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1.
BMC Neurol ; 24(1): 127, 2024 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-38627686

RESUMEN

BACKGROUND: Dementia prevalence is predicted to triple to 152 million globally by 2050. Alzheimer's disease (AD) constitutes 70% of cases. There is an urgent need to identify individuals with preclinical AD, a 10-20-year period of progressive brain pathology without noticeable cognitive symptoms, for targeted risk reduction. Current tests of AD pathology are either too invasive, specialised or expensive for population-level assessments. Cognitive tests are normal in preclinical AD. Emerging evidence demonstrates that movement analysis is sensitive to AD across the disease continuum, including preclinical AD. Our new smartphone test, TapTalk, combines analysis of hand and speech-like movements to detect AD risk. This study aims to [1] determine which combinations of hand-speech movement data most accurately predict preclinical AD [2], determine usability, reliability, and validity of TapTalk in cognitively asymptomatic older adults and [3], prospectively validate TapTalk in older adults who have cognitive symptoms against cognitive tests and clinical diagnoses of Mild Cognitive Impairment and AD dementia. METHODS: Aim 1 will be addressed in a cross-sectional study of at least 500 cognitively asymptomatic older adults who will complete computerised tests comprising measures of hand motor control (finger tapping) and oro-motor control (syllabic diadochokinesis). So far, 1382 adults, mean (SD) age 66.20 (7.65) years, range 50-92 (72.07% female) have been recruited. Motor measures will be compared to a blood-based AD biomarker, phosphorylated tau 181 to develop an algorithm that classifies preclinical AD risk. Aim 2 comprises three sub-studies in cognitively asymptomatic adults: (i) a cross-sectional study of 30-40 adults to determine the validity of data collection from different types of smartphones, (ii) a prospective cohort study of 50-100 adults ≥ 50 years old to determine usability and test-retest reliability, and (iii) a prospective cohort study of ~1,000 adults ≥ 50 years old to validate against cognitive measures. Aim 3 will be addressed in a cross-sectional study of ~200 participants with cognitive symptoms to validate TapTalk against Montreal Cognitive Assessment and interdisciplinary consensus diagnosis. DISCUSSION: This study will establish the precision of TapTalk to identify preclinical AD and estimate risk of cognitive decline. If accurate, this innovative smartphone app will enable low-cost, accessible screening of individuals for AD risk. This will have wide applications in public health initiatives and clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06114914, 29 October 2023. Retrospectively registered.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Femenino , Anciano , Persona de Mediana Edad , Anciano de 80 o más Años , Masculino , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/psicología , Teléfono Inteligente , Estudios Prospectivos , Estudios Transversales , Reproducibilidad de los Resultados , Disfunción Cognitiva/diagnóstico , Biomarcadores , Péptidos beta-Amiloides
2.
Alzheimers Dement ; 20(6): 4260-4289, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38687209

RESUMEN

Experimental laboratory research has an important role to play in dementia prevention. Mechanisms underlying modifiable risk factors for dementia are promising targets for dementia prevention but are difficult to investigate in human populations due to technological constraints and confounds. Therefore, controlled laboratory experiments in models such as transgenic rodents, invertebrates and in vitro cultured cells are increasingly used to investigate dementia risk factors and test strategies which target them to prevent dementia. This review provides an overview of experimental research into 15 established and putative modifiable dementia risk factors: less early-life education, hearing loss, depression, social isolation, life stress, hypertension, obesity, diabetes, physical inactivity, heavy alcohol use, smoking, air pollution, anesthetic exposure, traumatic brain injury, and disordered sleep. It explores how experimental models have been, and can be, used to address questions about modifiable dementia risk and prevention that cannot readily be addressed in human studies. HIGHLIGHTS: Modifiable dementia risk factors are promising targets for dementia prevention. Interrogation of mechanisms underlying dementia risk is difficult in human populations. Studies using diverse experimental models are revealing modifiable dementia risk mechanisms. We review experimental research into 15 modifiable dementia risk factors. Laboratory science can contribute uniquely to dementia prevention.


Asunto(s)
Demencia , Demencia/prevención & control , Humanos , Animales , Factores de Riesgo , Modelos Animales de Enfermedad
3.
Glia ; 71(4): 880-903, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36468604

RESUMEN

Traumatic brain injury (TBI) triggers neuroinflammatory cascades mediated by microglia, which promotes tissue repair in the short-term. These cascades may exacerbate TBI-induced tissue damage and symptoms in the months to years post-injury. However, the progression of the microglial function across time post-injury and whether this differs between biological sexes is not well understood. In this study, we examined the microglial proteome at 3-, 7-, or 28-days after a midline fluid percussion injury (mFPI) in male and female mice using label-free quantitative proteomics. Data are available via ProteomeXchange with identifier PXD033628. We identified a reduction in microglial proteins involved with clearance of neuronal debris via phagocytosis at 3- and 7-days post-injury. At 28 days post-injury, pro-inflammatory proteins were decreased and anti-inflammatory proteins were increased in microglia. These results indicate a reduction in microglial clearance of neuronal debris in the days post-injury with a shift to anti-inflammatory function by 28 days following TBI. The changes in the microglial proteome that occurred across time post-injury did not differ between biological sexes. However, we did identify an increase in microglial proteins related to pro-inflammation and phagocytosis as well as insulin and estrogen signaling in males compared with female mice that occurred with or without a brain injury. Although the microglial response was similar between males and females up to 28 days following TBI, biological sex differences in the microglial proteome, regardless of TBI, has implications for the efficacy of treatment strategies targeting the microglial response post-injury.


Asunto(s)
Traumatismos Difusos del Encéfalo , Lesiones Traumáticas del Encéfalo , Lesiones Encefálicas , Femenino , Ratones , Masculino , Animales , Microglía/metabolismo , Proteoma/metabolismo , Proteómica , Traumatismos Difusos del Encéfalo/metabolismo , Lesiones Encefálicas/metabolismo , Lesiones Traumáticas del Encéfalo/metabolismo , Ratones Endogámicos C57BL
4.
Glia ; 71(8): 1847-1869, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-36994950

RESUMEN

Cerebral blood flow (CBF) is important for the maintenance of brain function and its dysregulation has been implicated in Alzheimer's disease (AD). Microglia associations with capillaries suggest they may play a role in the regulation of CBF or the blood-brain-barrier (BBB). We explored the relationship between microglia and pericytes, a vessel-resident cell type that has a major role in the control of CBF and maintenance of the BBB, discovering a spatially distinct subset of microglia that closely associate with pericytes. We termed these pericyte-associated microglia (PEM). PEM are present throughout the brain and spinal cord in NG2DsRed × CX3 CR1+/GFP mice, and in the human frontal cortex. Using in vivo two-photon microscopy, we found microglia residing adjacent to pericytes at all levels of the capillary tree and found they can maintain their position for at least 28 days. PEM can associate with pericytes lacking astroglial endfeet coverage and capillary vessel width is increased beneath pericytes with or without an associated PEM, but capillary width decreases if a pericyte loses a PEM. Deletion of the microglia fractalkine receptor (CX3 CR1) did not disrupt the association between pericytes and PEM. Finally, we found the proportion of microglia that are PEM declines in the superior frontal gyrus in AD. In summary, we identify microglia that specifically associate with pericytes and find these are reduced in number in AD, which may be a novel mechanism contributing to vascular dysfunction in neurodegenerative diseases.


Asunto(s)
Enfermedad de Alzheimer , Pericitos , Ratones , Humanos , Animales , Pericitos/metabolismo , Ratones Transgénicos , Microglía , Encéfalo/metabolismo , Barrera Hematoencefálica/metabolismo , Enfermedad de Alzheimer/metabolismo
5.
J Sleep Res ; : e14109, 2023 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-38014898

RESUMEN

Isolated rapid eye movement (REM) sleep behaviour disorder (iRBD) is a sleep disorder that is characterised by dream enactment episodes during REM sleep. It is the strongest known predictor of α-synuclein-related neurodegenerative disease (αNDD), such that >80% of people with iRBD will eventually develop Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy in later life. More research is needed to understand the trajectory of phenoconversion to each αNDD. Only five 'gold standard' prevalence studies of iRBD in older adults have been undertaken previously, with estimates ranging from 0.74% to 2.01%. The diagnostic recommendations for video-polysomnography (vPSG) to confirm iRBD makes prevalence studies challenging, as vPSG is often unavailable to large cohorts. In Australia, there have been no iRBD prevalence studies, and little is known about the cognitive and motor profiles of Australian people with iRBD. The Island Study Linking Ageing and Neurodegenerative Disease (ISLAND) Sleep Study will investigate the prevalence of iRBD in Tasmania, an island state of Australia, using validated questionnaires and home-based vPSG. It will also explore several cognitive, motor, olfactory, autonomic, visual, tactile, and sleep profiles in people with iRBD to better understand which characteristics influence the progression of iRBD to αNDD. This paper details the ISLAND Sleep Study protocol and presents preliminary baseline results.

6.
BMC Public Health ; 23(1): 1886, 2023 09 29.
Artículo en Inglés | MEDLINE | ID: mdl-37773122

RESUMEN

BACKGROUND: Unmanaged cardiometabolic health, low physical and cognitive activity, poor diet, obesity, smoking and excessive alcohol consumption are modifiable health risk factors for dementia and public health approaches to dementia prevention have been called for. The Island Study Linking Ageing and Neurodegenerative Disease (ISLAND) is a dementia prevention public health study examining whether improving knowledge about modifiable dementia risk factors supports behaviour changes that reduce future dementia risk. METHODS: Residents of Tasmania, Australia, aged 50 + years who joined the 10-year ISLAND study were asked to complete annual online surveys about their knowledge, motivations and behaviours related to modifiable dementia risk. ISLAND included two knowledge-based interventions: a personalised Dementia Risk Profile (DRP) report based on survey responses, and the option to do a 4-week Preventing Dementia Massive Open Online Course (PDMOOC). Longitudinal regression models assessed changes in the number and type of risk factors, with effects moderated by exposures to the DRP report and engagement with the PDMOOC. Knowledge and motivational factors related to dementia risk were examined as mediators of risk behaviour change. RESULTS: Data collected between October 2019 and October 2022 (n = 3038, av. 63.7 years, 71.6% female) showed the mean number of modifiable dementia risk factors per participant (range 0 to 9) reduced from 2.17 (SD 1.24) to 1.66 (SD 1.11). This change was associated with the number of exposures to the DRP report (p = .042) and was stronger for PDMOOC participants (p = .001). The interaction between DRP and PDMOOC exposures yielded a significant improvement in risk scores (p = .004). The effect of PDMOOC engagement on behaviour change was partly mediated by increased knowledge (12%, p = .013). Self-efficacy enhanced the effect of knowledge on behaviour change, while perceived susceptibility to dementia mitigated this relationship. CONCLUSIONS: The ISLAND framework and interventions, a personalised DRP report and the four-week PDMOOC, work independently and synergistically to increase dementia risk knowledge and stimulate health behaviour change for dementia risk reduction. ISLAND offers a feasible and scalable public health approach for redressing the rising prevalence of dementia.


Asunto(s)
Demencia , Enfermedades Neurodegenerativas , Humanos , Femenino , Masculino , Salud Pública , Conductas Relacionadas con la Salud , Demencia/epidemiología , Demencia/prevención & control , Envejecimiento
7.
Int J Mol Sci ; 24(2)2023 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-36675282

RESUMEN

Neurodegenerative diseases present a progressive loss of neuronal structure and function, leading to cell death and irrecoverable brain atrophy. Most have disease-modifying therapies, in part because the mechanisms of neurodegeneration are yet to be defined, preventing the development of targeted therapies. To overcome this, there is a need for tools that enable a quantitative assessment of how cellular mechanisms and diverse environmental conditions contribute to disease. One such tool is genetically encodable fluorescent biosensors (GEFBs), engineered constructs encoding proteins with novel functions capable of sensing spatiotemporal changes in specific pathways, enzyme functions, or metabolite levels. GEFB technology therefore presents a plethora of unique sensing capabilities that, when coupled with induced pluripotent stem cells (iPSCs), present a powerful tool for exploring disease mechanisms and identifying novel therapeutics. In this review, we discuss different GEFBs relevant to neurodegenerative disease and how they can be used with iPSCs to illuminate unresolved questions about causes and risks for neurodegenerative disease.


Asunto(s)
Técnicas Biosensibles , Células Madre Pluripotentes Inducidas , Enfermedades Neurodegenerativas , Humanos , Enfermedades Neurodegenerativas/metabolismo , Neuronas , Colorantes/metabolismo
8.
Neurobiol Dis ; 172: 105821, 2022 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-35863521

RESUMEN

The mechanisms underlying the loss of motor neuron axon integrity in amyotrophic lateral sclerosis (ALS) are unclear. SARM1 has been identified as a genetic risk variant in sporadic ALS, and the SARM1 protein is a key mediator of axon degeneration. To investigate the role of SARM1 in ALS-associated axon degeneration, we knocked out Sarm1 (Sarm1KO) in mSOD1G93ATg (mSOD1) mice. Animals were monitored for ALS disease onset and severity, with motor function assessed at pre-symptomatic and late-stage disease and lumbar spinal cord and sciatic nerve harvested for immunohistochemistry at endpoint (20 weeks). Serum was collected monthly to assess protein concentrations of biomarkers linked to axon degeneration (neurofilament light (NFL) and tau), and astrogliosis (glial fibrillary acidic protein (GFAP)), using single molecule array (Simoa®) technology. Overall, loss of Sarm1 in mSOD1 mice did not slow or delay symptom onset, failed to improve functional declines, and failed to protect motor neurons. Serum NFL levels in mSOD1 mice increased between 8 -12 and 16-20 weeks of age, with the later increase significantly reduced by loss of SARM1. Similarly, loss of SARM1 significantly reduced an increase in serum GFAP between 16 and 20 weeks of age in mSOD1 mice, indicating protection of both global axon degeneration and astrogliosis. In the spinal cord, Sarm1 deletion protected against loss of excitatory VGluT2-positive puncta and attenuated astrogliosis in mSOD1 mice. In the sciatic nerve, absence of SARM1 in mSOD1 mice restored the average area of phosphorylated neurofilament reactivity towards WT levels. Together these data suggest that Sarm1KO in mSOD1 mice is not sufficient to ameliorate functional decline or motor neuron loss but does alter serum biomarker levels and provide protection to axons and glutamatergic synapses. This indicates that treatments targeting SARM1 could warrant further investigation in ALS, potentially as part of a combination therapy.


Asunto(s)
Esclerosis Amiotrófica Lateral , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Proteínas del Dominio Armadillo/genética , Proteínas del Dominio Armadillo/metabolismo , Biomarcadores/metabolismo , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Gliosis/metabolismo , Ratones , Ratones Transgénicos , Médula Espinal/metabolismo , Superóxido Dismutasa/genética
9.
BMC Neurol ; 22(1): 266, 2022 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-35850660

RESUMEN

BACKGROUND: The worldwide prevalence of dementia is rapidly rising. Alzheimer's disease (AD), accounts for 70% of cases and has a 10-20-year preclinical period, when brain pathology covertly progresses before cognitive symptoms appear. The 2020 Lancet Commission estimates that 40% of dementia cases could be prevented by modifying lifestyle/medical risk factors. To optimise dementia prevention effectiveness, there is urgent need to identify individuals with preclinical AD for targeted risk reduction. Current preclinical AD tests are too invasive, specialist or costly for population-level assessments. We have developed a new online test, TAS Test, that assesses a range of motor-cognitive functions and has capacity to be delivered at significant scale. TAS Test combines two innovations: using hand movement analysis to detect preclinical AD, and computer-human interface technologies to enable robust 'self-testing' data collection. The aims are to validate TAS Test to [1] identify preclinical AD, and [2] predict risk of cognitive decline and AD dementia. METHODS: Aim 1 will be addressed through a cross-sectional study of 500 cognitively healthy older adults, who will complete TAS Test items comprising measures of motor control, processing speed, attention, visuospatial ability, memory and language. TAS Test measures will be compared to a blood-based AD biomarker, phosphorylated tau 181 (p-tau181). Aim 2 will be addressed through a 5-year prospective cohort study of 10,000 older adults. Participants will complete TAS Test annually and subtests of the Cambridge Neuropsychological Test Battery (CANTAB) biennially. 300 participants will undergo in-person clinical assessments. We will use machine learning of motor-cognitive performance on TAS Test to develop an algorithm that classifies preclinical AD risk (p-tau181-defined) and determine the precision to prospectively estimate 5-year risks of cognitive decline and AD. DISCUSSION: This study will establish the precision of TAS Test to identify preclinical AD and estimate risk of cognitive decline and AD. If accurate, TAS Test will provide a low-cost, accessible enrichment strategy to pre-screen individuals for their likelihood of AD pathology prior to more expensive tests such as blood or imaging biomarkers. This would have wide applications in public health initiatives and clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05194787 , 18 January 2022. Retrospectively registered.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Anciano , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides , Biomarcadores , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/psicología , Estudios Transversales , Humanos , Pruebas Neuropsicológicas , Estudios Prospectivos , Proteínas tau
10.
Mol Cell Neurosci ; 114: 103627, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34015498

RESUMEN

TDP-43 is pathologically and genetically with associated amyotrophic lateral sclerosis and frontotemporal lobar degeneration. These diseases are characterized by significant neurite defects, including cytoskeletal pathology. The involvement of TDP-43 in the degeneration of neurons in these diseases are not yet well understood, however accumulating evidence shows involvement in neurite outgrowth, remodelling and in regulation of many components of the neuronal cytoskeleton. In order to investigate how alterations to TDP-43 expression levels may exert effects on the neuronal cytoskeleton, primary cortical neurons from transgenic mice overexpressing one or two copies of human wildtype TDP-43 under the prion promoter were examined. Label-free quantitative proteomic analysis, followed by functional annotation clustering to identify protein families that clustered together within up- or down-regulated protein groups, revealed that actin-binding proteins were significantly more abundant in neurons overexpressing TDP-43 compared to wildtype neurons. Morphological analysis demonstrated that during early development neurons expressing one copy of human TDP-43 had an increased number of neurite branches and alterations to growth cone morphology, while no changes were observed in neurons expressing two copies of TDP-43. These developmental processes require specific expression and organization of the cytoskeleton. The results from these studies provide further insight into the normal function of TDP-43 and how alterations in TDP-43 expression may impact the cytoskeleton.


Asunto(s)
Corteza Cerebral/metabolismo , Proteínas de Unión al ADN/genética , Proyección Neuronal/genética , Neuronas/metabolismo , Proteoma/genética , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Forma de la Célula/fisiología , Citoesqueleto/genética , Citoesqueleto/metabolismo , Proteínas de Unión al ADN/metabolismo , Degeneración Lobar Frontotemporal/genética , Degeneración Lobar Frontotemporal/metabolismo , Ratones , Ratones Transgénicos , Neuritas/metabolismo , Proteoma/metabolismo
11.
Semin Cell Dev Biol ; 94: 96-103, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-30826549

RESUMEN

The striking morphology of microglia is one of their most prominent characteristics, with many studies categorising microglial function based on morphology e.g. ramified, hyper-ramified, activated, or amoeboid. Communications regarding rod microglia in neurological disease are scant, and where reported, these cells are rarely the focus of discussion. These factors make it difficult to determine how widespread these cells are not only through the brain but also across diseases. Studies in experimental diffuse brain injury are the first reports of not only significant numbers of rod microglia, but distinct arrangements of these cells, reminiscent of carriages of a train. This review summarises the available reports of rod microglia in vivo and rod-like microglia in vitro and eludes to possible functions and signalling cascades that may evoke this distinct morphology. More investigations are required to fully elucidate the function that rod microglia play in neurological diseases.


Asunto(s)
Microglía/metabolismo , Enfermedades del Sistema Nervioso/metabolismo , Animales , Humanos , Microglía/patología , Enfermedades del Sistema Nervioso/patología
12.
J Neurochem ; 152(5): 542-555, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31705657

RESUMEN

Axon degeneration and axonal loss is a feature of neurodegenerative disease and injury and occurs via programmed pathways that are distinct from cell death pathways. While the pathways of axonal loss following axon severing are well described, less is known about axonal loss following other neurodegenerative insults. Here we use primary mouse cortical neuron cultures grown in compartmentalized chambers to investigate the role of calcium in the degeneration of axons that occurs following a somal insult by the excitotoxin kainic acid. Calcium influx has been implicated in both excitotoxicity and axon degeneration mechanisms, however the link between a somal insult and axonal calcium increase is unclear. Live imaging of axons demonstrated that pharmacologically preventing intracellular calcium increases through the endoplasmic reticulum or mitochondria significantly (p < 0.05) reduced axon degeneration. Live calcium-imaging with the Ca2+ indicator Fluo-4 demonstrated that kainic acid exposure to the soma resulted in a rapid, and transient, increase in calcium in the axon, which occured even at low kainic acid concentrations that do not cause axon degeneration within 24 h. However, this calcium transient was followed by a gradual increase in axonal calcium, which was associated with axonal loss. Furthermore, treatment with a range of doses of the microtubule stabilizing drug taxol, which protects against axon fragmentation in this model, prevented this gradual calcium increase, suggesting that the intra-axonal calcium changes are downstream of microtubule associated events. Biochemical analysis of taxol treated neurons demonstrated a shift in microtubule post-translational modifications, with a significant (p < 0.05) increase in acetylated tubulin and a significant (p < 0.05) decrease in tyrosinated tubulin, suggestive of a more stable microtubule pool. Together our results suggest that axonal degeneration following excitotoxicity is dependent on an increase in axonal calcium, which is downstream of a microtubule-dependent event.


Asunto(s)
Axones/metabolismo , Calcio/metabolismo , Microtúbulos/metabolismo , Degeneración Nerviosa/metabolismo , Animales , Axones/efectos de los fármacos , Axones/patología , Células Cultivadas , Agonistas de Aminoácidos Excitadores/toxicidad , Ácido Kaínico/toxicidad , Ratones , Ratones Endogámicos C57BL , Microtúbulos/efectos de los fármacos , Degeneración Nerviosa/inducido químicamente , Degeneración Nerviosa/patología
13.
Angiogenesis ; 21(1): 95-109, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29318471

RESUMEN

Ocular neovascularization is a common pathological feature in diabetic retinopathy and neovascular age-related macular degeneration that can lead to severe vision loss. We evaluated the therapeutic efficacy of a novel endogenous inhibitor of angiogenesis, the calreticulin anti-angiogenic domain (CAD180), and its functional 112-residue fragment, CAD-like peptide 112 (CAD112), delivered using a self-complementary adeno-associated virus serotype 2 (scAAV2) in rodent models of oxygen-induced retinopathy and laser-induced choroidal neovascularization. The expression of CAD180 and CAD112 was elevated in human umbilical vein endothelial cells transduced with scAAV2-CAD180 or scAAV2-CAD112, respectively, and both inhibited angiogenic activity in vitro. Intravitreal gene delivery of scAAV2-CAD180 or scAAV2-CAD112 significantly inhibited ischemia-induced retinal neovascularization in rat eyes (CAD180: 52.7% reduction; CAD112: 49.2% reduction) compared to scAAV2-mCherry, as measured in retinal flatmounts stained with isolectin B4. Moreover, the retinal structure and function were unaffected by scAAV2-CAD180 or scAAV2-CAD112, as measured by optical coherence tomography and electroretinography. Moreover, subretinal delivery of scAAV2-CAD180 or scAAV2-CAD112 significantly attenuated laser-induced choroidal neovascularization in mouse eyes compared to scAAV2-mCherry, as measured by fundus fluorescein angiography (CAD180: 62.4% reduction; CAD112: 57.5% reduction) and choroidal flatmounts (CAD180: 40.21% reduction; CAD112: 43.03% reduction). Gene delivery using scAAV2-CAD180 or scAAV2-CAD112 has significant potential as a therapeutic option for the management of ocular neovascularization.


Asunto(s)
Inhibidores de la Angiogénesis/biosíntesis , Calreticulina , Dependovirus , Retinopatía Diabética , Neovascularización Retiniana , Transducción Genética , Inhibidores de la Angiogénesis/genética , Angiografía , Animales , Calreticulina/biosíntesis , Calreticulina/genética , Retinopatía Diabética/diagnóstico por imagen , Retinopatía Diabética/genética , Retinopatía Diabética/metabolismo , Retinopatía Diabética/fisiopatología , Electrorretinografía , Femenino , Vectores Genéticos , Células HEK293 , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Proteínas Luminiscentes/biosíntesis , Proteínas Luminiscentes/genética , Degeneración Macular/diagnóstico por imagen , Degeneración Macular/genética , Degeneración Macular/metabolismo , Degeneración Macular/fisiopatología , Ratones , Ratas , Ratas Sprague-Dawley , Neovascularización Retiniana/diagnóstico por imagen , Neovascularización Retiniana/genética , Neovascularización Retiniana/metabolismo , Neovascularización Retiniana/fisiopatología , Tomografía de Coherencia Óptica , Proteína Fluorescente Roja
14.
J Neuroinflammation ; 15(1): 56, 2018 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-29471847

RESUMEN

BACKGROUND: The extracellular environment plays an important role in supporting the regeneration of axons after injury. Metallothionein-II (MTII) is a metal-binding protein known for its neuroprotective effect by directly stimulating the growth of axons after injury. Previous studies have shown that MTII also modulates the response of astrocytes and microglia after injury. However, a detailed analysis describing how MTII modulates the interaction between microglia and neurons is lacking. METHODS: We introduced fluorescently labelled MTII into the cortex at the time of needlestick injury to investigate the cellular uptake of MTII using immunohistochemistry with antibodies against cell-type-specific markers. The role of MTII in modulating the effect of microglia on axon outgrowth following an inflammatory response is further investigated using a co-culture model involving primary rodent microglia pre-treated with TNFα and primary rodent cortical neurons. The axon lengths were assessed 24 h after the plating of the neurons onto treated microglia. We also utilised siRNA to knockdown the expression of LRP1, which allows us to investigate the role of LRP1 receptors in the MTII-mediated effect of microglia on axon outgrowth. RESULTS: Fluorescently labelled MTII was found to be associated with neurons, astrocytes and microglia following injury in vivo. Microglia-neuron co-culture experiments demonstrated that exogenous MTII altered the response of microglia to TNFα. The neurons plated onto the TNFα-stimulated microglia pre-treated with MTII have shown a significantly longer axonal length compare to the TNFα-stimulated microglia without the MTII treatment. This suggested that MTII reduce cytokine-stimulated activation of microglia, which would ordinarily impair neurite outgrowth. This inhibitory effect of MTII on activated microglia was blocked by siRNA-mediated downregulation of LRP1 receptor expression in microglia, suggesting that MTII acts via the LRP1 receptor on microglia. CONCLUSIONS: This study demonstrates that exogenous MTII acts via the LRP1 receptor to alter the inflammatory response of microglia following TNFα stimulation, providing a more supportive environment for axon growth.


Asunto(s)
Corteza Cerebral/metabolismo , Metalotioneína/metabolismo , Microglía/metabolismo , Regeneración Nerviosa/fisiología , Neuronas/metabolismo , Factor de Necrosis Tumoral alfa/toxicidad , Animales , Animales Recién Nacidos , Células Cultivadas , Corteza Cerebral/efectos de los fármacos , Técnicas de Cocultivo , Metalotioneína/farmacología , Microglía/efectos de los fármacos , Regeneración Nerviosa/efectos de los fármacos , Neuronas/efectos de los fármacos , Conejos , Ratas , Ratas Sprague-Dawley
15.
J Neurosci Res ; 95(4): 992-999, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-27546887

RESUMEN

Alzheimer's disease (AD) is a complex, progressive neurological disorder characterized by the formation of extracellular amyloid plaques composed of ß-amyloid protein (Aß), the key component in pathogenesis of AD. Peripheral administration of enoxaparin (ENO) reportedly reduces the level of Aß and the amyloid plaques in the cortex of amyloid precursor protein (APP) transgenic mice. However, the exact mechanism of these effects is unclear. Our previous studies indicated that ENO can inhibit APP processing to Aß in primary cortical cells from Tg2576 mice by downregulating BACE1 levels. This study examines whether ENO-induced reduction of amyloid load is due to the decreased APP processing to Aß in Tg2576 mice. Surprisingly, our results indicated that ENO significantly increases the Aß42/Aß40 ratio in cortex and enhances the amyloid plaque load in both cortex and hippocampus, although overall APP processing was not influenced by ENO. Moreover, ENO stimulated the aggregation of both Aß40 and Aß42 in vitro. Although ENO has been reported to improve cognition in vivo and has potential as a therapeutic agent for AD, the results from our study suggest that ENO can exacerbate the amyloid pathology, and the strategy of using ENO for the treatment of AD may require further assessment. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides/metabolismo , Encéfalo/efectos de los fármacos , Enoxaparina/toxicidad , Fibrinolíticos/toxicidad , Placa Amiloide/inducido químicamente , Proteína ADAM10/metabolismo , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Transgénicos , Mutación/genética , Placa Amiloide/genética , Agregado de Proteínas/efectos de los fármacos , Agregado de Proteínas/genética
16.
Hum Mol Genet ; 23(13): 3579-95, 2014 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-24549040

RESUMEN

Intronic expansion of a hexanucleotide GGGGCC repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene is the major cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. However, the cellular function of the C9ORF72 protein remains unknown. Here, we demonstrate that C9ORF72 regulates endosomal trafficking. C9ORF72 colocalized with Rab proteins implicated in autophagy and endocytic transport: Rab1, Rab5, Rab7 and Rab11 in neuronal cell lines, primary cortical neurons and human spinal cord motor neurons, consistent with previous predictions that C9ORF72 bears Rab guanine exchange factor activity. Consistent with this notion, C9ORF72 was present in the extracellular space and as cytoplasmic vesicles. Depletion of C9ORF72 using siRNA inhibited transport of Shiga toxin from the plasma membrane to Golgi apparatus, internalization of TrkB receptor and altered the ratio of autophagosome marker light chain 3 (LC3) II:LC3I, indicating that C9ORF72 regulates endocytosis and autophagy. C9ORF72 also colocalized with ubiquilin-2 and LC3-positive vesicles, and co-migrated with lysosome-stained vesicles in neuronal cell lines, providing further evidence that C9ORF72 regulates autophagy. Investigation of proteins interacting with C9ORF72 using mass spectrometry identified other proteins implicated in ALS; ubiquilin-2 and heterogeneous nuclear ribonucleoproteins, hnRNPA2/B1 and hnRNPA1, and actin. Treatment of cells overexpressing C9ORF72 with proteasome inhibitors induced the formation of stress granules positive for hnRNPA1 and hnRNPA2/B1. Immunohistochemistry of C9ORF72 ALS patient motor neurons revealed increased colocalization between C9ORF72 and Rab7 and Rab11 compared with controls, suggesting possible dysregulation of trafficking in patients bearing the C9ORF72 repeat expansion. Hence, this study identifies a role for C9ORF72 in Rab-mediated cellular trafficking.


Asunto(s)
Esclerosis Amiotrófica Lateral/metabolismo , Endosomas/metabolismo , Demencia Frontotemporal/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Proteínas Adaptadoras del Transporte Vesicular/genética , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Esclerosis Amiotrófica Lateral/genética , Animales , Proteínas Relacionadas con la Autofagia , Transporte Biológico , Proteína C9orf72 , Demencia Frontotemporal/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/metabolismo , Humanos , Espectrometría de Masas , Ratones , Proteínas/genética , Proteínas/metabolismo , Proteínas de Unión al GTP rab/genética , Proteínas de Unión al GTP rab/metabolismo , Proteínas de Unión a GTP rab7
18.
Artículo en Inglés | MEDLINE | ID: mdl-38917432

RESUMEN

Metabolic changes are observed in patients with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although regulation of metabolic processes in the CNS is predominantly carried out within the hypothalamus, extra-hypothalamic CNS areas contain metabolic hormone receptors, including those for leptin (LEPR), insulin (INSR), and neuropeptide Y (NPY), indicating that they may play a role in biological processes underlying pathogenic disease processes. The status of these hormones within regions vulnerable in ALS/FTD is not well described. This study sought to determine whether the expression of these hormones and their receptors is altered in pathology-rich regions in cases of human FTD (superior frontal gyrus and insular cortex) and ALS (primary motor cortex and lumbar spinal cord) with TDP-43 pathology compared to matched healthy controls. LEPR mRNA was increased within the superior frontal gyrus of FTD cases and within primary motor cortex and lumbar spinal cord of ALS cases; INSR mRNA was increased in superior frontal gyrus and insular cortex of FTD cases. NPY protein was decreased in primary motor cortex and lumbar spinal cord of ALS cases. Our results demonstrate that metabolic hormones undergo complex alterations in ALS and FTD and suggest that these hormones could play critical roles in the pathogenesis of these diseases.

19.
ACS Chem Neurosci ; 15(2): 346-356, 2024 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-38149631

RESUMEN

Aptamers are functional oligonucleotide ligands used for the molecular recognition of various targets. The natural characteristics of aptamers make them an excellent alternative to antibodies in diagnostics, therapeutics, and biosensing. DNA aptamers are mainly single-stranded oligonucleotides (ssDNA) that possess a definite binding to targets. However, the application of aptamers to the fields of brain health and neurodegenerative diseases has been limited to date. Herein, a DNA aptamer against the brain-derived neurotrophic factor (BDNF) protein was obtained by in vitro selection. BDNF is a potential biomarker of brain health and neurodegenerative diseases and has functions in the synaptic plasticity and survival of neurons. We identified eight aptamers that have binding affinity for BDNF from a 50-nucleotide library. Among these aptamers, NV_B12 showed the highest sensitivity and selectivity for detecting BDNF. In an aptamer-linked immobilized sorbent assay (ALISA), the NV_B12 aptamer strongly bound to BDNF protein, in a dose-dependent manner. The dissociation constant (Kd) for NV_B12 was 0.5 nM (95% CI: 0.4-0.6 nM). These findings suggest that BDNF-specific aptamers could be used as an alternative to antibodies in diagnostic and detection assays for BDNF.


Asunto(s)
Aptámeros de Nucleótidos , Enfermedades Neurodegenerativas , Humanos , Aptámeros de Nucleótidos/farmacología , Aptámeros de Nucleótidos/química , Factor Neurotrófico Derivado del Encéfalo/genética , ADN de Cadena Simple , Biblioteca de Genes
20.
Alzheimers Dement (Amst) ; 16(1): e12520, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38274411

RESUMEN

INTRODUCTION: Low-cost simple tests for preclinical Alzheimer's disease are a research priority. We evaluated whether remote unsupervised webcam recordings of finger-tapping were associated with cognitive performance in older adults. METHODS: A total of 404 cognitively-asymptomatic participants (64.6 [6.77] years; 70.8% female) completed 10-second finger-tapping tests (Tasmanian [TAS] Test) and cognitive tests (Cambridge Neuropsychological Test Automated Battery [CANTAB]) online at home. Regression models including hand movement features were compared with null models (comprising age, sex, and education level); change in Akaike Information Criterion greater than 2 (ΔAIC > 2) denoted statistical difference. RESULTS: Hand movement features improved prediction of episodic memory, executive function, and working memory scores (ΔAIC > 2). Dominant hand features outperformed nondominant hand features for episodic memory (ΔAIC = 2.5), executive function (ΔAIC = 4.8), and working memory (ΔAIC = 2.2). DISCUSSION: This brief webcam test improved prediction of cognitive performance compared to age, sex, and education. Finger-tapping holds potential as a remote language-agnostic screening tool to stratify community cohorts at risk for cognitive decline.

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