ABSTRACT
Cerebral amyloid angiopathy is characterized by a weakening of the small- and medium-sized cerebral arteries, as their smooth muscle cells are progressively replaced with acellular amyloid ß, increasing vessel fragility and vulnerability to microhemorrhage. In this context, an aberrant overactivation of the complement system would further aggravate this process. The surface protein CD59 protects most cells from complement-induced cytotoxicity, but expression levels can fluctuate due to disease and varying cell types. The degree to which CD59 protects human cerebral vascular smooth muscle (HCSM) cells from complement-induced cytotoxicity has not yet been determined. To address this shortcoming, we selectively blocked the activity of HCSM-expressed CD59 with an antibody, and challenged the cells with complement, then measured cellular viability. Unblocked HCSM cells proved resistant to all tested concentrations of complement, and this resistance decreased progressively with increasing concentrations of anti-CD59 antibody. Complete CD59 blockage, however, did not result in a total loss of cellular viability, suggesting that additional factors may have some protective functions. Taken together, this implies that CD59 plays a predominant role in HCSM cellular protection against complement-induced cytotoxicity. The overexpression of CD59 could be an effective means of protecting these cells from excessive complement system activity, with consequent reductions in the incidence of microhemorrhage. The precise extent to which cellular repair mechanisms and other complement repair proteins contribute to this resistance has yet to be fully elucidated.
ABSTRACT
Cerebral amyloid angiopathy is characterized by a weakening of the small and medium sized cerebral arteries, as their smooth muscle cells are progressively replaced with acellular amyloid ß, increasing vessel fragility and vulnerability to microhemorrhage. In this context, an aberrant overactivation of the complement system would further aggravate this process. The surface protein CD59 protects most cells from complement-induced cytotoxicity, but expression levels can fluctuate due to disease and vary between cell types. The degree to which CD59 protects human cerebral vascular smooth muscle (HCSM) cells from complement-induced cytotoxicity has not yet been determined. To address this shortcoming, we selectively blocked the activity of HCSM-expressed CD59 with an antibody and challenged the cells with complement, then measured cellular viability. Unblocked HCSM cells proved resistant to all tested concentrations of complement, and this resistance decreased progressively with increasing concentrations of anti-CD59 antibody. Complete CD59 blockage, however, did not result in total loss of cellular viability, suggesting that additional factors may have some protective functions. Taken together, this implies that CD59 plays a predominant role in HCSM cellular protection against complement-induced cytotoxicity. Over-expression of CD59 could be an effective means of protecting these cells from excessive complement system activity, with consequent reduction in the incidence of microhemorrhage. The precise extent to which cellular repair mechanisms and other complement repair proteins contribute to this resistance has yet to be fully elucidated.
ABSTRACT
Niemann-Pick disease type C (NPC) is a fatal neurodegenerative condition caused by genetic mutations of the NPC1 or NPC2 genes that encode the NPC1 and NPC2 proteins, respectively, which are believed to be responsible for cholesterol efflux from late-endosomes/lysosomes. The pathogenic mechanisms that lead to neurodegeneration in NPC are not well understood. There are, however, well-defined spatiotemporal patterns of neurodegeneration that may provide insight into the pathogenic process. For example, the cerebellum is severely affected from early disease stages, compared with cerebral regions, which remain relatively spared until later stages. Using a genome-wide transcriptome analysis, we have recently identified an aberrant pattern of interferon activation in the cerebella of pre-symptomatic Npc1-/- mice. Here, we carried out a comparative transcriptomic analysis of cerebral cortices and cerebella of pre-symptomatic Npc1-/- mice and age-matched controls to identify differences that may help explain the pathological progression within the NPC brain. We report lower cerebral expression of genes within interferon signaling pathways, and significant differences in the regulation of oxidative stress, compared with the cerebellum. Our findings suggest that a delayed onset of interferon signaling, possibly linked to lower oxidative stress, may account for the slower onset of cerebral cortical pathology in the disease.
Subject(s)
Niemann-Pick Disease, Type C , Animals , Mice , Niemann-Pick Disease, Type C/genetics , Cerebellum , Cerebral Cortex , Oxidative Stress , Interferons/geneticsABSTRACT
Objetivos: Analizar las características del manejo de la vía aérea (VA) en emergencias prehospitalarias, sus complicaciones y establecer factores predictores de fracaso en el primer intento de intubación orotraqueal (FIPI). Método: Estudio observacional de cohortes retrospectivo de pacientes que precisaron intubación orotraqueal por el servicio de emergencias prehospitalarias de Castilla La Mancha, desde el 01-06-2017 hasta el 01-01-2021. Se analizaron características de los pacientes, del procedimiento y sus complicaciones, se realizó una regresión logística para detectar factores predictores de FIPI. Resultados: Se incluyeron 425 pacientes, 417 (98,1%) fueron intubados con éxito y 326 (76,7%) en el primer intento. Se registraron 183 complicaciones en 94 pacientes (22,1%). Los factores predictores de FIPI fueron la edad > 55 años (OR = 1,94; IC 95% 1,10-4,23), índice de masa corporal > 30 (OR = 9,14; IC 95% 4,40-19,00); saturación de oxígeno < 90% (OR = 3,33; IC 95% 1,06-10,58); puntuación en la Glasgow Coma Scale entre 9 y 13 (OR = 1,58; IC 95% 1,28-6,9); intubación realizada en vía pública (OR = 2,99; IC 95% 1,42-6,29); posición distinta a la bipedestación (OR = 2,09; IC 95% 1,08-7,25); laringoscopia directa (OR = 2,39; IC 95% 1,20-6,55); uso de estilete (OR = 1,80; IC 95% 1,40-3,78); y clasificación Cormack-Lehane $ 2 (OR = 6,50; IC 95% 3,96-30,68). Conclusiones: El procedimiento de intubación se realizó de forma habitual en el primer intento. Existen factores asociados a FIPI que permiten individualizar el manejo de la VA. (AU)
Objectives: To analyze the characteristics of prehospital emergency airway management, including complications; to explore predictors of first-attempt failure of orotracheal intubation. Material and methods: Observational retrospective cohort study of patients requiring orotracheal intubation by the prehospital emergency services of Castile-La Mancha between June 1, 2017, and January 1, 2021. We analyzed patient and procedure characteristics and complications using logistic regression analysis to detect factors that could predict firstattempt intubation failure. Results: A total of 425 patients were included; 417 (98.1%) were intubated successfully, including 326 (76.7%) on the first attempt. Complications occurred in 183 intubations in 94 patients (22.1%). Predictors of first-attempt failure were age over 55 years (odds ratio [OR], 1.94; 95% CI, 1.10-4.23), body mass index over 30 (OR, 9.14; 95% CI, 4.40-19.00), oxygen saturation less than 90% (OR, 3.33; 95% CI, 1.06-10.58), a Glasgow Coma Score between 9 and 13 (OR, 1.58; 95% CI, 1.28-6.9), intubation in a public place (OR, 2.99; 95% CI, 1.42-6.29), intubation done in any other than standing position (OR, 2.09; 95% CI, 1.08-7.25), direct laryngoscopy (OR, 2.39; 95% CI, 1.20- 6.55), use of a stylet (OR, 1.80; 95% CI, 1.40-3.78), and a Cormack-Lehane classification of 2 or higher (OR, 6.50; 95% CI, 3.96-30.68). Conclusion: Orotracheal intubation is generally accomplished on the first attempt. Factors associated with first-attempt failure can facilitate tailored approaches to upper airway management. (AU)
Subject(s)
Humans , Male , Female , Middle Aged , Aged , Laryngoscopy/methods , Emergency Medical Services/methods , Retrospective Studies , Intubation, Intratracheal/methods , Airway ManagementABSTRACT
OBJECTIVES: To analyze the characteristics of prehospital emergency airway management, including complications; to explore predictors of first-attempt failure of orotracheal intubation. MATERIAL AND METHODS: Observational retrospective cohort study of patients requiring orotracheal intubation by the prehospital emergency services of Castile-La Mancha between June 1, 2017, and January 1, 2021. We analyzed patient and procedure characteristics and complications using logistic regression analysis to detect factors that could predict firstattempt intubation failure. RESULTS: A total of 425 patients were included; 417 (98.1%) were intubated successfully, including 326 (76.7%) on the first attempt. Complications occurred in 183 intubations in 94 patients (22.1%). Predictors of first-attempt failure were age over 55 years (odds ratio [OR], 1.94; 95% CI, 1.10-4.23), body mass index over 30 (OR, 9.14; 95% CI, 4.40-19.00), oxygen saturation less than 90% (OR, 3.33; 95% CI, 1.06-10.58), a Glasgow Coma Score between 9 and 13 (OR, 1.58; 95% CI, 1.28-6.9), intubation in a public place (OR, 2.99; 95% CI, 1.42-6.29), intubation done in any other than standing position (OR, 2.09; 95% CI, 1.08-7.25), direct laryngoscopy (OR, 2.39; 95% CI, 1.20- 6.55), use of a stylet (OR, 1.80; 95% CI, 1.40-3.78), and a Cormack-Lehane classification of 2 or higher (OR, 6.50; 95% CI, 3.96-30.68). CONCLUSION: Orotracheal intubation is generally accomplished on the first attempt. Factors associated with first-attempt failure can facilitate tailored approaches to upper airway management.
OBJETIVO: Analizar las características del manejo de la vía aérea (VA) en emergencias prehospitalarias, sus complicaciones y establecer factores predictores de fracaso en el primer intento de intubación orotraqueal (FIPI). METODO: Estudio observacional de cohortes retrospectivo de pacientes que precisaron intubación orotraqueal por el servicio de emergencias prehospitalarias de Castilla La Mancha, desde el 01-06-2017 hasta el 01-01-2021. Se analizaron características de los pacientes, del procedimiento y sus complicaciones, se realizó una regresión logística para detectar factores predictores de FIPI. RESULTADOS: . Se incluyeron 425 pacientes, 417 (98,1%) fueron intubados con éxito y 326 (76,7%) en el primer intento. Se registraron 183 complicaciones en 94 pacientes (22,1%). Los factores predictores de FIPI fueron la edad > 55 años (OR = 1,94; IC 95% 1,10-4,23), índice de masa corporal > 30 (OR = 9,14; IC 95% 4,40-19,00); saturación de oxígeno 90% (OR = 3,33; IC 95% 1,06-10,58); puntuación en la Glasgow Coma Scale entre 9 y 13 (OR = 1,58; IC 95% 1,28-6,9); intubación realizada en vía pública (OR = 2,99; IC 95% 1,42-6,29); posición distinta a la bipedestación (OR = 2,09; IC 95% 1,08-7,25); laringoscopia directa (OR = 2,39; IC 95% 1,20-6,55); uso de estilete (OR = 1,80; IC 95% 1,40-3,78); y clasificación Cormack-Lehane $ 2 (OR = 6,50; IC 95% 3,96-30,68). CONCLUSIONES: El procedimiento de intubación se realizó de forma habitual en el primer intento. Existen factores asociados a FIPI que permiten individualizar el manejo de la VA.
Subject(s)
Emergency Medical Services , Laryngoscopy , Airway Management , Emergency Medical Services/methods , Humans , Intubation, Intratracheal/methods , Laryngoscopy/methods , Middle Aged , Retrospective StudiesABSTRACT
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to memory loss and is often accompanied by increased anxiety. Although AD is a heterogeneous disease, dysregulation of inflammatory pathways is a consistent event. Interestingly, the amyloid precursor protein (APP), which is the source of the amyloid peptide Aß, is also necessary for the efficient regulation of the innate immune response. Here, we hypothesize that loss of APP function in mice would lead to cognitive loss and anxiety behavior, both of which are typically present in AD, as well as changes in the expression of inflammatory mediators. To test this hypothesis, we performed open field, Y-maze and novel object recognition tests on 12-18-week-old male and female wildtype and AppKO mice to measure thigmotaxis, short-term spatial memory and long-term recognition memory. We then performed a quantitative multiplexed immunoassay to measure levels of 32 cytokines/chemokines associated with AD and anxiety. Our results showed that AppKO mice, compared to wildtype controls, experienced increased thigmotactic behavior but no memory impairments, and this phenotype correlated with increased IP-10 and IL-13 levels. Future studies will determine whether dysregulation of these inflammatory mediators contributes to pathogenesis in AD.
Subject(s)
Alzheimer Disease , Amyloid beta-Protein Precursor , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Animals , Brain/metabolism , Chemokine CXCL10/genetics , Disease Models, Animal , Female , Interleukin-13 , Male , Maze Learning , Mice , Mice, Inbred C57BL , Mice, TransgenicABSTRACT
Alzheimer's disease (AD) is a neurodegenerative condition associated with loss of memory function, depression and anxiety. The etiology of AD is poorly understood, but both cholesterol dyshomeostasis and dysregulation of the immune system are contributing factors. Current evidence is consistent with a detrimental effect of excess cholesterol on neuroinflammation, both in mouse models of memory loss and in dementia in humans. However, whether the impact of cholesterol on neuroinflammation occurs early and contributes to pathogenesis of the disease or simply reflects a pleiotropic impact at advanced stages of disease is unclear. To explore this question, we measured, in 9-13 week-old mice, cognitive status and changes in brain inflammatory mediators in response to a short-term high-cholesterol diet. We hypothesized that short-term exposure to excess dietary cholesterol would alter the early inflammatory responses associated with cognitive and/or behavioral impairment. We report that short-term exposure to a high-cholesterol diet led to decreased thigmotaxis and short-term spatial memory impairment without affecting long-term recognition memory. Furthermore, cognitive and behavioral phenotypes in these mice were associated with a reduction in interleukin-15 levels in the absence of changes in other inflammatory mediators. Our findings indicate that interleukin-15 may play a role in early stages of cognitive impairment secondary to hypercholesterolemia. Consequently, optimization of interleukin-15 signaling may be a viable effective cognitive therapy in the population susceptible to developing dementia due to risk factors associated with cholesterol dysregulation.
Subject(s)
Cholesterol, Dietary/administration & dosage , Encephalitis/metabolism , Interleukin-15/metabolism , Memory Disorders/metabolism , Animals , Down-Regulation , Encephalitis/chemically induced , Inflammation Mediators/metabolism , Male , Maze Learning/drug effects , Memory Disorders/chemically induced , Mice, Inbred C57BL , Motor Activity/drug effectsABSTRACT
BACKGROUND: Niemann-Pick disease type C (NPC) is a progressive neurodegenerative condition that results in early fatality. NPC is inherited in an autosomal recessive pattern from mutations in NPC1 or NPC2 genes. The etiology of NPC is poorly defined. In that regard, neuroinflammation occurs early in the disease and we have recently unveiled an atypical pattern of interferon signaling in pre-symptomatic Npc1-/- mice, with microglial activation, anti-viral response, activation of antigen-presenting cells, and activation and chemotaxis of T lymphocytes as the key affected pathologic pathways. Furthermore, IP-10/CXCL10, a potent IFN-γ-responsive cytokine, was identified as the potential mediator of these early inflammatory abnormalities. Here, we asked whether this aberrant signaling may be exacerbated by the loss of amyloid precursor protein (APP) function, a loss known to shorten lifespan and accelerate neurodegeneration in Npc1-/- mice. METHODS: We carried out genome-wide comparative transcriptome analyses of pre-symptomatic Npc1+/+/App+/+, Npc1-/-/App+/+, Npc1+/+/App-/-, and Npc1-/-/App-/- mouse cerebella to identify biological pathways in the NPC brain further affected by the loss of APP. Gene Set Enrichment Analysis and Ingenuity Pathway Analysis were utilized for molecular mapping and functional upstream pathway analyses of highly differentially expressed genes. We simultaneously measured the expression of 32 inflammatory cytokines and chemokines in the cerebella from these mice, including those identified in our genome-wide analyses. Finally, we used immunohistochemistry to measure T cell infiltration in the cerebellum. RESULTS: Expression of IFN-γ- and IFN-α-responsive genes in pre-symptomatic Npc1-/-/App-/- cerebella is upregulated compared with Npc1-/-/App+/+ mice, compounding the dysregulation of microglial activation, anti-viral response, activation of antigen-presenting cells, and T-lymphocyte activation and chemotaxis pathways present in the NPC brain. Multiplex protein analysis further showed elevated expression of IP-10/CXCL10, a potent downstream effector of IFN-γ, as well as RANTES/CCL5, eotaxin/CCL11 and IL-10, prior to symptomatic onset in Npc1-/-/App-/- cerebella, compared with Npc1-/-/App+/+mice. In the terminal disease stage, loss of APP caused pleiotropic differential expression of the vast majority of cytokines evaluated. Finally, we present evidence of T cell infiltration in Npc1-/-/App-/- cerebella. CONCLUSIONS: Loss of APP exacerbates the pathogenic neuroinflammation that occurs prior to symptomatic onset in the NPC brain. These findings shed new light on the function of APP as a cytoprotective modulator in the CNS, offering potential evidence-based therapies against NPC.
Subject(s)
Amyloid beta-Protein Precursor/metabolism , Brain/metabolism , Brain/pathology , Niemann-Pick Disease, Type C/metabolism , Niemann-Pick Disease, Type C/pathology , Animals , Inflammation/metabolism , Inflammation/pathology , Mice , Mice, KnockoutABSTRACT
Niemann-Pick disease type C (NPC) is a fatal neurodegenerative condition with no FDA-approved therapy. Previous studies demonstrated that neuroinflammation is an early pathologic event and a disease modifier of NPC, affecting symptomatic onset and overall lifespan. Therefore, NPC-specific anti-inflammatory therapy may result in clinical benefit. However, to date, the initial trigger of the inflammatory onset and the mechanism driving the sustained chronic neuroinflammation remain unknown. In this study, we utilized a genome-wide transcriptome analysis to identify the key pathways involved in early NPC. Our results showed that an atypical pattern of interferon downstream signaling that involves both IFN-γ- and IFN-α-responsive genes is activated in pre-symptomatic Npc1-/- cerebella. Functional analysis of the differentially expressed genes highlighted microglial activation, anti-viral response, and T-lymphocyte activation and chemotaxis pathways. Multiplex protein analysis confirmed that a potent IFN-γ-responsive cytokine, IP-10/CXCL10 was significantly upregulated in the pre-symptomatic stage and further exacerbated in the terminal stage. In addition, several IFN-γ-responsive cytokines were elevated in the terminal stage Npc1-/- cerebella, including MIG/CXCL9, MCP-1/CCL2, MIP-1α/CCL3, MIP-1ß/CCL4, RANTES/CCL5, M-CSF, and IL-1α. Together, our results describe a novel activation pattern of interferon downstream signaling in pre-symptomatic NPC, as well as key inflammatory mediators that could serve as potential targets for NPC-specific anti-inflammatory therapy.
Subject(s)
Cerebellum/metabolism , Interferons/metabolism , Niemann-Pick Disease, Type C/metabolism , Signal Transduction/genetics , Animals , Cytokines/metabolism , Gene Expression Profiling , Genome-Wide Association Study , Interferons/genetics , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Mice , Mice, Knockout , Niemann-Pick C1 Protein , Niemann-Pick Disease, Type C/genetics , Prodromal SymptomsABSTRACT
Chitosan polymers (Cs), from which microparticles (CsM) may be precipitated to deliver various intracellular payloads, are generally considered biologically inert. We examined the impact of cell culture conditions on CsM size and the effect of chitosan on CD59 expression in primary human smooth muscle cells. We found that particle concentration and incubation time in biological buffers augmented particle size. Between pH 7.0 and pH 7.5, CsM size increased abruptly. We utilized CsM containing a plasmid with a gene for CD59 (pCsM) to transfect cells. Both CD59 mRNA and the number of CD59-positive cells were increased after pCsM treatment. Unexpectedly, CsM also augmented the number of CD59-positive cells. Cs alone enhanced CD59 expression more potently than either pCSM or CsM. This observation strongly suggests that chitosan is in fact bioactive and that chitosan-only controls should be included to avoid misattributing the activity of the delivery agent with that of the payload.
Subject(s)
Chitosan/analogs & derivatives , Nanoparticles/chemistry , Transfection/methods , CD59 Antigens/genetics , CD59 Antigens/metabolism , Cells, Cultured , Humans , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/metabolism , Nanoparticles/adverse effects , Plasmids/genetics , Plasmids/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
The function of the amyloid precursor protein (APP) in brain health remains unclear. This study elucidated a novel cytoprotective signaling pathway initiated by the APP transcriptionally active intracellular domain (AICD) in response to 27-hydroxycholesterol (27OHC), an oxidized cholesterol metabolite associated with neurodegeneration. The cellular response to 27OHC was hormetic, such that low, but not high, doses promoted AICD transactivation of microtubule associated serine/threonine kinase family member 4 (MAST4). MAST4 in turn phosphorylated and inhibited FOXO1-dependent transcriptional repression of rhotekin 2 (RTKN2), an oxysterol stress responder, to optimize cell survival. A palmitate-rich diet, which increases serum 27OHC, or APP ablation, abrogated this response in vivo. Further, this pathway was downregulated in human Alzheimer's Disease (AD) brains but not in frontotemporal dementia brains. These results unveil MAST4 as functional kinase of FOXO1 in a 27OHC AICD-driven, hormetic pathway providing insight for therapeutic approaches against cholesterol associated neuronal disorders.
Subject(s)
Amyloid beta-Protein Precursor/genetics , Hormesis , Hydroxycholesterols/pharmacology , Intracellular Space/drug effects , Microtubule-Associated Proteins/metabolism , Protein Kinases/metabolism , Protein Serine-Threonine Kinases/metabolism , Transcription, Genetic/drug effects , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Animals , Cell Line, Tumor , Forkhead Box Protein O1/metabolism , Gene Expression Regulation/drug effects , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Intracellular Space/metabolism , Male , Mice , Phosphorylation/drug effects , RatsABSTRACT
Members of the cyclic-AMP response-element binding protein (CREB) transcription factor family regulate the expression of genes needed for long-term memory formation. Loss of Notch impairs long-term, but not short-term, memory in flies and mammals. We investigated if the Notch-1 (N1) exerts an effect on CREB-dependent gene transcription. We observed that N1 inhibits CREB mediated activation of cyclic-AMP response element (CRE) containing promoters in a γ-secretase-dependent manner. We went on to find that the γ-cleaved N1 intracellular domain (N1ICD) sequesters nuclear CREB1α, inhibits cAMP/PKA-mediated neurite outgrowth and represses the expression of specific CREB regulated genes associated with learning and memory in primary cortical neurons. Similar transcriptional effects were observed with the N2ICD, N3ICD and N4ICDs. Together, these observations indicate that the effects of Notch on learning and memory are, at least in part, via an effect on CREB-regulated gene expression.
Subject(s)
Cyclic AMP Response Element-Binding Protein/metabolism , Receptor, Notch1/metabolism , Amyloid Precursor Protein Secretases/metabolism , Animals , Cells, Cultured , Colforsin/pharmacology , Cyclic AMP/pharmacology , Cyclic AMP Response Element-Binding Protein/genetics , Cyclic AMP-Dependent Protein Kinases/metabolism , Embryo, Mammalian/cytology , Embryo, Mammalian/drug effects , Embryo, Mammalian/metabolism , Female , HEK293 Cells , Humans , Memory, Long-Term/physiology , Mice , Mice, Inbred C57BL , Neurites/physiology , Neurons/cytology , Neurons/metabolism , Protein Isoforms/chemistry , Protein Isoforms/genetics , Protein Isoforms/metabolism , Protein Structure, Tertiary , Rats , Receptor, Notch1/chemistry , Receptor, Notch1/genetics , Transcription, Genetic/drug effectsABSTRACT
BACKGROUND: High-profile Phase 3 clinical trials of bapineuzumab and solanezumab, antibodies targeted at amyloid-beta (Aß) removal, have failed to meet their primary endpoints. Neither drug improves clinical outcomes in patients with late onset AD, joining a long list of unsuccessful attempts to treat AD with anti-amyloid therapies. DISCUSSION: These therapies are based on the assumption that Aß accumulation is the primary pathogenic trigger of AD. Current evidence suggests that Aß may actually accumulate as part of an adaptive response to long-term chronic brain stress stimuli that would make more suitable candidates for therapeutic intervention. SUMMARY: At this juncture it is no longer unreasonable to suggest that further iterations of anti-Aß therapies should be halted. Clinicians and researchers should instead direct their attention toward greater understanding of the biological function of Aß both in healthy and demented brains, as well as the involvement of long-term chronic exposure to stress in the etiology of AD.
Subject(s)
Alzheimer Disease/etiology , Alzheimer Disease/pathology , Alzheimer Disease/therapy , Amyloid beta-Peptides , Antibodies, Monoclonal, Humanized/therapeutic use , Clinical Trials as Topic , Humans , Plaque, Amyloid/pathologyABSTRACT
The amyloid cascade hypothesis, which implicates the amyloid Aß peptide as the pathological initiator of both familial and sporadic, late onset Alzheimer's disease (AD), continues to guide the majority of research. We believe that current evidence does not support the amyloid cascade hypothesis for late onset AD. Instead, we propose that Aß is a key regulator of brain homeostasis. During AD, while Aß accumulation may occur in the long term in parallel with disease progression, it does not contribute to primary pathogenesis. This view predicts that amyloid-centric therapies will continue to fail, and that progress in developing successful alternative therapies for AD will be slow until closer attention is paid to understanding the physiological function of Aß and its precursor protein.
Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/metabolism , Brain/metabolism , Plaque, Amyloid , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Amyloid beta-Peptides/genetics , Amyloid beta-Protein Precursor/genetics , Animals , Brain/pathology , Disease Progression , Genetic Predisposition to Disease , Humans , Nerve Degeneration , Phenotype , Risk Factors , Time FactorsABSTRACT
According to the amyloid cascade hypothesis, accumulation of the amyloid peptide Aß, derived by proteolytic processing from the amyloid precursor protein (APP), is the key pathogenic trigger in Alzheimer's disease (AD). This view has led researchers for more than two decades and continues to be the most influential model of neurodegeneration. Nevertheless, close scrutiny of the current evidence does not support a central pathogenic role for Aß in late-onset AD. Furthermore, the amyloid cascade hypothesis lacks a theoretical foundation from which the physiological generation of Aß can be understood, and therapeutic approaches based on its premises have failed. We present an alternative model of neurodegeneration, in which sustained cholesterol-associated neuronal distress is the most likely pathogenic trigger in late-onset AD, directly causing oxidative stress, inflammation and tau hyperphosphorylation. In this scenario, Aß generation is part of an APP-driven adaptive response to the initial cholesterol distress, and its accumulation is neither central to, nor a requirement for, the initiation of the disease. Our model provides a theoretical framework that places APP as a regulator of cholesterol homeostasis, accounts for the generation of Aß in both healthy and demented brains, and provides suitable targets for therapeutic intervention.
Subject(s)
Amyloid/physiology , Cholesterol/metabolism , Animals , Humans , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/physiopathology , Signal Transduction/physiologyABSTRACT
BACKGROUND: The cyclin-dependent kinase 5 activator p35 can be cleaved into p25. Formation of p25 has been suggested to contribute to neurodegeneration in Alzheimer's disease (AD). However, overexpression of low levels of p25 in mice enhances memory formation. Therefore, it has been suggested that p25 formation might be an event early in AD to compensate for impairments in synaptic plasticity. Ongoing p25 formation has been hypothesized to contribute to neurodegeneration at the later stages of AD. METHODS: Here, we tested the early compensation hypothesis by analyzing the levels of p25 and its precursor p35 in AD postmortem samples from different brain regions at different stages of tau pathology, using quantitative Western blots. Furthermore, we studied p35 and p25 during spatial memory formation. By employing quantitative mass spectrometry, we identified proteins downstream of p25, which were then studied in AD samples. RESULTS: We found that p25 is generated during spatial memory formation. Furthermore, we demonstrate that overexpression of p25 in the physiological range increases the expression of two proteins implicated in spine formation, septin 7 and optic atrophy 1. We show that the expression of p35 and p25 is reduced as an early event in AD. Moreover, expression of the p25-regulated protein optic atrophy 1 was reduced in a time course similar to p25 expression. CONCLUSIONS: Our findings suggest that p25 generation is a mechanism underlying hippocampal memory formation that is impaired in the early stages of AD. Our findings argue against the previously raised early compensation hypothesis and they propose that p25-mediated neurotoxicity does not occur in AD.
Subject(s)
Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Down-Regulation/genetics , Memory/physiology , Nerve Tissue Proteins/metabolism , Alzheimer Disease/pathology , Animals , Brain/metabolism , Brain/pathology , Brain/ultrastructure , Cyclin D1/metabolism , Disease Models, Animal , GTP Phosphohydrolases/metabolism , Humans , Mass Spectrometry/methods , Maze Learning/physiology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Microscopy, Electron, Transmission , Mutation/genetics , Nerve Tissue Proteins/genetics , Phosphopyruvate Hydratase/metabolism , Septins/metabolism , Synapses/metabolism , Synapses/ultrastructure , Synaptosomes/metabolism , Synaptosomes/ultrastructure , tau Proteins/metabolismABSTRACT
AIM: The aim of this study was to investigate whether magnetoencephalographic oscillations underlying working memory dysfunction in the dorsolateral prefrontal cortex (DLPFC) are related to psychopathological disturbance in patients with schizophrenia-like psychosis of epilepsy (SLPE). METHODS: Twelve patients with SLPE and 14 non-psychotic epilepsy controls participated in this study. Magnetoencephalography was recorded while patients performed a visual working memory (WM) task. Psychopathology was assessed using a four-factor structure of the Brief Psychiatric Rating Scale, and regression analyses were carried out to examine the relative impact of severity of psychopathology on WM-induced activation of the DLPFC. RESULTS: We found that activation of the WM-compromising DLPFC, as indicated by increased alpha desynchronization in patients with SLPE compared with their non-psychotic counterparts, showed a positive linear correlation with disorganization symptom scores. This association remained significant after controlling for confounding factors, including age, task performance, IQ, and duration of psychosis. CONCLUSION: Our results indicate that abnormal activation in prefrontal areas engaged during working memory may be critical to domains of psychopathology, in particular disorganized thought-processing in patients with SLPE.
Subject(s)
Epilepsy/physiopathology , Magnetoencephalography/methods , Memory Disorders/physiopathology , Prefrontal Cortex/physiopathology , Psychotic Disorders/physiopathology , Adult , Brain Mapping/methods , Brain Waves/physiology , Epilepsy/complications , Female , Humans , Male , Memory Disorders/complications , Photic Stimulation , Psychomotor Performance/physiology , Psychotic Disorders/complicationsABSTRACT
Niemann-Pick type C disease (NPC) is a lysosomal storage disorder which, at the cellular level, shows amyloid Aß and tau pathologies comparable to those seen in the AD brain. Here, we have investigated, in a mouse model of NPC, the impact of removing the source of Aß, namely APP, on the disease phenotype and on the expression levels and phosphorylation patterns of tau. We reasoned that removing APP from the NPC brain might help to unveil its impact on the disease phenotype and shed light on the mechanisms governing the interaction, both physiological and pathological, between APP function and tau homeostasis, at least in NPC. We show that, unexpectedly, loss of APP in NPC mice leads to poorer neuromuscular coordination and cumulative survival rates; exacerbation of their cholesterol abnormalities; higher levels of astrocytosis and dysregulation of tau homeostasis. Our results are consistent with a mechanism of neurodegeneration in the NPC and AD brains in which cholesterol dysregulation is a key early pathogenic event affecting tau homeostasis in parallel with, and independently of, amyloid accumulation.
Subject(s)
Amyloid beta-Protein Precursor/metabolism , Brain/metabolism , Niemann-Pick Disease, Type C/metabolism , Phosphorylation/genetics , tau Proteins/metabolism , Amyloid beta-Protein Precursor/genetics , Analysis of Variance , Animals , Blotting, Western , Brain/pathology , Disease Models, Animal , Gliosis/genetics , Gliosis/metabolism , Gliosis/pathology , Male , Mice , Mice, Knockout , Motor Activity/physiology , Niemann-Pick Disease, Type C/genetics , Niemann-Pick Disease, Type C/pathology , Phenotype , Weight Loss/physiology , tau Proteins/geneticsABSTRACT
Neuronal cell cycle reentry, which is associated with aberrant tau phosphorylation, is thought to be a mechanism of neurodegeneration in AD. Caffeine is a neuroprotective drug known to inhibit the cell cycle, suggesting that its neuroprotective nature may rely, at least in part, on preventing tau abnormalities secondary to its inhibitory effect on neuronal cell cycle-related pathways. Accordingly, we have explored in the present study the impact of caffeine on cell cycle-linked parameters and tau phosphorylation patterns in an attempt to identify molecular clues to its neuroprotective effect. We show that caffeine blocks the cell cycle at G1 phase in neuroblastoma cells and leads to a decrease in tau phosphorylation; similarly, exposure of postmitotic neurons to caffeine led to changes in tau phosphorylation concomitantly with downregulation of Akt signaling. Taken together, our results show a unique impact of caffeine on tau phosphorylation and warrant further investigation to address whether caffeine may help prevent neuronal death by preventing tau abnormalities secondary to aberrant entry into the cell cycle.
Subject(s)
Caffeine/pharmacology , Neurons/drug effects , Neurons/physiology , Phosphorylation/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , tau Proteins/metabolism , Animals , Cell Line , Humans , Neurons/cytology , Phosphodiesterase Inhibitors/pharmacology , RatsABSTRACT
BACKGROUND/AIMS: A single-nucleotide polymorphism (SNP) in the KIBRA gene, rs17070145, was reported to be significantly associated with episodic memory in cognitively normal cohorts. This observation has expanded genetic studies on KIBRA to Alzheimer's disease (AD). Importantly, the association between KIBRA and episodic memory in AD has never been addressed. In this study, we investigated whether the KIBRA rs17070145 SNP influences AD episodic memory and the disease in a Japanese cohort. METHODS: Blood samples from 346 AD patients and 375 normal cognitive controls were collected and genotyped for rs17070145. Episodic memory was measured in 32 AD patients, diagnosed for the first time, by use of the Rivermead Behavioral Memory Test (RBMT). RESULTS: We found that KIBRA C allele carriers scored significantly lower than KIBRA non-C carriers on both RBMT total profile score (p = 0.042, effect size = 0.84) and RBMT total screening score (p < 0.001, effect size = 1.42). The KIBRA gene did not show association with AD in our Japanese cohort. CONCLUSION: Our results evidence a strong association between the KIBRA gene and episodic memory impairment in AD, but show no influence on AD in our Japanese cohort. We propose that KIBRA might have an effect similar to cognitive reserve.