛋白聚集的机制加剧了NPC表型，并确定了tau在NPC1-deficient细胞自噬调节中的关键作用。

BACKGROUND & AIMS: :The microtubule-associated protein tau is important to normal neuronal function in the mammalian nervous system. Aggregated tau is the major component of neurofibrillary tangles (NFTs), present in several neurodegenerative diseases, including Alzheimer's and frontotemporal dementia with Parkinsonism (FTDP). Splicing misregulation of adult-specific exon 10 results in expression of abnormal ratios of tau isoforms, leading to FTDP. Positions +3 to +16 of the intron downstream of exon 10 define a clustering region for point mutations that are found in FTDP. The serine/arginine-rich (SR) factor 9G8 strongly inhibits inclusion of tau exon 10. In this study, we established that 9G8 binds directly to this clustering region, requires a wild-type residue at position +14 to inhibit exon inclusion, and RNAi constructs against 9G8 increase exon 10 inclusion. These results indicate that 9G8 plays a key role in regulation of exon 10 splicing and imply a pathogenic role in neurodegenerative diseases.

背景与目标： : 微管相关蛋白tau对哺乳动物神经系统的正常神经元功能很重要。聚集的tau是神经原纤维缠结 (nft) 的主要成分，存在于几种神经退行性疾病中，包括阿尔茨海默氏病和患有帕金森病 (FTDP) 的额颞叶痴呆。成人特异性外显子10的剪接失调导致tau亚型异常比例的表达，导致FTDP。外显子10下游的内含子的位置3至16定义了在FTDP中发现的点突变的聚类区域。富含丝氨酸/精氨酸 (SR) 因子9G8强烈抑制tau外显子10的包含。在这项研究中，我们确定9G8直接与该聚类区域结合，需要在14位的野生型残基来抑制外显子包含，并且针对9G8的RNAi构建体增加了外显子10的包含。这些结果表明，9G8在调节外显子10剪接中起关键作用，并暗示了在神经退行性疾病中的致病作用。