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This study investigates various pathological tau isoforms in the retina of individuals with early and advanced Alzheimer's disease (AD), exploring their connection with disease status. Retinal cross-sections from predefined superior-temporal and inferior-temporal subregions and corresponding brains from neuropathologically confirmed AD patients with a clinical diagnosis of either mild cognitive impairment (MCI) or dementia (n = 45) were compared with retinas from age- and sex-matched individuals with normal cognition (n = 30) and non-AD dementia (n = 4). Retinal tau isoforms, including tau tangles, paired helical filament of tau (PHF-tau), oligomeric-tau (Oligo-tau), hyperphosphorylated-tau (p-tau), and citrullinated-tau (Cit-tau), were stereologically analyzed by immunohistochemistry and Nanostring GeoMx digital spatial profiling, and correlated with clinical and neuropathological outcomes. Our data indicated significant increases in various AD-related pretangle tau isoforms, especially p-tau (AT8, 2.9-fold, pS396-tau, 2.6-fold), Cit-tau at arginine residue 209 (CitR209-tau; 4.1-fold), and Oligo-tau (T22+, 9.2-fold), as well as pretangle and mature tau tangle forms like MC-1-positive (1.8-fold) and PHF-tau (2.3-fold), in AD compared to control retinas. MCI retinas also exhibited substantial increases in Oligo-tau (5.2-fold), CitR209-tau (3.5-fold), and pS396-tau (2.2-fold). Nanostring GeoMx analysis confirmed elevated retinal p-tau at epitopes: Ser214 (2.3-fold), Ser396 (2.6-fold), Ser404 (2.4-fold), and Thr231 (1.8-fold), particularly in MCI patients. Strong associations were found between retinal tau isoforms versus brain pathology and cognitive status: a) retinal Oligo-tau vs. Braak stage, neurofibrillary tangles (NFTs), and CDR cognitive scores (ρ = 0.63-0.71), b) retinal PHF-tau vs. neuropil threads (NTs) and ABC scores (ρ = 0.69-0.71), and c) retinal pS396-tau vs. NTs, NFTs, and ABC scores (ρ = 0.67-0.74). Notably, retinal Oligo-tau strongly correlated with retinal Aß42 and arterial Aß40 forms (r = 0.76-0.86). Overall, this study identifies and quantifies diverse retinal tau isoforms in MCI and AD patients, underscoring their link to brain pathology and cognition. These findings advocate for further exploration of retinal tauopathy biomarkers to facilitate AD detection and monitoring via noninvasive retinal imaging.
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Enfermedad de Alzheimer , Isoformas de Proteínas , Retina , Proteínas tau , Humanos , Proteínas tau/metabolismo , Masculino , Femenino , Anciano , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Retina/patología , Retina/metabolismo , Anciano de 80 o más Años , Disfunción Cognitiva/patología , Disfunción Cognitiva/metabolismo , Persona de Mediana Edad , Ovillos Neurofibrilares/patología , Ovillos Neurofibrilares/metabolismo , Encéfalo/patología , Encéfalo/metabolismoRESUMEN
There is emerging evidence that amyloid beta protein (Aß) and tau-related lesions in the retina are associated with Alzheimer's disease (AD). Aß and hyperphosphorylated (p)-tau deposits have been described in the retina and were associated with small amyloid spots visualized by in vivo imaging techniques as well as degeneration of the retina. These changes correlate with brain amyloid deposition as determined by histological quantification, positron emission tomography (PET) or clinical diagnosis of AD. However, the literature is not coherent on these histopathological and in vivo imaging findings. One important reason for this is the variability in the methods and the interpretation of findings across different studies. In this perspective, we indicate the critical methodological deviations among different groups and suggest a roadmap moving forward on how to harmonize (i) histopathologic examination of retinal tissue; (ii) in vivo imaging among different methods, devices, and interpretation algorithms; and (iii) inclusion/exclusion criteria for studies aiming at retinal biomarker validation.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Retina/diagnóstico por imagen , Biomarcadores/metabolismo , Tomografía de Emisión de Positrones/métodos , Encéfalo/patologíaRESUMEN
This editorial summarizes advances from the Clearance of Interstitial Fluid and Cerebrospinal Fluid (CLIC) group, within the Vascular Professional Interest Area (PIA) of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART). The overarching objectives of the CLIC group are to: (1) understand the age-related physiology changes that underlie impaired clearance of interstitial fluid (ISF) and cerebrospinal fluid (CSF) (CLIC); (2) understand the cellular and molecular mechanisms underlying intramural periarterial drainage (IPAD) in the brain; (3) establish novel diagnostic tests for Alzheimer's disease (AD), cerebral amyloid angiopathy (CAA), retinal amyloid vasculopathy, amyloid-related imaging abnormalities (ARIA) of spontaneous and iatrogenic CAA-related inflammation (CAA-ri), and vasomotion; and (4) establish novel therapies that facilitate IPAD to eliminate amyloid ß (Aß) from the aging brain and retina, to prevent or reduce AD and CAA pathology and ARIA side events associated with AD immunotherapy.
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Enfermedad de Alzheimer , Angiopatía Amiloide Cerebral , Trastornos Cerebrovasculares , Humanos , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Líquido Extracelular , Angiopatía Amiloide Cerebral/terapia , Angiopatía Amiloide Cerebral/patología , Encéfalo/metabolismo , Trastornos Cerebrovasculares/complicacionesRESUMEN
Air pollution poses a significant threat to human health, though a clear understanding of its mechanism remains elusive. In this study, we sought to better understand the effects of various sized particulate matter from polluted air on Alzheimer's disease (AD) development using an AD mouse model. We exposed transgenic Alzheimer's mice in their prodromic stage to different sized particulate matter (PM), with filtered clean air as control. After 3 or 6 months of exposure, mouse brains were harvested and analyzed. RNA-seq analysis showed that various PM have differential effects on the brain transcriptome, and these effects seemed to correlate with PM size. Many genes and pathways were affected after PM exposure. Among them, we found a strong activation in mRNA Nonsense Mediated Decay pathway, an inhibition in pathways related to transcription, neurogenesis and survival signaling as well as angiogenesis, and a dramatic downregulation of collagens. Although we did not detect any extracellular Aß plaques, immunostaining revealed that both intracellular Aß1-42 and phospho-Tau levels were increased in various PM exposure conditions compared to the clean air control. NanoString GeoMx analysis demonstrated a remarkable activation of immune responses in the PM exposed mouse brain. Surprisingly, our data also indicated a strong activation of various tumor suppressors including RB1, CDKN1A/p21 and CDKN2A/p16. Collectively, our data demonstrated that exposure to airborne PM caused a profound transcriptional dysregulation and accelerated Alzheimer's-related pathology.
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Alzheimer's disease (AD) pathologies were discovered in the accessible neurosensory retina. However, their exact nature and topographical distribution, particularly in the early stages of functional impairment, and how they relate to disease progression in the brain remain largely unknown. To better understand the pathological features of AD in the retina, we conducted an extensive histopathological and biochemical investigation of postmortem retina and brain tissues from 86 human donors. Quantitative examination of superior and inferior temporal retinas from mild cognitive impairment (MCI) and AD patients compared to those with normal cognition (NC) revealed significant increases in amyloid ß-protein (Aß42) forms and novel intraneuronal Aß oligomers (AßOi), which were closely associated with exacerbated retinal macrogliosis, microgliosis, and tissue atrophy. These pathologies were unevenly distributed across retinal layers and geometrical areas, with the inner layers and peripheral subregions exhibiting most pronounced accumulations in the MCI and AD versus NC retinas. While microgliosis was increased in the retina of these patients, the proportion of microglial cells engaging in Aß uptake was reduced. Female AD patients exhibited higher levels of retinal microgliosis than males. Notably, retinal Aß42, S100 calcium-binding protein B+ macrogliosis, and atrophy correlated with severity of brain Aß pathology, tauopathy, and atrophy, and most retinal pathologies reflected Braak staging. All retinal biomarkers correlated with the cognitive scores, with retinal Aß42, far-peripheral AßOi and microgliosis displaying the strongest correlations. Proteomic analysis of AD retinas revealed activation of specific inflammatory and neurodegenerative processes and inhibition of oxidative phosphorylation/mitochondrial, and photoreceptor-related pathways. This study identifies and maps retinopathy in MCI and AD patients, demonstrating the quantitative relationship with brain pathology and cognition, and may lead to reliable retinal biomarkers for noninvasive retinal screening and monitoring of AD.
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Enfermedad de Alzheimer , Masculino , Humanos , Femenino , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Proteoma/metabolismo , Proteómica , Retina/patología , Atrofia/patología , Biomarcadores/metabolismoRESUMEN
INTRODUCTION: Vascular amyloid beta (Aß) protein deposits were detected in retinas of mild cognitively impaired (MCI) and Alzheimer's disease (AD) patients. We tested the hypothesis that the retinal vascular tight junctions (TJs) were compromised and linked to disease status. METHODS: TJ components and Aß expression in capillaries and larger blood vessels were determined in post mortem retinas from 34 MCI or AD patients and 27 cognitively normal controls and correlated with neuropathology. RESULTS: Severe decreases in retinal vascular zonula occludens-1 (ZO-1) and claudin-5 correlating with abundant arteriolar Aß40 deposition were identified in MCI and AD patients. Retinal claudin-5 deficiency was closely associated with cerebral amyloid angiopathy, whereas ZO-1 defects correlated with cerebral pathology and cognitive deficits. DISCUSSION: We uncovered deficiencies in blood-retinal barrier markers for potential retinal imaging targets of AD screening and monitoring. Intense retinal arteriolar Aß40 deposition suggests a common pathogenic mechanism of failed Aß clearance via intramural periarterial drainage.
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Enfermedad de Alzheimer , Angiopatía Amiloide Cerebral , Retina , Humanos , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Angiopatía Amiloide Cerebral/patología , Claudina-5/metabolismo , Uniones Estrechas/metabolismo , Uniones Estrechas/patología , Retina/patología , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/patologíaRESUMEN
Acute neuropsychiatric impairments occur in over 70% of patients with acute lung injury. Mechanical ventilation is a well-known precipitant of acute lung injury and is strongly associated with the development of acute delirium and anxiety phenotypes. In prior studies, we demonstrated that IL-6 mediates neuropathological changes in the frontal cortex and hippocampus of animals with mechanical ventilation-induced brain injury; however, the effect of systemic IL-6 inhibition on structural and functional acute neuropsychiatric phenotypes is not known. We hypothesized that a murine model of mechanical ventilation-induced acute lung injury (VILI) would induce neural injury to the amygdala and hippocampus, brain regions that are implicated in diverse neuropsychiatric conditions, and corresponding delirium- and anxiety-like functional impairments. Furthermore, we hypothesized that these structural and functional changes would reverse with systemic IL-6 inhibition. VILI was induced using high tidal volume (35 cc/kg) mechanical ventilation. Cleaved caspase-3 (CC3) expression was quantified as a neural injury marker and found to be significantly increased in the VILI group compared to spontaneously breathing or anesthetized and mechanically ventilated mice with 10 cc/kg tidal volume. VILI mice treated with systemic IL-6 inhibition had significantly reduced amygdalar and hippocampal CC3 expression compared to saline-treated animals and demonstrated amelioration in acute neuropsychiatric behaviors in open field, elevated plus maze, and Y-maze tests. Overall, these data provide evidence of a pathogenic role of systemic IL-6 in mediating structural and functional acute neuropsychiatric symptoms in VILI and provide preclinical justification to assess IL-6 inhibition as a potential intervention to ameliorate acute neuropsychiatric phenotypes following VILI.
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Lesión Pulmonar Aguda , Delirio , Lesión Pulmonar Inducida por Ventilación Mecánica , Lesión Pulmonar Aguda/complicaciones , Lesión Pulmonar Aguda/tratamiento farmacológico , Animales , Delirio/complicaciones , Modelos Animales de Enfermedad , Interleucina-6 , Ratones , Fenotipo , Lesión Pulmonar Inducida por Ventilación Mecánica/patologíaRESUMEN
The Alzheimer's Association International Conference held its sixth Satellite Symposium in Sydney, Australia in 2019, highlighting the leadership of Australian researchers in advancing the understanding of and treatment developments for Alzheimer's disease (AD) and other dementias. This leadership includes the Australian Imaging, Biomarker, and Lifestyle Flagship Study of Ageing (AIBL), which has fueled the identification and development of many biomarkers and novel therapeutics. Two multimodal lifestyle intervention studies have been launched in Australia; and Australian researchers have played leadership roles in other global studies in diverse populations. Australian researchers have also played an instrumental role in efforts to understand mechanisms underlying vascular contributions to cognitive impairment and dementia; and through the Women's Healthy Aging Project have elucidated hormonal and other factors that contribute to the increased risk of AD in women. Alleviating the behavioral and psychological symptoms of dementia has also been a strong research and clinical focus in Australia.
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Envejecimiento/fisiología , Enfermedad de Alzheimer/epidemiología , Investigación Biomédica , Progresión de la Enfermedad , Síntomas Prodrómicos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/tratamiento farmacológico , Australia/epidemiología , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/metabolismo , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/tratamiento farmacológico , Humanos , Estilo de Vida , Tomografía de Emisión de PositronesRESUMEN
INTRODUCTION: Alzheimer's disease is a neurodegenerative disease pathologically characterized by accumulation of abnormal amyloid-beta (Aß) and tau proteins. Research is currently focused on developing treatments to reduce the risk of developing or inhibiting disease progression. Therefore, there is a need to identify diagnostic tools for the initial stages of the disease. The neuropathological processes in Alzheimer's disease exist several decades before symptoms appear and can be identified by PET imaging or CSF analysis. Still, these methods are limited in availability and may be expensive and invasive, and there is therefore a need to develop accessible, inexpensive and non-invasive diagnostic tools. The retina is a component of the central nervous system. Changes in the retina can reflect the cerebral pathological process in Alzheimer's disease. Indeed, evidence of Aß plaques and abnormal tau proteins in the retina of Alzheimer's patients has been reported. The advantage of the retina is its accessibility for direct visualization by existing and non-invasive means. The following review will examine retinal changes that are suggested as possible biomarkers for Alzheimer's disease and discuss directions for future research in the field.
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Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/metabolismo , Biomarcadores , Diagnóstico Precoz , Humanos , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Retina/diagnóstico por imagen , Retina/metabolismo , Retina/patología , Proteínas tau/metabolismoRESUMEN
Targeted overexpression of angiotensin-converting enzyme (ACE), an amyloid-ß protein degrading enzyme, to brain resident microglia and peripheral myelomonocytes (ACE10 model) substantially diminished Alzheimer's-like disease in double-transgenic APPSWE/PS1ΔE9 (AD+) mice. In this study, we explored the impact of selective and transient angiotensin-converting enzyme overexpression on macrophage behaviour and the relative contribution of bone marrow-derived ACE10 macrophages, but not microglia, in attenuating disease progression. To this end, two in vivo approaches were applied in AD+ mice: (i) ACE10/GFP+ bone marrow transplantation with head shielding; and (ii) adoptive transfer of CD115+-ACE10/GFP+ monocytes to the peripheral blood. Extensive in vitro studies were further undertaken to establish the unique ACE10-macrophage phenotype(s) in response to amyloid-ß1-42 fibrils and oligomers. The combined in vivo approaches showed that increased cerebral infiltration of ACE10 as compared to wild-type monocytes (â¼3-fold increase; P < 0.05) led to reductions in cerebral soluble amyloid-ß1-42, vascular and parenchymal amyloid-ß deposits, and astrocytosis (31%, 47-80%, and 33%, respectively; P < 0.05-0.0001). ACE10 macrophages surrounded brain and retinal amyloid-ß plaques and expressed 3.2-fold higher insulin-like growth factor-1 (P < 0.01) and â¼60% lower tumour necrosis factor-α (P < 0.05). Importantly, blood enrichment with CD115+-ACE10 monocytes in symptomatic AD+ mice resulted in pronounced synaptic and cognitive preservation (P < 0.05-0.001). In vitro analysis of macrophage response to well-defined amyloid-ß1-42 conformers (fibrils, prion rod-like structures, and stabilized soluble oligomers) revealed extensive resistance to amyloid-ß1-42 species by ACE10 macrophages. They exhibited 2-5-fold increased surface binding to amyloid-ß conformers as well as substantially more effective amyloid-ß1-42 uptake, at least 8-fold higher than those of wild-type macrophages (P < 0.0001), which were associated with enhanced expression of surface scavenger receptors (i.e. CD36, scavenger receptor class A member 1, triggering receptor expressed on myeloid cells 2, CD163; P < 0.05-0.0001), endosomal processing (P < 0.05-0.0001), and â¼80% increased extracellular degradation of amyloid-ß1-42 (P < 0.001). Beneficial ACE10 phenotype was reversed by the angiotensin-converting enzyme inhibitor (lisinopril) and thus was dependent on angiotensin-converting enzyme catalytic activity. Further, ACE10 macrophages presented distinct anti-inflammatory (low inducible nitric oxide synthase and lower tumour necrosis factor-α), pro-healing immune profiles (high insulin-like growth factor-1, elongated cell morphology), even following exposure to Alzheimer's-related amyloid-ß1-42 oligomers. Overall, we provide the first evidence for therapeutic roles of angiotensin-converting enzyme-overexpressing macrophages in preserving synapses and cognition, attenuating neuropathology and neuroinflammation, and enhancing resistance to defined pathognomonic amyloid-ß forms.
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Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Macrófagos/metabolismo , Microglía/metabolismo , Fragmentos de Péptidos/metabolismo , Peptidil-Dipeptidasa A/genética , Placa Amiloide/metabolismo , Traslado Adoptivo , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Trasplante de Médula Ósea , Modelos Animales de Enfermedad , Técnicas In Vitro , Factor I del Crecimiento Similar a la Insulina/metabolismo , Lisinopril/farmacología , Macrófagos/patología , Ratones , Ratones Transgénicos , Microglía/patología , Monocitos/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Placa Amiloide/patología , Presenilina-1/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
In the last 20 years, research focused on developing retinal imaging as a source of potential biomarkers for Alzheimer's disease and other neurodegenerative diseases, has increased significantly. The Alzheimer's Association and the Alzheimer's & Dementia: Diagnosis, Assessment, Disease Monitoring editorial team (companion journal to Alzheimer's & Dementia) convened an interdisciplinary discussion in 2019 to identify a path to expedite the development of retinal biomarkers capable of identifying biological changes associated with AD, and for tracking progression of disease severity over time. As different retinal imaging modalities provide different types of structural and/or functional information, the discussion reflected on these modalities and their respective strengths and weaknesses. Discussion further focused on the importance of defining the context of use to help guide the development of retinal biomarkers. Moving from research to context of use, and ultimately to clinical evaluation, this article outlines ongoing retinal imaging research today in Alzheimer's and other brain diseases, including a discussion of future directions for this area of study.
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Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedades Neurodegenerativas/diagnóstico por imagen , Retina/diagnóstico por imagen , Anciano , Anciano de 80 o más Años , Biomarcadores , Encéfalo/diagnóstico por imagen , Humanos , Persona de Mediana EdadRESUMEN
PURPOSE OF REVIEW: The retina is growingly recognized as a window into cerebrovascular and systemic vascular conditions. The utility of noninvasive retinal vessel biomarkers in cerebrovascular risk assessment has expanded due to advances in retinal imaging techniques and machine learning-based digital analysis. The purpose of this review is to underscore the latest evidence linking retinal vascular abnormalities with stroke and vascular-related cognitive disorders; to highlight modern developments in retinal vascular imaging modalities and software-based vasculopathy quantification. RECENT FINDINGS: Longitudinal studies undertaken for extended periods indicate that retinal vascular changes can predict cerebrovascular disorders (CVD). Cerebrovascular ties to dementia provoked recent explorations of retinal vessel imaging tools for conceivable early cognitive decline detection. Innovative biomedical engineering technologies and advanced dynamic and functional retinal vascular imaging methods have recently been added to the armamentarium, allowing an unbiased and comprehensive analysis of the retinal vasculature. Improved artificial intelligence-based deep learning algorithms have boosted the application of retinal imaging as a clinical and research tool to screen, risk stratify, and monitor with precision CVD and vascular cognitive impairment. SUMMARY: Mounting evidence supports the use of quantitative retinal vessel analysis in predicting CVD, from clinical stroke to neuroimaging markers of stroke and neurodegeneration.
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Trastornos Cerebrovasculares/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico , Demencia Vascular/diagnóstico , Vasos Retinianos/diagnóstico por imagen , Inteligencia Artificial , Biomarcadores , Disfunción Cognitiva/diagnóstico por imagen , Demencia Vascular/diagnóstico por imagen , Humanos , Neuroimagen/métodosRESUMEN
Pericyte loss and deficient vascular platelet-derived growth factor receptor-ß (PDGFRß) signaling are prominent features of the blood-brain barrier breakdown described in Alzheimer's disease (AD) that can predict cognitive decline yet have never been studied in the retina. Recent reports using noninvasive retinal amyloid imaging, optical coherence tomography angiography, and histological examinations support the existence of vascular-structural abnormalities and vascular amyloid ß-protein (Aß) deposits in retinas of AD patients. However, the cellular and molecular mechanisms of such retinal vascular pathology were not previously explored. Here, by modifying a method of enzymatically clearing non-vascular retinal tissue and fluorescent immunolabeling of the isolated blood vessel network, we identified substantial pericyte loss together with significant Aß deposition in retinal microvasculature and pericytes in AD. Evaluation of postmortem retinas from a cohort of 56 human donors revealed an early and progressive decrease in vascular PDGFRß in mild cognitive impairment (MCI) and AD compared to cognitively normal controls. Retinal PDGFRß loss significantly associated with increased retinal vascular Aß40 and Aß42 burden. Decreased vascular LRP-1 and early apoptosis of pericytes in AD retina were also detected. Mapping of PDGFRß and Aß40 levels in pre-defined retinal subregions indicated that certain geometrical and cellular layers are more susceptible to AD pathology. Further, correlations were identified between retinal vascular abnormalities and cerebral Aß burden, cerebral amyloid angiopathy (CAA), and clinical status. Overall, the identification of pericyte and PDGFRß loss accompanying increased vascular amyloidosis in Alzheimer's retina implies compromised blood-retinal barrier integrity and provides new targets for AD diagnosis and therapy.
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Enfermedad de Alzheimer/patología , Amiloidosis/patología , Encéfalo/patología , Pericitos/patología , Retina/patología , Anciano , Anciano de 80 o más Años , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Amiloidosis/complicaciones , Barrera Hematoencefálica/patología , Angiopatía Amiloide Cerebral/patología , Cognición/fisiología , Femenino , Humanos , MasculinoRESUMEN
PURPOSE OF REVIEW: To review recent studies exploring how myeloid cell overexpression of angiotensin-converting enzyme (ACE) affects the immune response and to formulate an approach for considering the effectiveness of inflammation in cardiovascular disease RECENT FINDINGS: While it is widely appreciated that the renin-angiotensin system affects aspects of inflammation through the action of angiotensin II, new studies reveal a previously unknown role of ACE in myeloid cell biology. This was apparent from analysis of two mouse lines genetically modified to overexpress ACE in monocytes/macrophages or neutrophils. Cells overexpressing ACE demonstrated an increased immune response. For example, mice with increased macrophage ACE expression have increased resistance to melanoma, methicillin-resistant Staphylococcus aureus, a mouse model of Alzheimer's disease, and ApoE-knockout-induced atherosclerosis. These data indicate the profound effect of increasing myeloid cell function. Further, they suggest that an appropriate way to evaluate inflammation in both acute and chronic diseases is to ask whether the inflammatory infiltrate is sufficient to eliminate the immune challenge. The expression of ACE by myeloid cells induces a heightened immune response by these cells. The overexpression of ACE is associated with immune function beyond that possible by wild type (WT) myeloid cells. A heightened immune response effectively resolves disease in a variety of acute and chronic models of disease including models of Alzheimer's disease and atherosclerosis.
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Hipertensión , Inflamación , Staphylococcus aureus Resistente a Meticilina , Peptidil-Dipeptidasa A , Animales , Enfermedad Crónica , Humanos , Ratones , Células Mieloides , Peptidil-Dipeptidasa A/metabolismoRESUMEN
BACKGROUND: Mechanical ventilation is strongly associated with cognitive decline after critical illness. This finding is particularly evident among older individuals who have pre-existing cognitive impairment, most commonly characterized by varying degrees of cerebral amyloid-ß accumulation, neuroinflammation, and blood-brain barrier dysfunction. We sought to test the hypothesis that short-term mechanical ventilation contributes to the neuropathology of cognitive impairment by (i) increasing cerebral amyloid-ß accumulation in mice with pre-existing Alzheimer's disease pathology, (ii) increasing neurologic and systemic inflammation in wild-type mice and mice with pre-existing Alzheimer's disease pathology, and (iii) increasing hippocampal blood-brain barrier permeability in wild-type mice and mice with pre-existing Alzheimer's disease pathology. METHODS: We subjected double transgenic Alzheimer's disease (APP/PSEN1) and wild-type mice to mechanical ventilation for 4 h and compared to non-mechanically ventilated Alzheimer's disease model and wild-type mice. Cerebral soluble/insoluble amyloid-ß1-40/amyloid-ß1-42 and neurological and systemic markers of inflammation were quantified. Hippocampal blood-brain barrier permeability was quantified using a novel methodology that enabled assessment of small and large molecule permeability across the blood-brain barrier. RESULTS: Mechanical ventilation resulted in (i) a significant increase in cerebral soluble amyloid-ß1-40 (p = 0.007) and (ii) significant increases in neuroinflammatory cytokines in both wild-type and Alzheimer's disease mice which, in most cases, were not reflected in the plasma. There were (i) direct correlations between polymorphonuclear cells in the bronchoalveolar fluid and cerebral soluble amyloid-ß1-40 (p = 0.0033), and several Alzheimer's disease-relevant neuroinflammatory biomarkers including cerebral TNF-α and IL-6; (iii) significant decreases in blood-brain barrier permeability in mechanically ventilated Alzheimer's disease mice and a trend towards increased blood-brain barrier permeability in mechanically ventilated wild-type mice. CONCLUSIONS: These results provide the first evidence that short-term mechanical ventilation independently promotes the neuropathology of Alzheimer's disease in subjects with and without pre-existing cerebral Alzheimer's disease pathology. Future studies are needed to further clarify the specific mechanisms by which this occurs and to develop neuroprotective mechanical ventilation strategies that mitigate the risk of cognitive decline after critical illness.
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Enfermedad de Alzheimer/terapia , Disfunción Cognitiva/etiología , Respiración Artificial/normas , Enfermedad de Alzheimer/enzimología , Análisis de Varianza , Animales , Disfunción Cognitiva/fisiopatología , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática/métodos , Ratones , Modelos Neurológicos , Respiración Artificial/métodos , Factores de TiempoRESUMEN
Osteopontin (OPN), a matricellular immunomodulatory cytokine highly expressed by myelomonocytic cells, is known to regulate immune cell migration, communication, and response to brain injury. Enhanced cerebral recruitment of monocytes achieved through glatiramer acetate (GA) immunization or peripheral blood enrichment with bone marrow (BM)-derived CD115+ monocytes (MoBM) curbs amyloid ß-protein (Aß) neuropathology and preserves cognitive function in murine models of Alzheimer's disease (ADtg mice). To elucidate the beneficial mechanisms of these immunomodulatory approaches in AD, we focused on the potential role of OPN in macrophage-mediated Aß clearance. Here, we found extensive OPN upregulation along with reduction of vascular and parenchymal Aß burden in cortices and hippocampi of GA-immunized ADtg mice. Treatment combining GA with blood-grafted MoBM further increased OPN levels surrounding residual Aß plaques. In brains from AD patients and ADtg mice, OPN was also elevated and predominantly expressed by infiltrating GFP+- or Iba1+-CD45high monocyte-derived macrophages engulfing Aß plaques. Following GA immunization, we detected a significant increase in a subpopulation of inflammatory blood monocytes (CD115+CD11b+Ly6Chigh) expressing OPN, and subsequently, an elevated population of OPN-expressing CD11b+Ly6C+CD45high monocyte/macrophages in the brains of these ADtg mice. Correlogram analyses indicate a strong linear correlation between cerebral OPN levels and macrophage infiltration, as well as a tight inverse relation between OPN and Aß-plaque burden. In vitro studies corroborate in vivo findings by showing that GA directly upregulates OPN expression in BM-derived macrophages (MФBM). Further, OPN promotes a phenotypic shift that is highly phagocytic (increased uptake of Aß fibrils and surface scavenger receptors) and anti-inflammatory (altered cell morphology, reduced iNOS, and elevated IL-10 and Aß-degrading enzyme MMP-9). Inhibition of OPN expression in MФBM, either by siRNA, knockout (KOOPN), or minocycline, impairs uptake of Aß fibrils and hinders GA's neuroprotective effects on macrophage immunological profile. Addition of human recombinant OPN reverses the impaired Aß phagocytosis in KOOPN-MФBM. This study demonstrates that OPN has an essential role in modulating macrophage immunological profile and their ability to resist pathogenic forms of Aß.
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Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Osteopontina/metabolismo , Animales , Encéfalo/irrigación sanguínea , Modelos Animales de Enfermedad , Encefalitis/metabolismo , Femenino , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Monocitos/metabolismo , Fagocitosis , Regulación hacia ArribaRESUMEN
Deficiency in cerebral amyloid ß-protein (Aß) clearance is implicated in the pathogenesis of the common late-onset forms of Alzheimer's disease (AD). Accumulation of misfolded Aß in the brain is believed to be a net result of imbalance between its production and removal. This in turn may trigger neuroinflammation, progressive synaptic loss, and ultimately cognitive decline. Clearance of cerebral Aß is a complex process mediated by various systems and cell types, including vascular transport across the blood-brain barrier, glymphatic drainage, and engulfment and degradation by resident microglia and infiltrating innate immune cells. Recent studies have highlighted a new, unexpected role for peripheral monocytes and macrophages in restricting cerebral Aß fibrils, and possibly soluble oligomers. In AD transgenic (ADtg) mice, monocyte ablation or inhibition of their migration into the brain exacerbated Aß pathology, while blood enrichment with monocytes and their increased recruitment to plaque lesion sites greatly diminished Aß burden. Profound neuroprotective effects in ADtg mice were further achieved through increased cerebral recruitment of myelomonocytes overexpressing Aß-degrading enzymes. This review summarizes the literature on cellular and molecular mechanisms of cerebral Aß clearance with an emphasis on the role of peripheral monocytes and macrophages in Aß removal.
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Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Microglía/metabolismo , Monocitos/metabolismo , Enfermedad de Alzheimer/genética , Animales , Humanos , ProteolisisRESUMEN
OBJECTIVE: Melanopsin retinal ganglion cells (mRGCs) are photoreceptors driving circadian photoentrainment, and circadian dysfunction characterizes Alzheimer disease (AD). We investigated mRGCs in AD, hypothesizing that they contribute to circadian dysfunction. METHODS: We assessed retinal nerve fiber layer (RNFL) thickness by optical coherence tomography (OCT) in 21 mild-moderate AD patients, and in a subgroup of 16 we evaluated rest-activity circadian rhythm by actigraphy. We studied postmortem mRGCs by immunohistochemistry in retinas, and axons in optic nerve cross-sections of 14 neuropathologically confirmed AD patients. We coimmunostained for retinal amyloid ß (Aß) deposition and melanopsin to locate mRGCs. All AD cohorts were compared with age-matched controls. RESULTS: We demonstrated an age-related optic neuropathy in AD by OCT, with a significant reduction of RNFL thickness (p = 0.038), more evident in the superior quadrant (p = 0.006). Axonal loss was confirmed in postmortem AD optic nerves. Abnormal circadian function characterized only a subgroup of AD patients. Sleep efficiency was significantly reduced in AD patients (p = 0.001). We also found a significant loss of mRGCs in postmortem AD retinal specimens (p = 0.003) across all ages and abnormal mRGC dendritic morphology and size (p = 0.003). In flat-mounted AD retinas, Aß accumulation was remarkably evident inside and around mRGCs. INTERPRETATION: We show variable degrees of rest-activity circadian dysfunction in AD patients. We also demonstrate age-related loss of optic nerve axons and specifically mRGC loss and pathology in postmortem AD retinal specimens, associated with Aß deposition. These results all support the concept that mRGC degeneration is a contributor to circadian rhythm dysfunction in AD.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides/metabolismo , Axones/patología , Trastornos Cronobiológicos , Nervio Óptico/patología , Células Ganglionares de la Retina , Actigrafía , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Trastornos Cronobiológicos/etiología , Trastornos Cronobiológicos/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patología , Opsinas de Bastones/metabolismo , Tomografía de Coherencia ÓpticaRESUMEN
Although historically perceived as a disorder confined to the brain, our understanding of Alzheimer's disease (AD) has expanded to include extra-cerebral manifestation, with mounting evidence of abnormalities in the eye. Among ocular tissues, the retina, a developmental outgrowth of the brain, is marked by an array of pathologies in patients suffering from AD, including nerve fiber layer thinning, degeneration of retinal ganglion cells, and changes to vascular parameters. While the hallmark pathological signs of AD, amyloid ß-protein (Aß) plaques and neurofibrillary tangles (NFT) comprising hyperphosphorylated tau (pTau) protein, have long been described in the brain, identification of these characteristic biomarkers in the retina has only recently been reported. In particular, Aß deposits were discovered in post-mortem retinas of advanced and early stage cases of AD, in stark contrast to non-AD controls. Subsequent studies have reported elevated Aß42/40 peptides, morphologically diverse Aß plaques, and pTau in the retina. In line with the above findings, animal model studies have reported retinal Aß deposits and tauopathy, often correlated with local inflammation, retinal ganglion cell degeneration, and functional deficits. This review highlights the converging evidence that AD manifests in the eye, especially in the retina, which can be imaged directly and non-invasively. Visual dysfunction in AD patients, traditionally attributed to well-documented cerebral pathology, can now be reexamined as a direct outcome of retinal abnormalities. As we continue to study the disease in the brain, the emerging field of ocular AD warrants further investigation of how the retina may faithfully reflect the neurological disease. Indeed, detection of retinal AD pathology, particularly the early presenting amyloid biomarkers, using advanced high-resolution imaging techniques may allow large-scale screening and monitoring of at-risk populations.
Asunto(s)
Enfermedad de Alzheimer/complicaciones , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/etiología , Vías Visuales/patología , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Humanos , Retina/metabolismo , Retina/patología , Proteínas tau/metabolismoRESUMEN
Weekly glatiramer acetate immunization of transgenic mice modelling Alzheimer's disease resulted in retained cognition (Morris water maze test), decreased amyloid-ß plaque burden, and regulation of local inflammation through a mechanism involving enhanced recruitment of monocytes. Ablation of bone marrow-derived myeloid cells exacerbated plaque pathology, whereas weekly administration of glatiramer acetate enhanced cerebral recruitment of innate immune cells, which dampened the pathology. Here, we assessed the therapeutic potential of grafted CD115(+) monocytes, injected once monthly into the peripheral blood of transgenic APPSWE/PS1ΔE9 Alzheimer's disease mouse models, with and without weekly immunization of glatiramer acetate, as compared to glatiramer acetate alone. All immune-modulation treatment groups were compared with age-matched phosphate-buffered saline-injected control transgenic and untreated non-transgenic mouse groups. Two independent cohorts of mice were assessed for behavioural performance (6-8 mice/group); treatments started in 10-month-old symptomatic mice and spanned a total of 2 months. For all three treatments, our data suggest a substantial decrease in cognitive deficit as assessed by the Barnes maze test (P < 0.0001-0.001). Improved cognitive function was associated with synaptic preservation and reduction in cerebral amyloid-ß protein levels and astrogliosis (P < 0.001 and P < 0.0001), with no apparent additive effects for the combined treatment. The peripherally grafted, green fluorescent protein-labelled and endogenous monocytes, homed to cerebral amyloid plaques and directly engulfed amyloid-ß; their recruitment was further enhanced by glatiramer acetate. In glatiramer acetate-immunized mice and, moreover, in the combined treatment group, monocyte recruitment to the brain was coupled with greater elevation of the regulatory cytokine IL10 surrounding amyloid-ß plaques. All treated transgenic mice had increased cerebral levels of MMP9 protein (P < 0.05), an enzyme capable of degrading amyloid-ß, which was highly expressed by the infiltrating monocytes. In vitro studies using primary cultures of bone marrow monocyte-derived macrophages, demonstrated that glatiramer acetate enhanced the ability of macrophages to phagocytose preformed fibrillar amyloid-ß1-42 (P < 0.0001). These glatiramer acetate-treated macrophages exhibited increased expression of the scavenger receptors CD36 and SCARA1 (encoded by MSR1), which can facilitate amyloid-ß phagocytosis, and the amyloid-ß-degrading enzyme MMP9 (P < 0.0001-0.001). Overall, our studies indicate that increased cerebral infiltration of monocytes, either by enrichment of their levels in the circulation or by weekly immunization with glatiramer acetate, resulted in substantial attenuation of disease progression in murine Alzheimer's models by mechanisms that involved enhanced cellular uptake and enzymatic degradation of toxic amyloid-ß as well as regulation of brain inflammation.