While melatonin is known to have protective effects in mitochondria‐related diseases, aging, and neurodegenerative disorders, there is poor understanding of the effects of melatonin treatment on ...mitophagy in Alzheimer's disease (AD). We used proteomic analysis to investigate the effects and underlying molecular mechanisms of oral melatonin treatment on mitophagy in the hippocampus of 4‐month‐old wild‐type mice versus age‐matched 5 × FAD mice, an animal model of AD. 5 × FAD mice showed disordered mitophagy and mitochondrial dysfunction as revealed by increased mtDNA, mitochondrial marker proteins and MDA production, decreased electron transport chain proteins and ATP levels, and co‐localization of Lamp1 and Tomm20. Melatonin treatment reversed the abnormal expression of proteins in the signaling pathway of lysosomes, pathologic phagocytosis of microglia, and mitochondrial energy metabolism. Moreover, melatonin restored mitophagy by improving mitophagosome–lysosome fusion via Mcoln1, and thus, ameliorated mitochondrial functions, attenuated Aβ pathology, and improved cognition. Concurrent treatment with chloroquine and melatonin blocked the positive behavioral and biochemical effects of administration with melatonin alone. Taken in concert, these results suggest that melatonin reduces AD‐related deficits in mitophagy such that the drug should be considered as a therapeutic candidate for the treatment of AD.
An increase in tau acetylation at K274 and K281 and abnormal mitochondrial dynamics have been observed in the brains of Alzheimer's disease (AD) patients. Here, we constructed three types of tau ...plasmids, TauKQ (acetylated tau mutant, by mutating its K274/K281 into glutamine to mimic disease‐associated lysine acetylation), TauKR (non‐acetylated tau mutant, by mutating its K274/K281 into arginine), and TauWT (wild‐type human full‐length tau). By transfecting these tau plasmids in HEK293 cells, we found that TauWT and TauKR induced mitochondrial fusion by increasing the level of mitochondrial fusion proteins. Conversely, TauKQ induced mitochondrial fission by reducing mitochondrial fusion proteins, exacerbating mitochondrial dysfunction and apoptosis. BGP‐15 ameliorated TauKQ‐induced mitochondrial dysfunction and apoptosis by improving mitochondrial dynamics. Our findings suggest that acetylation of K274/281 represents an important post‐translational modification site regulating mitochondrial dynamics, and that BGP‐15 holds potential as a therapeutic agent for mitochondria‐associated diseases such as AD.
Mitochondrial dynamics include two processes: mitochondrial fission and fusion. TauKQ induced mitochondrial fission by decreasing mitochondrial fusion proteins, which aggravated mitochondrial dysfunction and apoptosis. BGP‐15 reversed TauKQ‐induced mitochondrial dysfunctions and apoptosis by improving mitochondrial dynamics.
Macroautophagy/autophagy deficit induces intracellular MAPT/tau accumulation, the hallmark pathology in Alzheimer disease (AD) and other tauopathies; however, the reverse role of MAPT accumulation in ...autophagy and neurodegeneration is not clear. Here, we found that overexpression of human wild-type full-length MAPT, which models MAPT pathologies as seen in sporadic AD patients, induced autophagy deficits via repression of autophagosome-lysosome fusion leading to significantly increased LC3 (microtubule-associated protein 1 light chain 3)-II and SQSTM1/p62 (sequestosome 1) protein levels with autophagosome accumulation. At the molecular level, intracellular MAPT aggregation inhibited expression of IST1 (IST1 factor associated with ESCRT-III), a positive modulator for the formation of ESCRT (the Endosomal Sorting Complex Required for Transport) complex that is required for autophagosome-lysosome fusion. Upregulating IST1 in human MAPT transgenic mice attenuated autophagy deficit with reduced MAPT aggregation and ameliorated synaptic plasticity and cognitive functions, while downregulating IST1 per se induced autophagy deficit with impaired synapse and cognitive function in naïve mice. IST1 can facilitate association of CHMP2B (charged multivesicular body protein 2B) and CHMP4B/SNF7-2 to form ESCRT-III complex, while lack of IST1 impeded the complex formation. Finally, we demonstrate that MAPT accumulation suppresses IST1 transcription with the mechanisms involving the ANP32A-regulated mask of histone acetylation. Our findings suggest that the AD-like MAPT accumulation can repress autophagosome-lysosome fusion by deregulating ANP32A-INHAT-IST1-ESCRT-III pathway, which also reveals a vicious cycle of MAPT accumulation and autophagy deficit in the chronic course of AD neurodegeneration.Abbreviations: AAV: adeno-associated virus; Aβ: β-amyloid; aCSF: artificial cerebrospinal fluid; AD: Alzheimer disease; ANP32A: acidic nuclear phosphoprotein 32 family member A; ATG: autophagy related; AVs: autophagic vacuoles; CEBPB: CCAAT enhancer binding protein beta; CHMP: charged multivesicular body protein; DMEM: Dulbecco's modified eagle's medium; EBSS: Earle's balanced salt solution; EGFR: epidermal growth factor receptor; ESCRT: endosomal sorting complex required for transport; fEPSPs: field excitatory postsynaptic potentials; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GSK3B: glycogen synthase kinase 3 beta; HAT: histone acetyl transferase; HDAC: histone deacetylase; INHAT: inhibitor of histone acetyl transferase; IST1: IST1 factor associated with ESCRT-III; LAMP2: lysosomal associated membrane protein 2; LTP: long-term potentiation; MAP1LC3: microtubule associated protein 1 light chain 3; MAPT/tau: microtubule associated protein tau; MVB: multivesicular bodies; MWM: Morris water maze; PBS: phosphate-buffered saline solution; RAB7: member RAS oncogene family; SNAREs: soluble N-ethylmaleimide-sensitive factor attachment protein receptors; SQSTM1/p62: sequestosome 1
δ-Secretase, an age-dependent asparagine protease, cleaves both amyloid precursor protein (APP) and Tau and is required for amyloid plaque and neurofibrillary tangle pathologies in Alzheimer's ...disease (AD). However, whether δ-secretase activation is sufficient to trigger AD pathogenesis remains unknown. Here we show that the fragments of δ-secretase-cleavage, APP (586-695) and Tau(1-368), additively drive AD pathogenesis and cognitive dysfunctions. Tau(1-368) strongly augments BACE1 expression and Aβ generation in the presence of APP. The Tau(1-368) fragment is more robust than full-length Tau in binding active STAT1, a BACE1 transcription factor, and promotes its nuclear translocation, upregulating BACE1 and Aβ production. Notably, Aβ-activated SGK1 or JAK2 kinase phosphorylates STAT1 and induces its association with Tau(1-368). Inhibition of these kinases diminishes stimulatory effect of Tau(1-368). Knockout of STAT1 abolishes AD pathologies induced by δ-secretase-generated APP and Tau fragments. Thus, we show that Tau may not only be a downstream effector of Aβ in the amyloid hypothesis, but also act as a driving force for Aβ, when cleaved by δ-secretase.
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.
Alzheimer's disease is the most prevalent neurodegenerative disease affecting older adults. Primary features of Alzheimer's disease include extracellular aggregation of amyloid-β plaques and the ...accumulation of neurofibrillary tangles, formed by tau protein, in the cells. While there are amyloid-β-targeting therapies for the treatment of Alzheimer's disease, these therapies are costly and exhibit potential negative side effects. Mounting evidence suggests significant involvement of tau protein in Alzheimer's disease-related neurodegeneration. As an important microtubule-associated protein, tau plays an important role in maintaining the stability of neuronal microtubules and promoting axonal growth. In fact, clinical studies have shown that abnormal phosphorylation of tau protein occurs before accumulation of amyloid-β in the brain. Various therapeutic strategies targeting tau protein have begun to emerge, and are considered possible methods to prevent and treat Alzheimer's disease. Specifically, abnormalities in post-translational modifications of the tau protein, including aberrant phosphorylation, ubiquitination, small ubiquitin-like modifier (SUMO)ylation, acetylation, and truncation, contribute to its microtubule dissociation, misfolding, and subcellular missorting. This causes mitochondrial damage, synaptic impairments, gliosis, and neuroinflammation, eventually leading to neurodegeneration and cognitive deficits. This review summarizes the recent findings on the underlying mechanisms of tau protein in the onset and progression of Alzheimer's disease and discusses tau-targeted treatment of Alzheimer's disease.
Alzheimer's disease (AD) is characterized by profound synapse loss and impairments of learning and memory. Magnesium affects many biochemical mechanisms that are vital for neuronal properties and ...synaptic plasticity. Recent studies have demonstrated that the serum and brain magnesium levels are decreased in AD patients; however, the exact role of magnesium in AD pathogenesis remains unclear. Here, we found that the intraperitoneal administration of magnesium sulfate increased the brain magnesium levels and protected learning and memory capacities in streptozotocin-induced sporadic AD model rats. We also found that magnesium sulfate reversed impairments in long-term potentiation (LTP), dendritic abnormalities, and the impaired recruitment of synaptic proteins. Magnesium sulfate treatment also decreased tau hyperphosphorylation by increasing the inhibitory phosphorylation of GSK-3β at serine 9, thereby increasing the activity of Akt at Ser473 and PI3K at Tyr458/199, and improving insulin sensitivity. We conclude that magnesium treatment protects cognitive function and synaptic plasticity by inhibiting GSK-3β in sporadic AD model rats, which suggests a potential role for magnesium in AD therapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hyperhomocysteinemia (Hhcy) may induce memory deficits with β‐amyloid (Aβ) accumulation and tau hyperphosphorylation. Simultaneous supplement of folate and vitamin B12 partially restored the plasma ...homocysteine level and attenuated tau hyperphosphorylation, Aβ accumulation and memory impairments induced by Hhcy. However, folate and vitamin B12 treatment have no effects on Hhcy which has the methylenetetrahydrofolate reductase genotype mutation. In this study, we investigated the effects of simultaneous supplement of betaine on Alzheimer‐like pathological changes and memory deficits in hyperhomocysteinemic rats after a 2‐week induction by vena caudalis injection of homocysteine (Hcy). We found that supplementation of betaine could ameliorate the Hcy‐induced memory deficits, enhance long‐term potentiation (LTP) and increase dendritic branches numbers and the density of the dendritic spines, with up‐regulation of NR1, NR2A, synaptotagmin, synaptophysin, and phosphorylated synapsin I protein levels. Supplementation of betaine also attenuated the Hcy‐induced tau hyperphosphorylation at multiple AD‐related sites through activation protein phosphatase‐2A (PP2A) with decreased inhibitory demethylated PP2AC at Leu309 and phosphorylated PP2AC at Tyr307. In addition, supplementation of betaine also decreased Aβ production with decreased presenilin‐1 protein levels. Our data suggest that betaine could be a promising candidate for arresting Hcy‐induced AD‐like pathological changes and memory deficits.
We have found that betaine can attenuate Hcy‐induced spatial memory deficits with possible mechanisms that may involve in the expresions or/and activations of several memory‐related proteins, and increase the dendritic branches and spine density in hippocampal CA1 region. It also attenuated AD‐like tau hyperphosphorylation by activation PP2A, and inhibited Aβ aggregation by decreasing PS‐1.
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.
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