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1.
Cell ; 172(5): 952-965.e18, 2018 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-29474921

RESUMEN

Viruses that are typically benign sometimes invade the brainstem in otherwise healthy children. We report bi-allelic DBR1 mutations in unrelated patients from different ethnicities, each of whom had brainstem infection due to herpes simplex virus 1 (HSV1), influenza virus, or norovirus. DBR1 encodes the only known RNA lariat debranching enzyme. We show that DBR1 expression is ubiquitous, but strongest in the spinal cord and brainstem. We also show that all DBR1 mutant alleles are severely hypomorphic, in terms of expression and function. The fibroblasts of DBR1-mutated patients contain higher RNA lariat levels than control cells, this difference becoming even more marked during HSV1 infection. Finally, we show that the patients' fibroblasts are highly susceptible to HSV1. RNA lariat accumulation and viral susceptibility are rescued by wild-type DBR1. Autosomal recessive, partial DBR1 deficiency underlies viral infection of the brainstem in humans through the disruption of tissue-specific and cell-intrinsic immunity to viruses.


Asunto(s)
Encefalopatías Metabólicas Innatas/genética , Tronco Encefálico/metabolismo , Tronco Encefálico/virología , ARN/química , ARN/metabolismo , Alelos , Secuencia de Aminoácidos , Animales , Encefalopatías Metabólicas Innatas/patología , Tronco Encefálico/patología , Encefalitis Viral/genética , Escherichia coli/metabolismo , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Fibroblastos/virología , Herpesvirus Humano 1 , Humanos , Interferones/metabolismo , Intrones/genética , Masculino , Ratones , Proteínas Mutantes/metabolismo , Mutación/genética , Sistemas de Lectura Abierta/genética , Linaje , ARN Nucleotidiltransferasas/química , ARN Nucleotidiltransferasas/deficiencia , ARN Nucleotidiltransferasas/genética , Receptor Toll-Like 3/metabolismo , Replicación Viral
2.
J Neurosci ; 41(19): 4305-4320, 2021 05 12.
Artículo en Inglés | MEDLINE | ID: mdl-33888602

RESUMEN

Vascular dysfunction is a universal feature of aging and decreased cerebral blood flow has been identified as an early event in the pathogenesis of Alzheimer's disease (AD). Cerebrovascular dysfunction in AD includes deficits in neurovascular coupling (NVC), a mechanism that ensures rapid delivery of energy substrates to active neurons through the blood supply. The mechanisms underlying NVC impairment in AD, however, are not well understood. We have previously shown that mechanistic/mammalian target of rapamycin (mTOR) drives cerebrovascular dysfunction in models of AD by reducing the activity of endothelial nitric oxide synthase (eNOS), and that attenuation of mTOR activity with rapamycin is sufficient to restore eNOS-dependent cerebrovascular function. Here we show mTOR drives NVC impairments in an AD model through the inhibition of neuronal NOS (nNOS)- and non-NOS-dependent components of NVC, and that mTOR attenuation with rapamycin is sufficient to restore NVC and even enhance it above WT responses. Restoration of NVC and concomitant reduction of cortical amyloid-ß levels effectively treated memory deficits in 12-month-old hAPP(J20) mice. These data indicate that mTOR is a critical driver of NVC dysfunction and underlies cognitive impairment in an AD model. Together with our previous findings, the present studies suggest that mTOR promotes cerebrovascular dysfunction in AD, which is associated with early disruption of nNOS activation, through its broad negative impact on nNOS as well as on non-NOS components of NVC. Our studies highlight the potential of mTOR attenuation as an efficacious treatment for AD and potentially other neurologic diseases of aging.SIGNIFICANCE STATEMENT Failure of the blood flow response to neuronal activation [neurovascular coupling (NVC)] in a model of AD precedes the onset of AD-like cognitive symptoms and is driven, to a large extent, by mammalian/mechanistic target of rapamycin (mTOR)-dependent inhibition of nitric oxide synthase activity. Our studies show that mTOR also drives AD-like failure of non-nitric oxide (NO)-mediated components of NVC. Thus, mTOR attenuation may serve to treat AD, where we find that neuronal NO synthase is profoundly reduced early in disease progression, and potentially other neurologic diseases of aging with cerebrovascular dysfunction as part of their etiology.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Trastornos de la Memoria/tratamiento farmacológico , Acoplamiento Neurovascular/efectos de los fármacos , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/psicología , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Trastornos Cerebrovasculares/fisiopatología , Disfunción Cognitiva/genética , Disfunción Cognitiva/psicología , Miedo/psicología , Femenino , Humanos , Masculino , Trastornos de la Memoria/psicología , Ratones , Ratones Transgénicos , Microvasos/patología , Microvasos/ultraestructura , Óxido Nítrico Sintasa de Tipo III/metabolismo , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TOR/genética
3.
Adv Exp Med Biol ; 1128: 185-225, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31062331

RESUMEN

Accumulating evidence suggests that Alzheimer's disease may manifest as a metabolic disorder with pathology and/or dysfunction in numerous tissues. Adults with Alzheimer's disease suffer with significantly more comorbidities than demographically matched Medicare beneficiaries (Zhao et al, BMC Health Serv Res 8:108, 2008b). Reciprocally, comorbid health conditions increase the risk of developing Alzheimer's disease (Haaksma et al, PLoS One 12(5):e0177044, 2017). Type 2 diabetes mellitus is especially notable as the disease shares many overlapping pathologies observed in patients with Alzheimer's disease, including hyperglycemia, hyperinsulinemia, insulin resistance, glucose intolerance, dyslipidemia, inflammation, and cognitive dysfunction, as described in Chap. 8 of this book (Yoshitake et al, Neurology 45(6):1161-1168, 1995; Leibson et al, Am J Epidemiol 145(4):301-308, 1997; Ott et al, Neurology 53(9):1937-1942, 1999; Voisin et al, Rev Med Interne 24(Suppl 3):288s-291s, 2003; Janson et al. Diabetes 53(2):474-481, 2004; Ristow M, J Mol Med (Berl) 82(8):510-529, 2004; Whitmer et al, BMJ 330(7504):1360, 2005, Curr Alzheimer Res 4(2):103-109, 2007; Ohara et al, Neurology 77(12):1126-1134, 2011). Although nondiabetic older adults also experience age-related cognitive decline, diabetes is uniquely associated with a twofold increased risk of Alzheimer's disease, as described in Chap. 2 of this book (Yoshitake et al, Neurology 45(6):1161-1168, 1995; Leibson et al, Am J Epidemiol 145(4):301-308, 1997; Ott et al. Neurology 53(9):1937-1942, 1999; Ohara et al, Neurology 77(12):1126-1134, 2011). Good glycemic control has been shown to improve cognitive status (Cukierman-et al, Diabetes Care 32(2):221-226, 2009), and the use of insulin sensitizers is correlated with a lower rate of cognitive decline in older adults (Morris JK, Burns JM, Curr Neurol Neurosci Rep 12(5):520-527, 2012). At the molecular level, the mechanistic/mammalian target of rapamycin (mTOR) plays a key role in maintaining energy homeostasis. Nutrient availability and cellular stress information, both extracellular and intracellular, are integrated and transduced through mTOR signaling pathways. Aberrant regulation of mTOR occurs in the brains of patients with Alzheimer's disease and in numerous tissues of individuals with type 2 diabetes (Mannaa et al, J Mol Med (Berl) 91(10):1167-1175, 2013). Moreover, modulating mTOR activity with a pharmacological inhibitor, rapamycin, provides wide-ranging health benefits, including healthy life span extension in numerous model organisms (Vellai et al, Nature 426(6967):620, 2003; Jia et al, Development 131(16):3897-3906, 2004; Kapahi et al, Curr Biol 14(10):885-890, 2004; Kaeberlein et al, Science 310(5751):1193-1196, 2005; Powers et al, Genes Dev 20(2):174-184, 2006; Harrison et al, Nature 460(7253):392-395, 2009; Selman et al, Science 326(5949):140-144, 2009; Sharp ZD, Strong R, J Gerontol A Biol Sci Med Sci 65(6):580-589, 2010), which underscores its importance to overall organismal health and longevity. In this chapter, we discuss the physiological role of mTOR signaling and the consequences of mTOR dysregulation in the brain and peripheral tissues, with emphasis on its relevance to the development of Alzheimer's disease and link to type 2 diabetes.


Asunto(s)
Enfermedad de Alzheimer/patología , Diabetes Mellitus Tipo 2/patología , Transducción de Señal , Serina-Treonina Quinasas TOR/fisiología , Humanos
4.
Am J Physiol Heart Circ Physiol ; 314(4): H693-H703, 2018 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-29351469

RESUMEN

An intact blood-brain barrier (BBB) limits entry of proinflammatory and neurotoxic blood-derived factors into the brain parenchyma. The BBB is damaged in Alzheimer's disease (AD), which contributes significantly to the progression of AD pathologies and cognitive decline. However, the mechanisms underlying BBB breakdown in AD remain elusive, and no interventions are available for treatment or prevention. We and others recently established that inhibition of the mammalian/mechanistic target of rapamycin (mTOR) pathway with rapamycin yields significant neuroprotective effects, improving cerebrovascular and cognitive function in mouse models of AD. To test whether mTOR inhibition protects the BBB in neurological diseases of aging, we treated hAPP(J20) mice modeling AD and low-density lipoprotein receptor-null (LDLR-/-) mice modeling vascular cognitive impairment with rapamycin. We found that inhibition of mTOR abrogates BBB breakdown in hAPP(J20) and LDLR-/- mice. Experiments using an in vitro BBB model indicated that mTOR attenuation preserves BBB integrity through upregulation of specific tight junction proteins and downregulation of matrix metalloproteinase-9 activity. Together, our data establish mTOR activity as a critical mediator of BBB breakdown in AD and, potentially, vascular cognitive impairment and suggest that rapamycin and/or rapalogs could be used for the restoration of BBB integrity. NEW & NOTEWORTHY This report establishes mammalian/mechanistic target of rapamycin as a critical mediator of blood-brain barrier breakdown in models of Alzheimer's disease and vascular cognitive impairment and suggests that drugs targeting the target of rapamycin pathway could be used for the restoration of blood-brain barrier integrity in disease states.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Conducta Animal , Barrera Hematoencefálica/efectos de los fármacos , Cognición , Demencia Vascular/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Animales , Barrera Hematoencefálica/enzimología , Barrera Hematoencefálica/patología , Línea Celular , Demencia Vascular/enzimología , Demencia Vascular/patología , Demencia Vascular/psicología , Modelos Animales de Enfermedad , Femenino , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de LDL/deficiencia , Receptores de LDL/genética , Serina-Treonina Quinasas TOR/metabolismo , Proteínas de Uniones Estrechas/metabolismo , Uniones Estrechas/efectos de los fármacos , Uniones Estrechas/enzimología , Uniones Estrechas/patología
5.
Gerontology ; 64(3): 205-211, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29320772

RESUMEN

Cerebrovascular dysfunction is detected prior to the onset of cognitive and histopathological changes in Alzheimer's disease (AD). Increasing evidence indicates a critical role of cerebrovascular dysfunction in the initiation and progression of AD. Recent studies identified the mechanistic/mammalian target of rapamycin (mTOR) as a critical effector of cerebrovascular dysfunction in AD. mTOR has a key role in the regulation of metabolism, but some mTOR-dependent mechanisms are uniquely specific to the regulation of cerebrovascular function. These include the regulation of cerebral blood flow, blood-brain barrier integrity and maintenance, neurovascular coupling, and cerebrovascular reactivity. This article examines the available evidence for a role of mTOR-driven cerebrovascular dysfunction in the pathogenesis of AD and of vascular cognitive impairment and dementia (VCID) and highlights the therapeutic potential of targeting mTOR and/or specific downstream effectors for vasculoprotection in AD, VCID, and other age-associated neurological diseases with cerebrovascular etiology.


Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Trastornos Cerebrovasculares/fisiopatología , Serina-Treonina Quinasas TOR/fisiología , Enfermedad de Alzheimer/etiología , Barrera Hematoencefálica/fisiopatología , Circulación Cerebrovascular/fisiología , Trastornos Cerebrovasculares/complicaciones , Disfunción Cognitiva/etiología , Disfunción Cognitiva/fisiopatología , Demencia/etiología , Demencia/fisiopatología , Demencia Vascular/etiología , Humanos
6.
Alcohol Clin Exp Res ; 39(2): 262-71, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25684048

RESUMEN

BACKGROUND: Ethanol (EtOH) dependence and tolerance in the adult are marked by increased function of NMDA receptors and decreased function of GABAA receptors, which coincide with altered receptor subunit expression in specific brain regions. Adolescents often use EtOH at levels greater than adults, yet the receptor subunit expression profiles following chronic intermittent EtOH (CIE) exposure in adolescents are not known. Persistent age-dependent changes in receptor subunit alterations coupled with withdrawal-related anxiety may help explain the increase in alcohol abuse following adolescent experimentation with the drug. METHODS: Adolescent and adult rats received 10 intraperitoneal administrations of 4.0 g/kg EtOH or saline every 48 hours. At either 24 hours or 12 days after the final exposure, anxiety-like behavior was assessed on the elevated plus maze and tissue was collected. Western blotting was used to assess changes in selected NMDA and GABAA receptor subunits in whole cortex and bilateral hippocampus. RESULTS: CIE exposure yields a persistent increase in anxiety-like behavior in both age groups. However, selected NMDA and GABAA receptor subunits were not differentially altered by this CIE exposure paradigm in adolescents or adults. CONCLUSIONS: CIE exposure produced persistent anxiety-like behavior, which has important implications for alcohol cessation. Given the reported behavioral and neuropeptide expression changes in response to this dose of EtOH, it is important for future work to consider the circumstances under which these measures are altered by EtOH exposure.


Asunto(s)
Ansiedad , Depresores del Sistema Nervioso Central/farmacología , Corteza Cerebral/efectos de los fármacos , Etanol/farmacología , Conducta Exploratoria/efectos de los fármacos , Hipocampo/efectos de los fármacos , Receptores de GABA-A/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Depresores del Sistema Nervioso Central/administración & dosificación , Corteza Cerebral/metabolismo , Etanol/administración & dosificación , Hipocampo/metabolismo , Inyecciones Intraperitoneales , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de GABA-A/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
7.
Alcohol Clin Exp Res ; 38(10): 2509-16, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25156779

RESUMEN

BACKGROUND: This review incorporates current research examining alcohol's differential effects on adolescents, adults, and aged populations in both animal and clinical models. METHODS: The studies presented range from cognitive, behavioral, molecular, and neuroimaging techniques, leading to a more comprehensive understanding of how acute and chronic alcohol use affects the brain throughout the life span. RESULTS: Age of life is a significant factor in determining the effect of alcohol on brain functioning. Adolescents and aged populations may be more negatively affected by heavy alcohol use when compared to adults. CONCLUSIONS: Investigations limiting alcohol effects to a single age group constrains understanding of differential trajectories and outcomes following acute and chronic use. To meaningfully address the sequencing and interaction effects of alcohol and age, the field must incorporate collaborative and integrated research efforts focused on interdisciplinary questions facilitated by engaging basic and applied scientists with expertise in a range of disciplines including alcohol, neurodevelopment, and aging.


Asunto(s)
Envejecimiento/fisiología , Envejecimiento/psicología , Consumo de Bebidas Alcohólicas/efectos adversos , Encéfalo/fisiopatología , Cognición/fisiología , Adolescente , Adulto , Anciano , Envejecimiento/patología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Niño , Cognición/efectos de los fármacos , Trastornos del Conocimiento/patología , Trastornos del Conocimiento/fisiopatología , Trastornos del Conocimiento/psicología , Modelos Animales de Enfermedad , Etanol/farmacología , Femenino , Humanos , Masculino , Trastornos Mentales/patología , Trastornos Mentales/fisiopatología , Trastornos Mentales/psicología , Persona de Mediana Edad , Neuroimagen , Ratas
8.
Alcohol Clin Exp Res ; 37(8): 1317-24, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23550918

RESUMEN

BACKGROUND: Aging in both humans and rodents appears to be accompanied by physiological changes that increase biologic sensitivity to ethanol (EtOH) intoxication. However, animal models designed to investigate this increased alcohol sensitivity have yet to be established. For this reason, we sought to determine whether acute EtOH administration produces differential effects on motor coordination and spatial cognition in young adult and aged rats. METHODS: Male young adult (postnatal day 70 to 72) and aged (~18 months) Sprague-Dawley rats were assessed on 2 motor tasks (the accelerating rotarod [RR] and the aerial righting reflex [ARR]) and a single cognitive performance task (the Morris water maze [MWM]). Following acute EtOH exposure via intraperitoneal injection, animals' performance was reassessed. RESULTS: Aged rats showed a dramatic increase in EtOH-induced ataxia on the RR and the ARR relative to young adult animals. Similarly, results from the MWM revealed that aged animals had slightly greater EtOH-induced impairments compared with young adult animals. Importantly, the increased impairments produced by EtOH were not due to differential blood EtOH levels. CONCLUSIONS: We demonstrate for the first time that aged rats show greater EtOH-induced deficits compared with young adults in tasks of motor and cognitive performance. The possible role of protein kinase C as a mechanism for increased sensitivity to the motor-impairing effects of EtOH is discussed. Given the high prevalence of alcohol use among the elderly, increased vulnerability to alcohol-induced deficits may have a profound effect on injury in this population.


Asunto(s)
Envejecimiento/psicología , Ataxia/inducido químicamente , Depresores del Sistema Nervioso Central/efectos adversos , Disfunción Cognitiva/inducido químicamente , Etanol/efectos adversos , Desempeño Psicomotor/efectos de los fármacos , Animales , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Reflejo de Enderezamiento/efectos de los fármacos , Prueba de Desempeño de Rotación con Aceleración Constante , Conducta Espacial/efectos de los fármacos
9.
Geroscience ; 45(3): 1987-1996, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37052770

RESUMEN

Peripheral artery disease (PAD), defined as reduced blood flow to the lower limbs, is a serious disorder that can lead to loss of function in the lower extremities and even loss of limbs. One of the main risk factors for PAD is age, with up to 25% of adults over the age of 55 and up to 40% over the age of 80 presenting with some form of the disease. While age is the largest risk factor for PAD, other risk factors include atherosclerosis, smoking, hypertension, and diabetes. Furthermore, previous studies have suggested that the incidence of PAD is significantly increased in patients with Alzheimer's disease (AD). Attenuation of mTOR with rapamycin significantly improves cerebral blood flow and heart function in aged rodents as well as in mouse models of atherosclerosis, atherosclerosis-driven cognitive impairment, and AD. In this study, we show that rapamycin treatment improves peripheral blood flow in aged mice and in mouse models of atherosclerosis and AD. Inhibition of mTOR with rapamycin ameliorates deficits in baseline hind paw perfusion in aged mice and restores levels of blood flow to levels indistinguishable from those of young controls. Furthermore, rapamycin treatment ameliorates peripheral blood flow deficits in mouse models of atherosclerosis and AD. These data indicate that mTOR is causally involved in the reduction of blood flow to lower limbs associated with aging, atherosclerosis, and AD-like progression in model mice. Rapamycin or other mTOR inhibitors may have potential as interventions to treat peripheral artery disease and other peripheral circulation-related conditions.


Asunto(s)
Enfermedad de Alzheimer , Aterosclerosis , Enfermedad Arterial Periférica , Ratones , Animales , Enfermedad de Alzheimer/complicaciones , Sirolimus/farmacología , Serina-Treonina Quinasas TOR , Aterosclerosis/tratamiento farmacológico , Enfermedad Arterial Periférica/tratamiento farmacológico , Enfermedad Arterial Periférica/complicaciones
10.
Nat Commun ; 14(1): 2367, 2023 04 25.
Artículo en Inglés | MEDLINE | ID: mdl-37185259

RESUMEN

Vascular mechanisms of Alzheimer's disease (AD) may constitute a therapeutically addressable biological pathway underlying dementia. We previously demonstrated that soluble pathogenic forms of tau (tau oligomers) accumulate in brain microvasculature of AD and other tauopathies, including prominently in microvascular endothelial cells. Here we show that soluble pathogenic tau accumulates in brain microvascular endothelial cells of P301S(PS19) mice modeling tauopathy and drives AD-like brain microvascular deficits. Microvascular impairments in P301S(PS19) mice were partially negated by selective removal of pathogenic soluble tau aggregates from brain. We found that similar to trans-neuronal transmission of pathogenic forms of tau, soluble tau aggregates are internalized by brain microvascular endothelial cells in a heparin-sensitive manner and induce microtubule destabilization, block endothelial nitric oxide synthase (eNOS) activation, and potently induce endothelial cell senescence that was recapitulated in vivo in microvasculature of P301S(PS19) mice. Our studies suggest that soluble pathogenic tau aggregates mediate AD-like brain microvascular deficits in a mouse model of tauopathy, which may arise from endothelial cell senescence and eNOS dysfunction triggered by internalization of soluble tau aggregates.


Asunto(s)
Enfermedad de Alzheimer , Tauopatías , Ratones , Animales , Proteínas tau/genética , Proteínas tau/metabolismo , Células Endoteliales/metabolismo , Tauopatías/metabolismo , Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Senescencia Celular , Ratones Transgénicos
11.
J Vis Exp ; (183)2022 05 19.
Artículo en Inglés | MEDLINE | ID: mdl-35661097

RESUMEN

Resuscitative endovascular balloon occlusion of the aorta (REBOA) devices grew out of a military-civilian partnership to develop new capabilities for hemorrhage control. With the advent of purpose-built devices, REBOA has become increasingly common in civilian trauma and acute care settings. Currently available REBOA catheters were designed as complete aortic occlusion devices. However, the therapeutic window for complete aortic occlusion is time-limited due to ischemia-reperfusion injury. The partial procedure allows blood flow past the level of occlusion while maintaining targeted proximal pressure, which has been shown to reduce distal ischemia and adjunctive resuscitation requirements in preclinical studies with prolonged occlusion times as compared to traditional complete occlusion. pREBOA-PRO is the first catheter designed to enable partial and complete aortic occlusion and is currently in limited market release at seven Level I trauma centers in North America. This paper will focus on procedural considerations for REBOA, including patient selection criteria and a comparison of complete and partial aortic occlusion in a simulator, along with highlighting critical steps to improve clinical outcomes. Additionally, this paper reviews a contrast-enhanced CT scan from a trauma patient that shows distal perfusion after 2 h of partial aortic occlusion using this newly designed catheter and discusses representative results from the limited market release to highlight the profound effect of technological innovation on outcomes in vascular emergencies.


Asunto(s)
Enfermedades de la Aorta , Oclusión con Balón , Procedimientos Endovasculares , Choque Hemorrágico , Aorta/cirugía , Oclusión con Balón/métodos , Procedimientos Endovasculares/métodos , Hemorragia/terapia , Humanos , Resucitación/métodos , Choque Hemorrágico/terapia
12.
Sci Adv ; 8(23): eabk2252, 2022 06 10.
Artículo en Inglés | MEDLINE | ID: mdl-35675410

RESUMEN

The proteasome has key roles in neuronal proteostasis, including the removal of misfolded and oxidized proteins, presynaptic protein turnover, and synaptic efficacy and plasticity. Proteasome dysfunction is a prominent feature of Alzheimer's disease (AD). We show that prevention of proteasome dysfunction by genetic manipulation delays mortality, cell death, and cognitive deficits in fly and cell culture AD models. We developed a transgenic mouse with neuronal-specific proteasome overexpression that, when crossed with an AD mouse model, showed reduced mortality and cognitive deficits. To establish translational relevance, we developed a set of TAT-based proteasome-activating peptidomimetics that stably penetrated the blood-brain barrier and enhanced 20S/26S proteasome activity. These agonists protected against cell death, cognitive decline, and mortality in cell culture, fly, and mouse AD models. The protective effects of proteasome overexpression appear to be driven, at least in part, by the proteasome's increased turnover of the amyloid precursor protein along with the prevention of overall proteostatic dysfunction.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Modelos Animales de Enfermedad , Drosophila melanogaster , Ratones , Ratones Transgénicos , Complejo de la Endopetidasa Proteasomal/metabolismo
13.
Mol Neurodegener ; 16(1): 64, 2021 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-34526055

RESUMEN

BACKGROUND: Human genetic association studies point to immune response and lipid metabolism, in addition to amyloid-beta (Aß) and tau, as major pathways in Alzheimer's disease (AD) etiology. Accumulating evidence suggests that chronic neuroinflammation, mainly mediated by microglia and astrocytes, plays a causative role in neurodegeneration in AD. Our group and others have reported early and dramatic losses of brain sulfatide in AD cases and animal models that are mediated by ApoE in an isoform-dependent manner and accelerated by Aß accumulation. To date, it remains unclear if changes in specific brain lipids are sufficient to drive AD-related pathology. METHODS: To study the consequences of CNS sulfatide deficiency and gain insights into the underlying mechanisms, we developed a novel mouse model of adult-onset myelin sulfatide deficiency, i.e., tamoxifen-inducible myelinating glia-specific cerebroside sulfotransferase (CST) conditional knockout mice (CSTfl/fl/Plp1-CreERT), took advantage of constitutive CST knockout mice (CST-/-), and generated CST/ApoE double knockout mice (CST-/-/ApoE-/-), and assessed these mice using a broad range of methodologies including lipidomics, RNA profiling, behavioral testing, PLX3397-mediated microglia depletion, mass spectrometry (MS) imaging, immunofluorescence, electron microscopy, and Western blot. RESULTS: We found that mild central nervous system (CNS) sulfatide losses within myelinating cells are sufficient to activate disease-associated microglia and astrocytes, and to increase the expression of AD risk genes (e.g., Apoe, Trem2, Cd33, and Mmp12), as well as previously established causal regulators of the immune/microglia network in late-onset AD (e.g., Tyrobp, Dock, and Fcerg1), leading to chronic AD-like neuroinflammation and mild cognitive impairment. Notably, neuroinflammation and mild cognitive impairment showed gender differences, being more pronounced in females than males. Subsequent mechanistic studies demonstrated that although CNS sulfatide losses led to ApoE upregulation, genetically-induced myelin sulfatide deficiency led to neuroinflammation independently of ApoE. These results, together with our previous studies (sulfatide deficiency in the context of AD is mediated by ApoE and accelerated by Aß accumulation) placed both Aß and ApoE upstream of sulfatide deficiency-induced neuroinflammation, and suggested a positive feedback loop where sulfatide losses may be amplified by increased ApoE expression. We also demonstrated that CNS sulfatide deficiency-induced astrogliosis and ApoE upregulation are not secondary to microgliosis, and that astrogliosis and microgliosis seem to be driven by activation of STAT3 and PU.1/Spi1 transcription factors, respectively. CONCLUSION: Our results strongly suggest that sulfatide deficiency is an important contributor and driver of neuroinflammation and mild cognitive impairment in AD pathology.


Asunto(s)
Disfunción Cognitiva/metabolismo , Modelos Animales de Enfermedad , Trastornos de la Memoria/metabolismo , Vaina de Mielina/química , Enfermedades Neuroinflamatorias/metabolismo , Sulfoglicoesfingolípidos/metabolismo , Edad de Inicio , Enfermedad de Alzheimer/etiología , Aminopiridinas/toxicidad , Animales , Apolipoproteínas E/metabolismo , Química Encefálica , Sistema Nervioso Central/metabolismo , Disfunción Cognitiva/etiología , Perfilación de la Expresión Génica , Gliosis/metabolismo , Humanos , Trastornos de la Memoria/etiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Noqueados para ApoE , Prueba del Laberinto Acuático de Morris , Neuroglía/enzimología , Neuroglía/fisiología , Enfermedades Neuroinflamatorias/etiología , Prueba de Campo Abierto , Proteínas Proto-Oncogénicas/fisiología , Pirroles/toxicidad , Factor de Transcripción STAT3/fisiología , Sulfoglicoesfingolípidos/análisis , Sulfotransferasas/deficiencia , Transactivadores/fisiología
14.
Alcohol Clin Exp Res ; 34(12): 2070-80, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20860615

RESUMEN

BACKGROUND: Adolescent rats are less sensitive to the motor-impairing effects of ethanol than adults. However, the cellular and molecular mechanisms underlying this age-dependent effect of ethanol have yet to be fully elucidated. METHOD: Male rats of various ages were used to investigate ethanol-induced ataxia and its underlying cellular correlates. In addition, Purkinje neurons from adolescent and adult rats were recorded both in vivo and in vitro. Finally, protein kinase C (PKCγ) expression was determined in 3 brain regions in both adolescent and adult rats. RESULTS: The present multi-methodological investigation confirms that adolescents are less sensitive to the motor-impairing effects of ethanol, and this differential effect is not because of differential blood ethanol levels. In addition, we identify a particular cellular correlate that may underlie the reduced motor impairment. Specifically, the in vivo firing rate of cerebellar Purkinje neurons recorded from adolescent rats was insensitive to an acute ethanol challenge, while the firing rate of adult cerebellar Purkinje neurons was significantly depressed. Finally, it is demonstrated that PKCγ expression in the cortex and cerebellum mirrors the age-dependent effect of ethanol: adolescents have significantly less PKCγ expression compared to adults. CONCLUSIONS: Adolescents are less sensitive than adults to the motor-impairing effects of ethanol, and a similar effect is seen with in vivo electrophysiological recordings of cerebellar Purkinje neurons. While still under investigation, PKCγ expression mirrors the age effect of ethanol and may contribute to the age-dependent differences in the ataxic effects of ethanol.


Asunto(s)
Potenciales de Acción/efectos de los fármacos , Cerebelo/efectos de los fármacos , Etanol/farmacología , Potenciales de la Membrana/efectos de los fármacos , Proteína Quinasa C/metabolismo , Potenciales de Acción/fisiología , Factores de Edad , Animales , Ataxia/inducido químicamente , Cerebelo/metabolismo , Cerebelo/fisiología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Etanol/sangre , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Potenciales de la Membrana/fisiología , Células de Purkinje/fisiología , Ratas , Ratas Sprague-Dawley
15.
Aging Cell ; 19(1): e13057, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31693798

RESUMEN

Cerebrovascular dysfunction and cognitive decline are highly prevalent in aging, but the mechanisms underlying these impairments are unclear. Cerebral blood flow decreases with aging and is one of the earliest events in the pathogenesis of Alzheimer's disease (AD). We have previously shown that the mechanistic/mammalian target of rapamycin (mTOR) drives disease progression in mouse models of AD and in models of cognitive impairment associated with atherosclerosis, closely recapitulating vascular cognitive impairment. In the present studies, we sought to determine whether mTOR plays a role in cerebrovascular dysfunction and cognitive decline during normative aging in rats. Using behavioral tools and MRI-based functional imaging, together with biochemical and immunohistochemical approaches, we demonstrate that chronic mTOR attenuation with rapamycin ameliorates deficits in learning and memory, prevents neurovascular uncoupling, and restores cerebral perfusion in aged rats. Additionally, morphometric and biochemical analyses of hippocampus and cortex revealed that mTOR drives age-related declines in synaptic and vascular density during aging. These data indicate that in addition to mediating AD-like cognitive and cerebrovascular deficits in models of AD and atherosclerosis, mTOR drives cerebrovascular, neuronal, and cognitive deficits associated with normative aging. Thus, inhibitors of mTOR may have potential to treat age-related cerebrovascular dysfunction and cognitive decline. Since treatment of age-related cerebrovascular dysfunction in older adults is expected to prevent further deterioration of cerebral perfusion, recently identified as a biomarker for the very early (preclinical) stages of AD, mTOR attenuation may potentially block the initiation and progression of AD.


Asunto(s)
Envejecimiento/genética , Circulación Cerebrovascular/fisiología , Disfunción Cognitiva/fisiopatología , Serina-Treonina Quinasas TOR/genética , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratas
16.
Alcohol ; 79: 105-125, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-30981807

RESUMEN

Addiction has been conceptualized as a specific form of memory that appropriates typically adaptive neural mechanisms of learning to produce the progressive spiral of drug-seeking and drug-taking behavior, perpetuating the path to addiction through aberrant processes of drug-related learning and memory. From that perspective, to understand the development of alcohol use disorders, it is critical to identify how a single exposure to alcohol enters into or alters the processes of learning and memory, so that involvement of and changes in neuroplasticity processes responsible for learning and memory can be identified early. This review characterizes the effects produced by acute alcohol intoxication as a function of brain region and memory neurocircuitry. In general, exposure to ethanol doses that produce intoxicating effects causes consistent impairments in learning and memory processes mediated by specific brain circuitry, whereas lower doses either have no effect or produce a facilitation of memory under certain task conditions. Therefore, acute ethanol does not produce a global impairment of learning and memory, and can actually facilitate particular types of memory, perhaps particular types of memory that facilitate the development of excessive alcohol use. In addition, the effects on cognition are dependent on brain region, task demands, dose received, pharmacokinetics, and tolerance. Additionally, we explore the underlying alterations in neurophysiology produced by acute alcohol exposure that help to explain these changes in cognition and highlight future directions for research. Through understanding the impact that acute alcohol intoxication has on cognition, the preliminary changes potentially causing a problematic addiction memory can better be identified.


Asunto(s)
Intoxicación Alcohólica/fisiopatología , Encéfalo/efectos de los fármacos , Cognición/efectos de los fármacos , Etanol/farmacología , Aprendizaje/efectos de los fármacos , Memoria/efectos de los fármacos , Trastornos Relacionados con Alcohol/fisiopatología , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/fisiología , Animales , Conducta Adictiva/psicología , Cerebelo/efectos de los fármacos , Cerebelo/fisiología , Señales (Psicología) , Etanol/farmacocinética , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Humanos , Recuerdo Mental/efectos de los fármacos , Ratones , Plasticidad Neuronal/efectos de los fármacos
17.
J Cereb Blood Flow Metab ; 38(1): 58-74, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-28511572

RESUMEN

We recently showed that mTOR attenuation blocks progression and abrogates established cognitive deficits in Alzheimer's disease (AD) mouse models. These outcomes were associated with the restoration of cerebral blood flow (CBF) and brain vascular density (BVD) resulting from relief of mTOR inhibition of NO release. Recent reports suggested a role of mTOR in atherosclerosis. Because mTOR drives aging and vascular dysfunction is a universal feature of aging, we hypothesized that mTOR may contribute to brain vascular and cognitive dysfunction associated with atherosclerosis. We measured CBF, BVD, cognitive function, markers of inflammation, and parameters of cardiovascular disease in LDLR-/- mice fed maintenance or high-fat diet ± rapamycin. Cardiovascular pathologies were proportional to severity of brain vascular dysfunction. Aortic atheromas were reduced, CBF and BVD were restored, and cognitive dysfunction was attenuated potentially through reduction in systemic and brain inflammation following chronic mTOR attenuation. Our studies suggest that mTOR regulates vascular integrity and function and that mTOR attenuation may restore neurovascular function and cardiovascular health. Together with our previous studies in AD models, our data suggest mTOR-driven vascular damage may be a mechanism shared by age-associated neurological diseases. Therefore, mTOR attenuation may have promise for treatment of cognitive impairment in atherosclerosis.


Asunto(s)
Aterosclerosis/metabolismo , Circulación Cerebrovascular/fisiología , Disfunción Cognitiva/metabolismo , Demencia Vascular/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Animales , Aterosclerosis/complicaciones , Disfunción Cognitiva/etiología , Demencia Vascular/etiología , Modelos Animales de Enfermedad , Ratones , Ratones Noqueados , Receptores de LDL/deficiencia
18.
Alcohol ; 61: 33-42, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28479015

RESUMEN

Understanding how alcohol exposure during adolescence affects aging is a critical but understudied area. In the present study, male rats were exposed to either alcohol or saline during adolescence, then tested every 4 months following either an ethanol or saline challenge; animals were tested until postnatal day (PD) 532. It was found that long-lasting tolerance to high-dose ethanol exists through the test period, as measured by loss of righting reflex, while tolerance to lower doses of ethanol is not found. In addition, alcohol exposure during adolescence facilitated spatial memory impairments to acute ethanol challenges later in life. The current work demonstrates that exposure to ethanol during adolescent development can produce long-lasting detrimental impairments.


Asunto(s)
Tolerancia a Medicamentos/fisiología , Etanol/administración & dosificación , Trastornos de la Memoria/inducido químicamente , Memoria Espacial/efectos de los fármacos , Consumo de Alcohol en Menores , Adolescente , Animales , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Ratas , Ratas Sprague-Dawley , Reflejo de Enderezamiento/efectos de los fármacos , Reflejo de Enderezamiento/fisiología
19.
Aging Dis ; 8(3): 257-266, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28580182

RESUMEN

The importance of vascular contributions to cognitive impairment and dementia (VCID) associated with Alzheimer's disease (AD) and related neurodegenerative diseases is increasingly recognized, however, the underlying mechanisms remain obscure. There is growing evidence that in addition to Aß deposition, accumulation of hyperphosphorylated oligomeric tau contributes significantly to AD etiology. Tau oligomers are toxic and it has been suggested that they propagate in a "prion-like" fashion, inducing endogenous tau misfolding in cells. Their role in VCID, however, is not yet understood. The present study was designed to determine the severity of vascular deposition of oligomeric tau in the brain in patients with AD and related tauopathies, including dementia with Lewy bodies (DLB) and progressive supranuclear palsy (PSP). Further, we examined a potential link between vascular deposition of fibrillar Aß and that of tau oligomers in the Tg2576 mouse model. We found that tau oligomers accumulate in cerebral microvasculature of human patients with AD and PSP, in association with vascular endothelial and smooth muscle cells. Cerebrovascular deposition of tau oligomers was also found in DLB patients. We also show that tau oligomers accumulate in cerebral microvasculature of Tg2576 mice, partially in association with cerebrovascular Aß deposits. Thus, our findings add to the growing evidence for multifaceted microvascular involvement in the pathogenesis of AD and other neurodegenerative diseases. Accumulation of tau oligomers may represent a potential novel mechanism by which functional and structural integrity of the cerebral microvessels is compromised.

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