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1.
J Neurol Neurosurg Psychiatry ; 94(9): 670-680, 2023 09.
Article in English | MEDLINE | ID: mdl-37414536

ABSTRACT

BACKGROUND: While obesity in midlife is a risk factor for dementia, several studies suggested that obesity also protected against dementia, hence so-called obesity paradox. The current study aims to address the relationship between apolipoprotein E (APOE) genotype and obesity in dementia. METHODS: Clinical and neuropathological records of the National Alzheimer's Coordinating Center (NACC) in the USA, which longitudinally followed approximately 20 000 subjects with different cognitive statues, APOE genotype and obesity states, were reviewed. RESULTS: Obesity was associated with cognitive decline in early elderly cognitively normal individuals without APOE4, especially those with APOE2. Neuropathological analyses adjusted for dementia status showed that APOE2 carriers tended to have more microinfarcts and haemorrhages due to obesity. On the other hand, obesity was associated with a lower frequency of dementia and less cognitive impairment in individuals with mild cognitive impairment or dementia. Such trends were particularly strong in APOE4 carriers. Obesity was associated with fewer Alzheimer's pathologies in individuals with dementia. CONCLUSIONS: Obesity may accelerate cognitive decline in middle to early elderly cognitive normal individuals without APOE4 likely by provoking vascular impairments. On the other hand, obesity may ease cognitive impairment in both individuals with dementia and individuals at the predementia stage, especially those with APOE4, through protecting against Alzheimer's pathologies. These results support that APOE genotype modifies the obesity paradox in dementia.


Subject(s)
Alzheimer Disease , Aged , Humans , Alzheimer Disease/complications , Alzheimer Disease/genetics , Alzheimer Disease/psychology , Apolipoprotein E2/genetics , Apolipoprotein E4/genetics , Apolipoproteins E/genetics , Genotype , Obesity/complications , Obesity/genetics , Obesity Paradox
2.
Science ; 353(6299): 603-8, 2016 Aug 05.
Article in English | MEDLINE | ID: mdl-27493188

ABSTRACT

Mutations in the optineurin (OPTN) gene have been implicated in both familial and sporadic amyotrophic lateral sclerosis (ALS). However, the role of this protein in the central nervous system (CNS) and how it may contribute to ALS pathology are unclear. Here, we found that optineurin actively suppressed receptor-interacting kinase 1 (RIPK1)-dependent signaling by regulating its turnover. Loss of OPTN led to progressive dysmyelination and axonal degeneration through engagement of necroptotic machinery in the CNS, including RIPK1, RIPK3, and mixed lineage kinase domain-like protein (MLKL). Furthermore, RIPK1- and RIPK3-mediated axonal pathology was commonly observed in SOD1(G93A) transgenic mice and pathological samples from human ALS patients. Thus, RIPK1 and RIPK3 play a critical role in mediating progressive axonal degeneration. Furthermore, inhibiting RIPK1 kinase may provide an axonal protective strategy for the treatment of ALS and other human degenerative diseases characterized by axonal degeneration.


Subject(s)
Amyotrophic Lateral Sclerosis/pathology , Apoptosis , Axons/pathology , Nerve Degeneration/genetics , Receptor-Interacting Protein Serine-Threonine Kinases/physiology , Transcription Factor TFIIIA/metabolism , Amyotrophic Lateral Sclerosis/genetics , Animals , Apoptosis/genetics , Cell Cycle Proteins , Humans , Inflammation/genetics , Inflammation/pathology , Membrane Transport Proteins , Mice , Mice, Transgenic , Necrosis , Receptor-Interacting Protein Serine-Threonine Kinases/genetics , Spinal Cord/pathology , Superoxide Dismutase/genetics , Superoxide Dismutase-1 , Suppression, Genetic , Transcription Factor TFIIIA/genetics
3.
Cell ; 135(7): 1311-23, 2008 Dec 26.
Article in English | MEDLINE | ID: mdl-19109899

ABSTRACT

Stimulation of death receptors by agonists such as FasL and TNFalpha activates apoptotic cell death in apoptotic-competent conditions or a type of necrotic cell death dependent on RIP1 kinase, termed necroptosis, in apoptotic-deficient conditions. In a genome-wide siRNA screen for regulators of necroptosis, we identify a set of 432 genes that regulate necroptosis, a subset of 32 genes that act downstream and/or as regulators of RIP1 kinase, 32 genes required for death-receptor-mediated apoptosis, and 7 genes involved in both necroptosis and apoptosis. We show that the expression of subsets of the 432 genes is enriched in the immune and nervous systems, and cellular sensitivity to necroptosis is regulated by an extensive signaling network mediating innate immunity. Interestingly, Bmf, a BH3-only Bcl-2 family member, is required for death-receptor-induced necroptosis. Our study defines a cellular signaling network that regulates necroptosis and the molecular bifurcation that controls apoptosis and necroptosis.


Subject(s)
Apoptosis , Necrosis , Signal Transduction , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Animals , Cell Line , Gene Expression Profiling , Genome , Humans , Mice , Oncogenes , Protein Biosynthesis , Protein Interaction Mapping , Transcription, Genetic
4.
Nat Chem Biol ; 4(5): 313-21, 2008 May.
Article in English | MEDLINE | ID: mdl-18408713

ABSTRACT

Necroptosis is a cellular mechanism of necrotic cell death induced by apoptotic stimuli in the form of death domain receptor engagement by their respective ligands under conditions where apoptotic execution is prevented. Although it occurs under regulated conditions, necroptotic cell death is characterized by the same morphological features as unregulated necrotic death. Here we report that necrostatin-1, a previously identified small-molecule inhibitor of necroptosis, is a selective allosteric inhibitor of the death domain receptor-associated adaptor kinase RIP1 in vitro. We show that RIP1 is the primary cellular target responsible for the antinecroptosis activity of necrostatin-1. In addition, we show that two other necrostatins, necrostatin-3 and necrostatin-5, also target the RIP1 kinase step in the necroptosis pathway, but through mechanisms distinct from that of necrostatin-1. Overall, our data establish necrostatins as the first-in-class inhibitors of RIP1 kinase, the key upstream kinase involved in the activation of necroptosis.


Subject(s)
Imidazoles/metabolism , Protein Kinases/metabolism , Animals , Apoptosis , Mice , Protein Kinase Inhibitors/pharmacology , Structure-Activity Relationship
5.
Neurochem Int ; 52(4-5): 683-7, 2008.
Article in English | MEDLINE | ID: mdl-17942194

ABSTRACT

In the previous reports, we showed that the familial Alzheimer's disease (AD)-linked presenilin-1 (PS1) mutation induced the fragility to the endoplasmic reticulum (ER) stress and that caspase-4 mediates ER stress-induced- and beta-amyloid induced-apoptotic signaling in human cells. These results suggest the involvement of ER stress and caspase-4 in the cell death observed in AD. In this report, we studied the activation of caspase-4 in the familial AD-linked PS1 mutation (DeltaE9). Cleavage of caspase-4 under ER stress was enhanced by the overexpression of the familial AD-linked mutation (DeltaE9), showing that caspase-4 is a key caspase involved in the apoptotic signaling of AD. We also showed that the overexpression of caspase-4 induced cleavage of caspase-9 and caspase-3 without releasing cytochrome-c from the mitochondria. Thus, caspase-4 activates downstream caspases independently of mitochondrial apoptotic signaling and this might contribute to the pathogenesis of AD. To sum up our data, the familial AD-linked PS1 mutation accelerates the cleavage of caspase-4 under the ER stress and results in the activation of caspase-9 and caspase-3, apoptosis signal, without releasing cytochrome-c.


Subject(s)
Apoptosis/physiology , Caspases, Initiator/biosynthesis , Endoplasmic Reticulum/enzymology , Presenilin-1/genetics , Signal Transduction/physiology , Actins/metabolism , Animals , Apoptosis/genetics , Blotting, Western , COS Cells , Caspase 3/metabolism , Caspase 9/metabolism , Caspases, Initiator/genetics , Cells, Cultured , Chlorocebus aethiops , Cytochromes c/metabolism , Cytochromes c/physiology , Enzyme Activation/physiology , Humans , Mutation/physiology , Signal Transduction/genetics , Stress, Physiological/physiopathology , Subcellular Fractions/metabolism
6.
PLoS One ; 2(10): e1030, 2007 Oct 10.
Article in English | MEDLINE | ID: mdl-17925878

ABSTRACT

Neuronal Lewy body-like hyaline inclusions (LBHI) and astrocytic hyaline inclusions (Ast-HI) containing mutant Cu/Zn superoxide dismutase 1 (SOD1) are morphological hallmarks of familial amyotrophic lateral sclerosis (FALS) associated with mutant SOD1. However, the mechanisms by which mutant SOD1 contributes to formation of LBHI/Ast-HI in FALS remain poorly defined. Here, we report induction of LBHI/Ast-HI-like hyaline inclusions (LHIs) in vitro by ER stress in neuroblastoma cells. These LHI closely resemble LBHI/Ast-HI in patients with SOD1-linked FALS. LHI and LBHI/Ast-HI share the following features: 1) eosinophilic staining with a pale core, 2) SOD1, ubiquitin and ER resident protein (KDEL) positivity and 3) the presence of approximately 15-25 nm granule-coated fibrils, which are morphological hallmark of mutant SOD1-linked FALS. Moreover, in spinal cord neurons of L84V SOD1 transgenic mice at presymptomatic stage, we observed aberrant aggregation of ER and numerous free ribosomes associated with abnormal inclusion-like structures, presumably early stage neuronal LBHI. We conclude that the LBHI/Ast-HI seen in human patients with mutant SOD1-linked FALS may arise from ER dysfunction.


Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Astrocytes/cytology , Endoplasmic Reticulum/metabolism , Lewy Bodies/metabolism , Mutation , Superoxide Dismutase/genetics , Animals , Cell Line, Tumor , Golgi Apparatus/metabolism , Humans , In Vitro Techniques , Lysosomes/metabolism , Mice , Mice, Transgenic , Ribosomes/metabolism , Superoxide Dismutase-1 , Ubiquitin/chemistry
7.
J Chem Neuroanat ; 28(1-2): 67-78, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15363492

ABSTRACT

Recent studies have suggested that neuronal death in Alzheimer's disease (AD) or ischemia could arise from dysfunction of the endoplasmic reticulum (ER). Inhibition of protein glycosylation, perturbation of calcium homeostasis, and reduction of disulfide bonds provoke accumulation of unfolded protein in the ER, and are called 'ER stress'. Normal cells respond to ER stress by increasing transcription of genes encoding ER-resident chaperones such as GRP78/BiP, to facilitate protein folding or by suppressing the mRNA translation to synthesize proteins. These systems are termed the unfolded protein response (UPR). Familial Alzheimer's disease-linked presenilin-1 (PS1) mutation downregulates the unfolded protein response and leads to vulnerability to ER stress. The mechanisms by which mutant PS1 affects the ER stress response are attributed to the inhibited activation of ER stress transducers such as IRE1, PERK and ATF6. On the other hand, in sporadic Alzheimer's disease (sAD), we found the aberrant splicing isoform (PS2V), generated by exon 5 skipping of the Presenilin-2 (PS2) gene transcript, responsible for induction of high mobility group A1a protein (HMGA1a). The PS2V also downregulates the signaling pathway of the UPR, in a similar fashion to that reported for mutants of PS1 linked to familial AD. It was clarified what molecules related to cell death are activated in the case of AD and we discovered that caspase-4 plays a key role in ER stress-induced apoptosis. Caspase-4 also seems to act upstream of the beta-amyloid-induced ER stress pathway, suggesting that activation of caspase-4 might mediate neuronal cell death in AD.


Subject(s)
Alzheimer Disease/metabolism , Endoplasmic Reticulum/metabolism , Neurons/metabolism , Neurons/pathology , Stress, Physiological/metabolism , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Animals , Cell Death/physiology , Endoplasmic Reticulum/genetics , Endoplasmic Reticulum/pathology , Endoplasmic Reticulum Chaperone BiP , Humans , Stress, Physiological/genetics , Stress, Physiological/pathology
8.
Neurochem Int ; 45(5): 765-72, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15234121

ABSTRACT

Recent papers have reported that neuronal death in patients with Alzheimer's disease, Parkinson's disease, and cerebral ischemia has its origin in the endoplasmic reticulum (ER). IRE1alpha is one of the ER stress transducers that detect the accumulation of unfolded proteins in the ER. IRE1alpha mediates two major cellular responses, which are the unfolded protein response (UPR), a defensive response, and apoptosis that leads to cell death. However, little is known about the regulatory mechanisms that select between the UPR and apoptosis. We identified Jun activation domain-binding protein-1 (JAB1) as a molecule that interacts with IRE1alpha using a yeast two-hybrid system. We demonstrated that JAB1 binds to IRE1alpha in the absence of stress, but that binding is decreased by ER stress inducers. Moreover, mutant JAB1 down-regulates the UPR signaling pathway through tight binding with IRE1alpha. These results suggested that JAB1 may act as a key molecule in selecting the UPR or cell death by association and dissociation with IRE1alpha.


Subject(s)
DNA-Binding Proteins/physiology , Membrane Proteins/physiology , Protein Folding , Protein Serine-Threonine Kinases/physiology , Transcription Factors/physiology , Antibodies/chemistry , Blotting, Western , COP9 Signalosome Complex , Cell Death/physiology , Cell Line , DNA, Complementary/biosynthesis , DNA, Complementary/genetics , DNA-Binding Proteins/genetics , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/physiology , Endoribonucleases , Humans , Immunohistochemistry , Intracellular Signaling Peptides and Proteins , Membrane Proteins/genetics , Mutation/genetics , Mutation/physiology , Nucleotide Mapping , Peptide Hydrolases , Precipitin Tests , Protein Serine-Threonine Kinases/genetics , Reverse Transcriptase Polymerase Chain Reaction , Saccharomyces cerevisiae/metabolism , Transcription Factors/genetics
9.
J Cell Biol ; 165(3): 347-56, 2004 May 10.
Article in English | MEDLINE | ID: mdl-15123740

ABSTRACT

Recent studies have suggested that neuronal death in Alzheimer's disease or ischemia could arise from dysfunction of the endoplasmic reticulum (ER). Although caspase-12 has been implicated in ER stress-induced apoptosis and amyloid-beta (Abeta)-induced apoptosis in rodents, it is controversial whether similar mechanisms operate in humans. We found that human caspase-4, a member of caspase-1 subfamily that includes caspase-12, is localized to the ER membrane, and is cleaved when cells are treated with ER stress-inducing reagents, but not with other apoptotic reagents. Cleavage of caspase-4 is not affected by overexpression of Bcl-2, which prevents signal transduction on the mitochondria, suggesting that caspase-4 is primarily activated in ER stress-induced apoptosis. Furthermore, a reduction of caspase-4 expression by small interfering RNA decreases ER stress-induced apoptosis in some cell lines, but not other ER stress-independent apoptosis. Caspase-4 is also cleaved by administration of Abeta, and Abeta-induced apoptosis is reduced by small interfering RNAs to caspase-4. Thus, caspase-4 can function as an ER stress-specific caspase in humans, and may be involved in pathogenesis of Alzheimer's disease.


Subject(s)
Amyloid beta-Peptides/toxicity , Apoptosis/physiology , Caspases/metabolism , Endoplasmic Reticulum/enzymology , Nerve Degeneration/enzymology , Oxidative Stress/physiology , Apoptosis/drug effects , Caspases/genetics , Caspases, Initiator , Down-Regulation/genetics , HSP70 Heat-Shock Proteins/metabolism , HeLa Cells , Humans , Immunohistochemistry , Intracellular Membranes/enzymology , Membrane Proteins/metabolism , Nerve Degeneration/pathology , Nerve Degeneration/physiopathology , Neurodegenerative Diseases/enzymology , Neurodegenerative Diseases/physiopathology , Oxidative Stress/drug effects , Proto-Oncogene Proteins c-bcl-2/metabolism , RNA Interference , Signal Transduction/physiology
10.
Cell Mol Neurobiol ; 24(1): 137-47, 2004 Feb.
Article in English | MEDLINE | ID: mdl-15049518

ABSTRACT

The human ADP-ribosylation factor-like protein, ARF4L is a member of the ARF family, which are small GTP-binding proteins that play significant roles in vesicle transport and protein secretion. However, little is known about the physiological roles of ARF4L. In this study, to understand the biological functions of ARF4L, we carried out immunocytochemical analysis of ARF4L molecules with mutations in the functional domains. ARF4L was shown to be distributed to the plasma membrane following binding to GTP (Q80L), and into endosomes following binding to GDP (T35N). Moreover, the inactive-form of ARF4L (T35N) causes localization of transferrin receptors to the endosomal compartment, while the active form (Q80L) causes transport to the plasma membrane. These findings indicate that ARF4L drive the transport of cargo protein and subsequent fusion of recycling vesicles with the plasma membrane for maintenance of the cell surface.


Subject(s)
ADP-Ribosylation Factors/metabolism , Cell Membrane/metabolism , Endocytosis/physiology , Endosomes/metabolism , Transport Vesicles/metabolism , ADP-Ribosylation Factors/genetics , Cell Membrane/ultrastructure , Endosomes/ultrastructure , Guanosine Diphosphate/metabolism , Guanosine Triphosphate/metabolism , HeLa Cells , Humans , Immunohistochemistry , Membrane Fusion/physiology , Microscopy, Electron , Mutation/genetics , Protein Binding/physiology , Protein Isoforms/genetics , Protein Isoforms/metabolism , Protein Structure, Tertiary/genetics , Protein Transport/physiology , Receptors, Transferrin/metabolism , Transport Vesicles/ultrastructure
11.
Neurosci Lett ; 357(2): 127-30, 2004 Mar 04.
Article in English | MEDLINE | ID: mdl-15036591

ABSTRACT

Recently, endoplasmic reticulum (ER) dysfunction has been implicated in neuronal death in patients with Alzheimer's disease. Treatment of human neuroblastoma cells with ER stress inducers causes apoptotic death. We confirmed that ER stress inducers specifically targeted the ER to cause apoptotic morphological changes. We also found that caspase-3, and not caspase-9 (a known mitochondrial apoptotic mediator), was mainly activated by ER stress. We generated the neuroblastoma cells that stably expressed caspase-12 and analyzed its influence on caspase-3 activation and vulnerability to ER stress. Cells expressing caspase-12 were more vulnerable to ER stress than cells expressing the empty vector, concomitant with increased activation of caspase-3. These findings suggested that activation of ER-resident caspase-12 indirectly activates cytoplasmic caspase-3 and might be important in ER stress-induced neuronal apoptosis.


Subject(s)
Apoptosis/physiology , Caspases/metabolism , Endoplasmic Reticulum/enzymology , Apoptosis/drug effects , Caspase 12 , Caspase 3 , Caspases/physiology , Cell Line, Tumor , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/ultrastructure , Enzyme Activation/drug effects , Enzyme Activation/physiology , Humans , Tunicamycin/pharmacology
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