Phospho-tau accumulation and adult hippocampal neurogenesis (AHN) impairment both contribute importantly to the cognitive decline in Alzheimer’s disease (AD), but whether and how tau dysregulates AHN ...in AD remain poorly understood. Here, we found a prominent accumulation of phosphorylated tau in GABAergic interneurons in the dentate gyrus (DG) of AD patients and mice. Specific overexpression of human tau (hTau) in mice DG interneurons induced AHN deficits but increased neural stem cell-derived astrogliosis, associating with a downregulation of GABA and hyperactivation of neighboring excitatory neurons. Chemogenetic inhibition of excitatory neurons or pharmacologically strengthening GABAergic tempos rescued the tau-induced AHN deficits and improved contextual cognition. These findings evidenced that intracellular accumulation of tau in GABAergic interneurons impairs AHN by suppressing GABAergic transmission and disinhibiting neural circuits within the neurogenic niche, suggesting a potential of GABAergic potentiators for pro-neurogenic or cell therapies of AD.
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•Phospho-tau is accumulated in DG GABAergic interneurons of AD patients and mice•Interneuron overexpressing human tau impairs adult hippocampal neurogenesis•Tau accumulation reduces GABA, disinhibits local circuits, and promotes astrogliosis•THIP, a δ-GABAAR agonist, improves neurogenesis and cognition in AD mice
Impaired adult hippocampal neurogenesis contributes to the cognitive decline in Alzheimer’s disease. Zheng et al. report that phospho-tau accumulation in dentate gyrus GABAergic interneurons disrupts adult hippocampal neurogenesis and increased astrogliosis. Importantly, strengthening GABAergic signaling can rescue neurogenesis and improve cognitive functions in mouse models of Alzheimer’s disease.
Arabidopsis phytochromes （phyA-phyE） are photoreceptors dedicated to sensing red/far-red light. Phyto- chromes promote photomorphogenic developments upon light irradiation via a signaling pathway ...that involves rapid degradation of PIFs （PHYTOCHROME INTERACTING FACTORS） and suppression of COP1 （CONSTITUTIVE PHOTOMORPHOGENIC 1） nuclear accumulation, through physical interactions with PIFs and COP1, respectively. Both phyA and phyB, the two best characterized phytochromes, regulate plant photomorphogenesis predominantly under far-red light and red light, respectively. It has been demonstrated that SPA1 （SUPPRESSOR OF PHYTOCHROME A 1） associates with COP1 to promote COP1 activity and suppress photomorphogenesis. Here, we report that the mechanism underlying phyB- promoted photomorphogenesis in red light involves direct physical and functional interactions between red-light-activated phyB and SPA1. We found that SPA1 acts genetically downstream of PHYB to repress photomorphogenesis in red light. Protein interaction studies in both yeast and Arabidopsis demonstrated that the photoactivated phyB represses the association of SPA1 with COP1, which is mediated, at least in part, through red-light-dependent interaction of phyB with SPA1. Moreover, we show that phyA physically interacts with SPA1 in a Pfr-form-dependent manner, and that SPA1 acts downstream of PHYA to regulate photomorphogenesis in far-red light. This study provides a genetic and biochemical model of how photo- activated phyB represses the activity of COP1-SPA1 complex through direct interaction with SPA1 to promote photomorphogenesis in red light.
Intracellular tau accumulation forming neurofibrillary tangles is hallmark pathology of Alzheimer's disease (AD), but how tau accumulation induces synapse impairment is elusive. By overexpressing ...human full‐length wild‐type tau (termed hTau) to mimic tau abnormality as seen in the brain of sporadic AD patients, we find that hTau accumulation activates JAK2 to phosphorylate STAT1 (signal transducer and activator of transcription 1) at Tyr701 leading to STAT1 dimerization, nuclear translocation, and its activation. STAT1 activation suppresses expression of N‐methyl‐D‐aspartate receptors (NMDARs) through direct binding to the specific GAS element of GluN1, GluN2A, and GluN2B promoters, while knockdown of STAT1 by AAV‐Cre in STAT1flox/flox mice or expressing dominant negative Y701F‐STAT1 efficiently rescues hTau‐induced suppression of NMDAR expression with amelioration of synaptic functions and memory performance. These findings indicate that hTau accumulation impairs synaptic plasticity through JAK2/STAT1‐induced suppression of NMDAR expression, revealing a novel mechanism for hTau‐associated synapse and memory deficits.
Synopsis
Tau accumulation, one hallmark of Alzheimer's disease, induces synaptic impairment by activating JAK2/STAT1 signaling, which transcriptionally suppresses N‐methyl‐D‐aspartate receptors. Downregulation of STAT1 ameliorates synaptic function and memory performance in mice.
Accumulation of hTau triggers JAK2‐dependent STAT1 dimerization, activation and nuclear translocation.
STAT1 activation directly suppresses N‐methyl‐D‐aspartate receptor expression.
Downregulation of STAT1 rescues hTau‐induced N‐methyl‐D‐aspartate receptor suppression.
Tau accumulation, one hallmark of Alzheimer's disease, induces synaptic impairment by activating JAK2/STAT1 signaling, which transcriptionally suppresses N‐methyl‐D‐aspartate receptors. Downregulation of STAT1 ameliorates synaptic function and memory performance in mice.
Chronic hypoxia is a risk factor for Alzheimer's disease (AD), and the neurofibrillary tangle (NFT) formed by hyperphosphorylated tau is one of the two major pathological changes in AD. However, the ...effect of chronic hypoxia on tau phosphorylation and its mechanism remains unclear. In this study, we investigated the role of HIF-1α (the functional subunit of hypoxia-inducible factor 1) in tau pathology. It was found that in Sprague-Dawley (SD) rats, global hypoxia (10% O
, 6 h per day) for one month induced cognitive impairments. Meanwhile it induced HIF-1α increase, tau hyperphosphorylation, and protein phosphatase 2A (PP2A) deficiency with leucine carboxyl methyltransferase 1(LCMT1, increasing PP2A activity) decrease in the rats' hippocampus. The results were replicated by hypoxic treatment in primary hippocampal neurons and C6/tau cells (rat C6 glioma cells stably expressing human full-length tau441). Conversely, HIF-1α silencing impeded the changes induced by hypoxia, both in primary neurons and SD rats. The result of dual luciferase assay proved that HIF-1α acted as a transcription factor of LCMT1. Unexpectedly, HIF-1α decreased the protein level of LCMT1. Further study uncovered that both overexpression of HIF-1α and hypoxia treatment resulted in a sizable degradation of LCMT1 via the autophagy--lysosomal pathway. Together, our data strongly indicated that chronic hypoxia upregulates HIF-1α, which obviously accelerated LCMT1 degradation, thus counteracting its transcriptional expression. The increase in HIF-1α decreases PP2A activity, finally resulting in tau hyperphosphorylation and cognitive dysfunction. Lowering HIF-1α in chronic hypoxia conditions may be useful in AD prevention.
Anthocyanins are critical for plants. It is shown that the expression of genes encoding the key enzymes such as dihydroflavonol 4-reductase (DFR), UDP-Glc: flavonoid 3-O-glucosyltransferase (UF3GT), ...and leucoanthocyanidin dioxygenase (LDOX) in anthocyanin biosynthesis pathway is regulated by MYB75, a R2R3 MYB transcription factor. The production of anthocyanin is known to be promoted by jasmonic acid (JA) in light but not in darkness. The photoreceptors cryptochrome 1 (CRY1), phytochrome B (phyB), and phytochrome A (phyA) are also shown to mediate light promotion of anthocyanin accumulation, respectively, whereas their downstream factor COP1, a master negative regulator of photomorphogensis, represses anthocyanin accumulation. However, whether JA coordinates with photoreceptors in the regulation of anthocyanin accumulation is unknown. Here, we show that under far-red light, JA promotes anthocyanin accumulation in a phyA signaling pathway-dependent manner. The phyA mutant is hyposensitive to jasmonic acid analog methyl jasmonic acid (MeJA) under far-red light. The dominant mutant of MYB75, pap1-D, accumulates significantly higher levels of anthocyanin than wild type under far-red light, whereas knockdown of MYBs (MYB75, MYB90, MYB113, and MYB114) through RNAi significantly reduces MeJA promotion of anthocyanin accumulation. The phyA pap1-D double mutant shows reduced responsiveness to MeJA, similar to phyA mutant under far-red light. In darkness, a mutant allele of cop1, cop1-4, shows enhanced responsiveness to MeJA, but pap1-D mutant is barely responsive to MeJA. Upon MeJA application, the cop1-4 pap1-D double mutant accumulates considerably higher levels of anthocyanin than cop1-4 in darkness. Protein studies indicate that MYB75 protein is stabilized by white light and far-red light. Further gene expression studies suggest that MeJA promotes the expression of DFR, UF3GT, and LDOX genes in a phyA- and MYB75-dependent manner under far-red light. Our findings suggest that JA promotion of anthocyanin accumulation under far-red light is dependent on phyA signaling pathway, consisting of phyA, COP1, and MYB75.
Proper timing of flowering is essential for reproduction of plants. Although it is well known that both light and gibberellin (GA) signaling play critical roles in promoting flowering in Arabidopsis ...thaliana, whether and how they are integrated to regulate flowering remain largely unknown. Here, we show through biochemical studies that DELLA proteins physically interact with CONSTANS (CO). Furthermore, the interaction of CO with NF‐YB2 is inhibited by the DELLA protein, RGA. Our findings suggest that regulation of flowering by GA signaling in leaves under long days is mediated, at least in part, through repression of DELLA proteins on CO, providing a molecular link between DELLA proteins, key components in GA signaling pathway, and CO, a critical flowering activator in photoperiod signaling pathway.
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.
Synopsis
Tau acetylates β‐catenin at K49, which stabilizes β‐catenin by inhibiting its phosphorylation and ubiquitination‐associated proteolysis. β‐catenin mediates the anti‐apoptotic effects of Tau by increasing the expression of survival‐promoting genes.
Tau can acetylate β‐catenin at K49 in a concentration‐, time‐ pH‐ and acetyltransferase domain‐dependent manner.
K49‐acetylation by Tau preserves β‐catenin by inhibiting its phosphorylation and ubiquitination‐associated proteolysis, resulting in increased nuclear translocation and enhanced transcriptional activity of β‐catenin.
β‐catenin K49‐acetylation mediates the anti‐apoptotic effects of Tau by augmenting the expression of survival‐promoting genes.
Tau acetylates β‐catenin at K49, which stabilizes β‐catenin by inhibiting its phosphorylation and ubiquitination‐associated proteolysis. β‐catenin mediates the anti‐apoptotic effects of Tau by increasing the expression of survival‐promoting genes.
Different emotional states lead to distinct behavioural consequences even when faced with the same challenging events. Emotions affect learning and memory capacities, but the underlying ...neurobiological mechanisms remain elusive. Here we establish models of learned helplessness (LHL) and learned hopefulness (LHF) by exposing animals to inescapable foot shocks or with anticipated avoidance trainings. The LHF animals show spatial memory potentiation with excitatory monosynaptic upscaling between posterior basolateral amygdale (BLP) and ventral hippocampal CA1 (vCA1), whereas the LHL show memory deficits with an attenuated BLP-vCA1 connection. Optogenetic disruption of BLP-vCA1 inputs abolishes the effects of LHF and impairs synaptic plasticity. By contrast, targeted BLP-vCA1 stimulation rescues the LHL-induced memory deficits and mimics the effects of LHF. BLP-vCA1 stimulation increases synaptic transmission and dendritic plasticity with the upregulation of CREB and intrasynaptic AMPA receptors in CA1. These findings indicate that opposite excitatory monosynaptic scaling of BLP-vCA1 controls LHF- and LHL-modulated spatial memory, revealing circuit-specific mechanisms linking emotions to memory.
The trophodynamics of toxic trace metals is significant for assessing the threat of toxic trace metals to the aquatic ecosystem and human safety. However, due to the difficulty of accurately ...calculating the trophic positions of freshwater aquatic organisms in the food web, the comprehensive process of trophodynamics of toxic trace metals in freshwater ecosystems was still rarely known. By integrating the compound-specific nitrogen stable isotopic analysis of amino acids (CSIA-AAs) and the Bayesian stable isotope mixing model (SIMM) as a novel approach, the present study investigated the trophodynamics of five toxic trace metals (Zn, As, Cr, Cu, and Hg) in the food web of the YangZong Lake, a plateau freshwater lake that was once heavily polluted by arsenic in Yunnan Province, China. The results revealed that Hg tended to be efficiently biomagnified in the food web with a trophic magnification factor of 1.75; As, Cr, and Cu were biodiluted significantly, while Zn showed no biomagnification or biodilution trends. The dietary health risk assessment indicated the potential health risk of toxic trace metals for the local residents of long-term fish consumption. The present work highlights the accuracy and reliability of the novel CSIA-AAS+SIMM approach in the calculation of the trophic positions of freshwater organisms.
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The negative impacts of toxic trace metals on the environment and human health are well-known duo to its highly hazardous and long-time bioaccumulation. However, due to the difficulty of accurately calculating the trophic positions of freshwater aquatic organisms in the food web, the comprehensive process of trophic transfer and bioaccumulation of toxic trace metals in freshwater ecosystems was still rarely known. The present work revealed the complicated trophodynamics process of toxic trace metals in the food web of a plateau freshwater lake and accessed the potential health risk of toxic trace metals for the local residents.
•CSIA-AAs+SIMMR approach can precisely determine the trophic positions of organisms.•Hg tended to be efficiently biomagnified in the food web of YangZong Lake.•As, Cr, and Cu were significantly biodiluted in the freshwater food web.•There is a potential dietary health risk of toxic trace metals for residents.
Protein post-translational modifications (PPTMs) refer to a series of chemical modifications that occur after the synthesis of protein. Proteins undergo different modifications such as ...phosphorylation, acetylation, ubiquitination, and so on. These modifications can alter the protein's structure, function, and interaction, thereby regulating its biological activity. In neurodegenerative diseases, several proteins undergo abnormal post-translational modifications, which leads to aggregation and abnormal deposition of protein, thus resulting in neuronal death and related diseases. For example, the main pathological features of Alzheimer's disease are the aggregation of beta-amyloid protein and abnormal phosphorylation of tau protein. The abnormal ubiquitination and loss of α-synuclein are related to the onset of Parkinson's disease. Other neurodegenerative diseases such as Huntington's disease, amyotrophic lateral sclerosis, and so on are also connected with abnormal PPTMs. Therefore, studying the abnormal PPTMs in neurodegenerative diseases is critical for understanding the mechanism of these diseases and the development of significant therapeutic strategies. This work reviews the implications of PPTMs in neurodegenerative diseases and discusses the relevant therapeutic strategies.
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