RESUMO
Disturbances in autophagy and stress granule dynamics have been implicated as potential mechanisms underlying inclusion body myopathy (IBM) and related disorders. Yet the roles of core autophagy proteins in IBM and stress granule dynamics remain poorly characterized. Here, we demonstrate that disrupted expression of the core autophagy proteins ULK1 and ULK2 in mice causes a vacuolar myopathy with ubiquitin and TDP-43-positive inclusions; this myopathy is similar to that caused by VCP/p97 mutations, the most common cause of familial IBM. Mechanistically, we show that ULK1/2 localize to stress granules and phosphorylate VCP, thereby increasing VCP's activity and ability to disassemble stress granules. These data suggest that VCP dysregulation and defective stress granule disassembly contribute to IBM-like disease in Ulk1/2-deficient mice. In addition, stress granule disassembly is accelerated by an ULK1/2 agonist, suggesting ULK1/2 as targets for exploiting the higher-order regulation of stress granules for therapeutic intervention of IBM and related disorders.
Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Doenças por Armazenamento dos Lisossomos/genética , Doenças Musculares/genética , Proteínas Serina-Treonina Quinases/genética , Proteína com Valosina/genética , Adenosina Trifosfatases/genética , Animais , Autofagia/genética , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Humanos , Corpos de Inclusão/genética , Corpos de Inclusão/patologia , Doenças por Armazenamento dos Lisossomos/metabolismo , Doenças por Armazenamento dos Lisossomos/patologia , Camundongos , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Fosforilação/genética , Estresse Fisiológico/genética , Ubiquitina/genéticaRESUMO
Proteinopathy in neurodegenerative diseases is typically characterized by deteriorating activity of specific protein aggregates. In tauopathies, including Alzheimer's disease (AD), tau protein abnormally accumulates and induces dysfunction of the affected neurons. Despite active identification of tau modifications responsible for tau aggregation, a critical modulator inducing tau proteinopathy by affecting its protein degradation flux is not known. Here, we report that anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase, is crucial for the tau-mediated AD pathology. ALK caused abnormal accumulation of highly phosphorylated tau in the somatodendritic region of neurons through its tyrosine kinase activity. ALK-induced LC3-positive axon swelling and loss of spine density, leading to tau-dependent neuronal degeneration. Notably, ALK activation in neurons impaired Stx17-dependent autophagosome maturation and this defect was reversed by a dominant-negative Grb2. In a Drosophila melanogaster model, transgenic flies neuronally expressing active Drosophila Alk exhibited the aggravated tau rough eye phenotype with retinal degeneration and shortened lifespan. In contrast, expression of kinase-dead Alk blocked these phenotypes. Consistent with the previous RNAseq analysis showing upregulation of ALK expression in AD [1], ALK levels were significantly elevated in the brains of AD patients showing autophagosomal defects. Injection of an ALK.Fc-lentivirus exacerbated memory impairment in 3xTg-AD mice. Conversely, pharmacologic inhibition of ALK activity with inhibitors reversed the memory impairment and tau accumulation in both 3xTg-AD and tauC3 (caspase-cleaved tau) transgenic mice. Together, we propose that aberrantly activated ALK is a bona fide mediator of tau proteinopathy that disrupts autophagosome maturation and causes tau accumulation and aggregation, leading to neuronal dysfunction in AD.
Assuntos
Doença de Alzheimer , Tauopatias , Doença de Alzheimer/genética , Quinase do Linfoma Anaplásico/genética , Animais , Drosophila melanogaster , Humanos , Camundongos , Camundongos Transgênicos , Tauopatias/genética , Proteínas tau/genéticaRESUMO
SRC-family kinases (SFKs) have been implicated in Alzheimer's disease (AD), but their mode of action was scarcely understood. Here, we show that LYN plays an essential role in amyloid ß (Aß)-triggered neurotoxicity and tau hyperphosphorylation by phosphorylating Fcγ receptor IIb2 (FcγRIIb2). We found that enzyme activity of LYN was increased in the brain of AD patients and was promoted in neuronal cells exposed to Aß 1-42 (Aß1-42). Knockdown of LYN expression inhibited Aß1-42-induced neuronal cell death. Of note, LYN interacted with FcγRIIb2 upon exposure to Aß1-42 and phosphorylated FcγRIIb2 at Tyr273 within immunoreceptor tyrosine-based inhibitory motif in neuronal cells. With the use of the structure-based drug design, we isolated KICG2576, an ATP-competitive inhibitor of LYN. Determination of cocrystal structure illustrated that KICG2576 bound to the cleft in the LYN kinase domain and inhibited LYN with a half-maximal inhibitory concentration value of 0.15 µM. KICG2576 inhibited Aß- or FcγRIIb2-induced cell death, and this effect was better than pyrazolopyrimidine 1, a widely used inhibitor of SFK. Upon exposure to Aß, KICG2576 blocked the phosphorylation of FcγRIIb2 and translocation of phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2, a binding protein to the phosphorylated FcγRIIb2, to the plasma membrane, resulting in the inhibition of tau hyperphosphorylation, the downstream event of Aß1-42-FcγRIIb2 binding. Furthermore, intracerebroventricular injection of KICG2576 into mice ameliorated Aß-induced memory impairment. These results suggest that LYN plays a crucial role in Aß1-42-mediated neurotoxicity and tau pathology, providing a therapeutic potential of LYN in AD.-Gwon, Y., Kim, S.-H., Kim, H. T., Kam, T.-I., Park, J., Lim, B., Cha, H., Chang, H.-J., Hong, Y. R., Jung, Y.-K. Amelioration of amyloid ß-FcγRIIb neurotoxicity and tau pathologies by targeting LYN.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Neurônios/metabolismo , Receptores de IgG/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Animais , Linhagem Celular , Membrana Celular/metabolismo , Hipocampo/metabolismo , Humanos , Transtornos da Memória/metabolismo , Camundongos , Fragmentos de Peptídeos/metabolismo , Fosfatidilinositóis/metabolismo , Fosforilação/fisiologia , Ratos , Quinases da Família src/metabolismoRESUMO
Emerging evidences suggest that intraneuronal Aß correlates with the onset of Alzheimer's disease (AD) and highly contributes to neurodegeneration. However, critical mediator responsible for Aß uptake in AD pathology needs to be clarified. Here, we report that FcγRIIb2, a variant of Fcγ-receptor IIb (FcγRIIb), functions in neuronal uptake of pathogenic Aß. Cellular accumulation of oligomeric Aß1-42, not monomeric Aß1-42 or oligomeric Aß1-40, was blocked by Fcgr2b knock-out in neurons and partially in astrocytes. Aß1-42 internalization was FcγRIIb2 di-leucine motif-dependent and attenuated by TOM1, a FcγRIIb2-binding protein that repressed the receptor recycling. TOM1 expression was downregulated in the hippocampus of male 3xTg-AD mice and AD patients, and regulated by miR-126-3p in neuronal cells after exposure to Aß1-42 In addition, memory impairments in male 3xTg-AD mice were rescued by the lentiviral administration of TOM1 gene. Augmented Aß uptake into lysosome caused its accumulation in cytoplasm and mitochondria. Moreover, neuronal accumulation of Aß in both sexes of 3xTg-AD mice and memory deficits in male 3xTg-AD mice were ameliorated by forebrain-specific expression of Aß-uptake-defective Fcgr2b mutant. Our findings suggest that FcγRIIb2 is essential for neuropathic uptake of Aß in AD.SIGNIFICANCE STATEMENT Accumulating evidences suggest that intraneuronal Aß is found in the early step of AD brain and is implicated in the pathogenesis of AD. However, the critical mediator involved in these processes is uncertain. Here, we describe that the FcγRIIb2 variant is responsible for both neuronal uptake and intraneuronal distribution of pathogenic Aß linked to memory deficits in AD mice, showing a pathologic significance of the internalized Aß. Further, Aß internalization is attenuated by TOM1, a novel FcγRIIb2-binding protein. Together, we provide a molecular mechanism responsible for neuronal uptake of pathogenic Aß found in AD.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Hipocampo/metabolismo , Neurônios/metabolismo , Proteínas/metabolismo , Receptores de IgG/metabolismo , Animais , Astrócitos/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Camundongos Knockout , MicroRNAs/metabolismo , Fragmentos de Peptídeos/metabolismo , Receptores de IgG/genéticaRESUMO
Alzheimer's disease (AD) is the most common neurodegenerative disease. Although a major cause of AD is the accumulation of amyloid-ß (Aß) peptide that induces neuronal loss and cognitive impairments, our understanding of its neurotoxic mechanisms is limited. Recent studies have identified putative Aß-binding receptors that mediate Aß neurotoxicity in cells and models of AD. Once Aß interacts with a receptor, a toxic signal is transduced into neurons, resulting in cellular defects including endoplasmic reticulum stress and mitochondrial dysfunction. In addition, Aß can also be internalized into neurons through unidentified Aß receptors and induces malfunction of subcellular organelles, which explains some part of Aß neurotoxicity. Understanding the neurotoxic signaling initiated by Aß-receptor binding and cellular defects provide insight into new therapeutic windows for AD. In the present review, we summarize the findings on Aß-binding receptors and the neurotoxicity of oligomeric Aß.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Neurônios/metabolismo , Síndromes Neurotóxicas/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Humanos , Modelos Biológicos , Neurônios/patologia , Ligação Proteica , Transdução de SinaisRESUMO
Abnormally hyperphosphorylated tau is often caused by tau kinases, such as GSK3ß and Cdk5. Such occurrence leads to neurofibrillary tangle formation and neuronal degeneration in tauopathy, including Alzheimer's disease (AD). However, little is known about the signaling cascade underlying the pathologic phosphorylation of tau by Aß(42). In this study, we show that adenylate kinase 1 (AK1) is a novel regulator of abnormal tau phosphorylation. AK1 expression is markedly increased in the brains of AD patients and AD model mice and is significantly induced by Aß(42) in the primary neurons. Ectopic expression of AK1 alone augments the pathologic phosphorylation of tau at PHF1, CP13 and AT180 epitopes and enhances the formation of tau aggregates. Inversely, downregulation of AK1 alleviates Aß(42)-induced hyperphosphorylation of tau. AK1 plays a role in Aß(42)-induced impairment of AMPK activity and GSK3ß activation in the primary neurons. Pharmacologic studies show that treatment with an AMPK inhibitor activates GSK3ß, and a GSK3ß inhibitor attenuates AK1-mediated tau phosphorylation. In a Drosophila model of human tauopathy, the retinal expression of human AK1 severely exacerbates rough eye phenotype and increases abnormal tau phosphorylation. Further, neural expression of AK1 reduces the lifespan of tau transgenic files. Taken together, these observations indicate that the neuronal expression of AK1 is induced by Aß(42) to increase abnormal tau phosphorylation via AMPK-GSK3ß and contributes to tau-mediated neurodegeneration, providing a new upstream modulator of GSK3ß in the pathologic phosphorylation of tau.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adenilato Quinase/metabolismo , Doença de Alzheimer/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Proteínas tau/metabolismo , Adenilato Quinase/genética , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/farmacologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Animais Geneticamente Modificados , Western Blotting , Linhagem Celular Tumoral , Células Cultivadas , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Glicogênio Sintase Quinase 3 beta , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Hipocampo/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Microscopia de Fluorescência , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fragmentos de Peptídeos/farmacologia , Fosforilação/efeitos dos fármacos , Interferência de RNA , Proteínas tau/genéticaRESUMO
Cellular senescence, which is triggered by various stressors, manifests as irreversible cell cycle arrest, resulting in the disruption of multiple nuclear condensates. One of the affected structures is the nucleolus, whose tripartite layout, separated into distinct liquid phases, allows for the stepwise progression of ribosome biogenesis. The dynamic properties of dense fibrillar components, a sub-nucleolar phase, are crucial for mediating pre-rRNA processing. However, the mechanistic link between the material properties of dense fibrillar components and cellular senescence remains unclear. We established a significant association between cellular senescence and alterations in nucleolar materiality and characteristics, including the number, size, and sphericity of individual subphases of the nucleolus. Senescent cells exhibit reduced fibrillarin dynamics, aberrant accumulation of high-order protein assemblies, such as oligomers and fibrils, and increased dense fibrillar component density. Intriguingly, the addition of RNA-interacting entities mirrored the diminished diffusion of fibrillarin in the nucleolus during cellular senescence. Thus, our findings contribute to a broader understanding of the intricate changes in the materiality of the nucleolus associated with cellular senescence and shed light on nucleolar dynamics in the context of aging and cellular stress.
RESUMO
Biomolecular condensates are subcellular organizations where functionally related proteins and nucleic acids are assembled through liquid-liquid phase separation, allowing them to develop on a larger scale without a membrane. However, biomolecular condensates are highly vulnerable to disruptions from genetic risks and various factors inside and outside the cell and are strongly implicated in the pathogenesis of many neurodegenerative diseases. In addition to the classical view of the nucleation-polymerization process that triggers the protein aggregation from the misfolded seed, the pathologic transition of biomolecular condensates can also promote the aggregation of proteins found in the deposits of neurodegenerative diseases. Furthermore, it has been suggested that several protein or protein-RNA complexes located in the synapse and along the neuronal process are neuron-specific condensates displaying liquid-like properties. As their compositional and functional modifications play a crucial role in the context of neurodegeneration, further research is needed to fully understand the role of neuronal biomolecular condensates. In this article, we will discuss recent findings that explore the pivotal role of biomolecular condensates in the development of neuronal defects and neurodegeneration.
RESUMO
Impaired activities and abnormally enlarged structures of endolysosomes are frequently observed in Alzheimer disease (AD) brains. However, little is known about whether and how endolysosomal dysregulation is triggered and associated with AD. Here, we show that vacuolar ATPase (V-ATPase) is a hub that mediates proteopathy of oligomeric amyloid beta (Aß) and hyperphosphorylated MAPT/Tau (p-MAPT/Tau). Endolysosomal integrity was largely destroyed in Aß-overloaded or p-MAPT/Tau-positive neurons in culture and AD brains, which was a necessary step for triggering neurotoxicity, and treatments with acidic nanoparticles or endocytosis inhibitors rescued the endolysosomal impairment and neurotoxicity. Interestingly, we found that the lumenal ATP6V0C and cytosolic ATP6V1B2 subunits of the V-ATPase complex bound to the internalized Aß and cytosolic PHF-1-reactive MAPT/Tau, respectively. Their interactions disrupted V-ATPase activity and accompanying endolysosomal activity in vitro and induced neurodegeneration. Using a genome-wide functional screen, we isolated a suppressor, HYAL (hyaluronidase), which reversed the endolysosomal dysfunction and proteopathy and alleviated the memory impairment in 3xTg-AD mice. Further, we found that its metabolite hyaluronic acid (HA) and HA receptor CD44 attenuated neurotoxicity in affected neurons via V-ATPase. We propose that endolysosomal V-ATPase is a bona fide proteotoxic receptor that binds to pathogenic proteins and deteriorates endolysosomal function in AD, leading to neurodegeneration in proteopathy.Abbreviations: AAV, adeno-associated virus; Aß, amyloid beta; AD, Alzheimer disease; APP, amyloid beta precursor protein; ATP6V0C, ATPase H+ transporting V0 subunit c; ATP6V1A, ATPase H+ transporting V1 subunit A; ATP6V1B2, ATPase H+ transporting V1 subunit B2; CD44.Fc, CD44-mouse immunoglobulin Fc fusion construct; Co-IP, co-immunoprecipitation; CTSD, cathepsin D; HA, hyaluronic acid; HMWHA, high-molecular-weight hyaluronic acid; HYAL, hyaluronidase; i.c.v, intracerebroventricular; LMWHA, low-molecular-weight hyaluronic acid; NPs, nanoparticles; p-MAPT/Tau, hyperphosphorylated microtubule associated protein tau; PI3K, phosphoinositide 3-kinase; V-ATPase, vacuolar-type H+-translocating ATPase; WT, wild-type.
Assuntos
Doença de Alzheimer , ATPases Vacuolares Próton-Translocadoras , Camundongos , Animais , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , ATPases Vacuolares Próton-Translocadoras/metabolismo , Hialuronoglucosaminidase/metabolismo , Ácido Hialurônico , Fosfatidilinositol 3-Quinases/metabolismo , Autofagia , Proteínas tau/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Proteínas de Transporte , Camundongos Transgênicos , Modelos Animais de DoençasRESUMO
Eukaryotic cells respond to stress through adaptive programs that include reversible shutdown of key cellular processes, the formation of stress granules, and a global increase in ubiquitination. The primary function of this ubiquitination is thought to be for tagging damaged or misfolded proteins for degradation. Here, working in mammalian cultured cells, we found that different stresses elicited distinct ubiquitination patterns. For heat stress, ubiquitination targeted specific proteins associated with cellular activities that are down-regulated during stress, including nucleocytoplasmic transport and translation, as well as stress granule constituents. Ubiquitination was not required for the shutdown of these processes or for stress granule formation but was essential for the resumption of cellular activities and for stress granule disassembly. Thus, stress-induced ubiquitination primes the cell for recovery after heat stress.
Assuntos
Grânulos Citoplasmáticos/metabolismo , Resposta ao Choque Térmico , Proteoma/metabolismo , Proteínas Ubiquitinadas/metabolismo , Ubiquitinação , Transporte Ativo do Núcleo Celular , Animais , Linhagem Celular , Células Cultivadas , Humanos , Camundongos , Neurônios , Pressão Osmótica , Estresse Oxidativo , Biossíntese de Proteínas , Proteólise , Ribonucleoproteínas/metabolismo , Estresse Fisiológico , Raios Ultravioleta , Proteína com Valosina/antagonistas & inibidores , Proteína com Valosina/metabolismoRESUMO
Stress granules are dynamic, reversible condensates composed of RNA and protein that assemble in eukaryotic cells in response to a variety of stressors and are normally disassembled after stress is removed. The composition and assembly of stress granules is well understood, but little is known about the mechanisms that govern disassembly. Impaired disassembly has been implicated in some diseases including amyotrophic lateral sclerosis, frontotemporal dementia, and multisystem proteinopathy. Using cultured human cells, we found that stress granule disassembly was context-dependent: Specifically in the setting of heat shock, disassembly required ubiquitination of G3BP1, the central protein within the stress granule RNA-protein network. We found that ubiquitinated G3BP1 interacted with the endoplasmic reticulumassociated protein FAF2, which engaged the ubiquitin-dependent segregase p97/VCP (valosin-containing protein). Thus, targeting of G3BP1 weakened the stress granulespecific interaction network, resulting in granule disassembly.
Assuntos
Proteínas Sanguíneas/metabolismo , Grânulos Citoplasmáticos/metabolismo , DNA Helicases/metabolismo , Resposta ao Choque Térmico , Proteínas de Membrana/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , RNA Helicases/metabolismo , Proteínas com Motivo de Reconhecimento de RNA/metabolismo , Proteínas Ubiquitinadas/metabolismo , Proteína com Valosina/metabolismo , Autofagia , Linhagem Celular Tumoral , DNA Helicases/química , DNA Helicases/genética , Retículo Endoplasmático/metabolismo , Células HEK293 , Humanos , Membranas Intracelulares/metabolismo , Mutação , Proteínas de Ligação a Poli-ADP-Ribose/química , Proteínas de Ligação a Poli-ADP-Ribose/genética , Poliubiquitina/metabolismo , Domínios Proteicos , Proteólise , RNA Helicases/química , RNA Helicases/genética , Proteínas com Motivo de Reconhecimento de RNA/química , Proteínas com Motivo de Reconhecimento de RNA/genética , Proteínas Ubiquitinadas/química , UbiquitinaçãoRESUMO
The enzyme γ-secretase generates ß-amyloid (Aß) peptides by cleaving amyloid protein precursor (APP); the aggregation of these peptides is associated with Alzheimer's disease (AD). Despite the development of various γ-secretase regulators, their clinical use is limited by coincident disruption of other γ-secretase-regulated substrates, such as Notch. Using a genome-wide functional screen of γ-secretase activity in cells and a complementary DNA expression library, we found that SERP1 is a previously unknown γ-secretase activator that stimulates Aß generation in cells experiencing endoplasmic reticulum (ER) stress, such as is seen with diabetes. SERP1 interacted with a subcomplex of γ-secretase (APH1A/NCT) through its carboxyl terminus to enhance the assembly and, consequently, the activity of the γ-secretase holoenzyme complex. In response to ER stress, SERP1 preferentially recruited APP rather than Notch into the γ-secretase complex and enhanced the subcellular localization of the complex into lipid rafts, increasing Aß production. Moreover, SERP1 abundance, γ-secretase assembly, and Aß production were increased both in cells exposed to high amounts of glucose and in diabetic AD model mice. Conversely, Aß production was decreased by knocking down SERP1 in cells or in the hippocampi of mice. Compared to postmortem samples from control individuals, those from patients with AD showed increased SERP1 expression in the hippocampus and parietal lobe. Together, our findings suggest that SERP1 is an APP-biased regulator of γ-secretase function in the context of cell stress, providing a possible molecular explanation for the link between diabetes and sporadic AD.
Assuntos
Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Proteínas de Membrana/metabolismo , Transdução de Sinais , Estresse Fisiológico , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Animais , Linhagem Celular Tumoral , Células Cultivadas , Células HEK293 , Células HeLa , Humanos , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ligação ProteicaRESUMO
In ischemic human hearts, the induction of adenosine receptor A2B (ADORA2B) is associated with cardioprotection against ischemic heart damage, but the mechanism underlying this association remains unclear. Apaf-1-interacting protein (APIP) and ADORA2B transcript levels in human hearts are substantially higher in patients with heart failure than in controls. Interestingly, the APIP and ADORA2B mRNA levels are highly correlated with each other (R = 0.912). APIP expression was significantly increased in primary neonatal cardiomyocytes under hypoxic conditions and this induction reduced myocardial cell death via the activation of the AKT-HIF1α pathway. Accordingly, infarct sizes of APIP transgenic mice after left anterior descending artery ligation were significantly reduced compared to those of wild-type mice. Strikingly, knockdown of APIP expression impaired the cytoprotective effects of ADORA2B during hypoxic damage. Immunoprecipitation and proximity ligation assays revealed that APIP interacts with ADORA2B, leading to the stabilization of both proteins by interfering with lysosomal degradation, and to the activation of the downstream PKA-CREB signaling pathways. ADORA2B levels in the hearts of APIPTg/Tg, APIPTg/+, and Apip+/- mice were proportionally downregulated. In addition, ADORA2B D296G derived from the rs200741295 polymorphism failed to bind to APIP and did not exert cardioprotective activity during hypoxia. Moreover, Adora2b D296G knock-in mice were more vulnerable than control mice to myocardial infarction and intentional increases in APIP levels overcame the defective protection of the ADORA2B SNP against ischemic injury. Collectively, APIP is crucial for cardioprotection against myocardial infarction by virtue of binding to and stabilizing ADORA2B, thereby dampening ischemic heart injury.
Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Receptor A2B de Adenosina/metabolismo , Animais , Apoptose/genética , Apoptose/fisiologia , Proteínas Reguladoras de Apoptose/genética , Linhagem Celular , Células Cultivadas , Feminino , Células HEK293 , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Infarto do Miocárdio/genética , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Polimorfismo Genético/genética , Polimorfismo de Nucleotídeo Único/genética , Receptor A2B de Adenosina/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologiaRESUMO
Amyloid-ß (Aß)-containing extracellular plaques and hyperphosphorylated tau-loaded intracellular neurofibrillary tangles are neuropathological hallmarks of Alzheimer's disease (AD). Although Aß exerts neuropathogenic activity through tau, the mechanistic link between Aß and tau pathology remains unknown. Here, we showed that the FcγRIIb-SHIP2 axis is critical in Aß1-42-induced tau pathology. Fcgr2b knockout or antagonistic FcγRIIb antibody inhibited Aß1-42-induced tau hyperphosphorylation and rescued memory impairments in AD mouse models. FcγRIIb phosphorylation at Tyr273 was found in AD brains, in neuronal cells exposed to Aß1-42, and recruited SHIP2 to form a protein complex. Consequently, treatment with Aß1-42 increased PtdIns(3,4)P2 levels from PtdIns(3,4,5)P3 to mediate tau hyperphosphorylation. Further, we found that targeting SHIP2 expression by lentiviral siRNA in 3xTg-AD mice or pharmacological inhibition of SHIP2 potently rescued tau hyperphosphorylation and memory impairments. Thus, we concluded that the FcγRIIb-SHIP2 axis links Aß neurotoxicity to tau pathology by dysregulating PtdIns(3,4)P2 metabolism, providing insight into therapeutic potential against AD.
Assuntos
Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/metabolismo , Fosfatidilinositóis/metabolismo , Receptores de IgG/metabolismo , Proteínas tau/metabolismo , Animais , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Camundongos , Receptores de IgG/genéticaRESUMO
Amyloid-ß (Aß) induces neuronal loss and cognitive deficits and is believed to be a prominent cause of Alzheimer's disease (AD); however, the cellular pathology of the disease is not fully understood. Here, we report that IgG Fcγ receptor II-b (FcγRIIb) mediates Aß neurotoxicity and neurodegeneration. We found that FcγRIIb is significantly upregulated in the hippocampus of AD brains and neuronal cells exposed to synthetic Aß. Neuronal FcγRIIb activated ER stress and caspase-12, and Fcgr2b KO primary neurons were resistant to synthetic Aß-induced cell death in vitro. Fcgr2b deficiency ameliorated Aß-induced inhibition of long-term potentiation and inhibited the reduction of synaptic density by naturally secreted Aß. Moreover, genetic depletion of Fcgr2b rescued memory impairments in an AD mouse model. To determine the mechanism of action of FcγRIIb in Aß neurotoxicity, we demonstrated that soluble Aß oligomers interact with FcγRIIb in vitro and in AD brains, and that inhibition of their interaction blocks synthetic Aß neurotoxicity. We conclude that FcγRIIb has an aberrant, but essential, role in Aß-mediated neuronal dysfunction.