Showing papers by "Costantino Iadecola published in 2014"
TL;DR: Among patients hospitalized for surgery, perioperative atrial fibrillation was associated with an increased long-term risk of ischemic stroke, especially following noncardiac surgery.
Abstract: MAIN OUTCOMES AND MEASURES Previously validated diagnosis codes were used to identify ischemic strokes after discharge from the index hospitalization for surgery. The primary predictor variable was atrial fibrillation newly diagnosed during the index hospitalization, as defined by previously validated present-on-admission codes. Patients were censored at postdischarge emergency department encounters or hospitalizations with a recorded diagnosis of atrial fibrillation. RESULTS Of 1 729 360 eligible patients, 24 711 (1.43%; 95% CI, 1.41%-1.45%) had new-onset perioperative atrial fibrillation during the index hospitalization and 13 952 (0.81%; 95% CI, 0.79%-0.82%) experienced a stroke after discharge. In a Cox proportional hazards analysis accounting for potential confounders, perioperative atrial fibrillation was associated with subsequent stroke both after noncardiac and cardiac surgery.
269 citations
TL;DR: Patients with acute ischemic stroke in the setting of active cancer (especially adenocarcinoma) face a substantial short-term risk of recurrent isChemic stroke and other types of thromboembolism.
Abstract: Objective: To determine the cumulative rate and characteristics of recurrent thromboembolic events after acute ischemic stroke in patients with cancer. Methods: We retrospectively identified consecutive adult patients with active systemic cancer diagnosed with acute ischemic stroke at a tertiary-care cancer center from 2005 through 2009. Two neurologists independently reviewed all electronic records to ascertain the composite outcome of recurrent ischemic stroke, myocardial infarction, systemic embolism, TIA, or venous thromboembolism. Kaplan-Meier statistics were used to determine cumulative outcome rates. In exploratory analyses, Cox proportional hazard analysis was used to evaluate potential independent associations between a priori selected clinical factors and recurrent thromboembolic events. Results: Among 263 study patients, complete follow-up until death was available in 230 (87%). Most patients had an adenocarcinoma as their underlying cancer (60%) and had systemic metastases (69%). Despite a median survival of 84 days (interquartile range 24–419 days), 90 patients (34%; 95% confidence interval 28%–40%) had 117 recurrent thromboembolic events, consisting of 57 cases of venous thromboembolism, 36 recurrent ischemic strokes, 13 myocardial infarctions, 10 cases of systemic embolism, and one TIA. Kaplan-Meier rates of recurrent thromboembolism were 21%, 31%, and 37% at 1, 3, and 6 months, respectively; cumulative rates of recurrent ischemic stroke were 7%, 13%, and 16%. Adenocarcinoma histology (hazard ratio 1.65, 95% confidence interval 1.02–2.68) was independently associated with recurrent thromboembolism. Conclusions: Patients with acute ischemic stroke in the setting of active cancer (especially adenocarcinoma) face a substantial short-term risk of recurrent ischemic stroke and other types of thromboembolism.
118 citations
TL;DR: In the past 3 years, several articles published in Hypertension have provided new insight into the link between high blood pressure and dementia, and one of the key issues still unsettled concerns the temporal relationships between blood pressure elevation and cognitive decline.
Abstract: The negative impact of hypertension on cognitive function was already hinted at in the 1960s in a study on psychomotor speed of air traffic controllers and pilots and has received extensive confirmation during the following decades.1 Thus, hypertension has been associated with a wide variety of cognitive deficits, including reduced abstract reasoning (executive dysfunction), impaired memory, attention deficit, and slowing of mental processing speed.1,2 Indeed, hypertension is a leading cause of vascular cognitive impairment, a term that includes all cognitive deficits attributable to vascular factors.3 The most extreme case of vascular cognitive impairment is vascular dementia, in which multiple cognitive domains are affected, with a negative impact on the activities of daily living. Increasing evidence also suggests that hypertension is a risk factor for Alzheimer disease (AD), highlighting its participation in all major causes of cognitive impairment.4,5 In the past 3 years (2011–2013), several articles published in Hypertension have provided new insight into the link between high blood pressure and dementia. These articles will be briefly discussed, highlighting their contribution to current concepts of pathobiology, prevention, and treatment of the end-organ damage to the brain inflicted by hypertension.
Although it is well established that hypertension impairs cognition, one of the key issues still unsettled concerns the temporal relationships between blood pressure elevation and cognitive decline. On the one hand, cross-sectional studies indicated that individuals with dementia have lower blood pressure, challenging the involvement of hypertension.6 On the other hand, longitudinal studies, in which patient were followed for decades, revealed that individuals who develop dementia have a history of high blood pressure earlier in life.6,7 The effect is independent of other cardiovascular risk factors or comorbidities and is observed in both men and women. In this context, Joas et …
118 citations
TL;DR: It is established that iNOS in both neutrophils and endothelium mediates tissue damage and identifies these cell types as putative therapeutic targets for stroke injury.
Abstract: NO produced by inducible NO synthase (iNOS) contributes to ischemic brain injury, but the cell types expressing iNOS and mediating tissue damage have not been elucidated. To examine the relative contribution of iNOS in resident brain cells and peripheral leukocytes infiltrating the ischemic brain, we used bone marrow (BM) chimeric mice in which the middle cerebral artery was occluded and infarct volume was determined 3 d later. iNOS−/− mice engrafted with iNOS+/+ BM exhibited larger infarcts (44 ± 2 mm3; n = 13; mean ± SE) compared with autologous transplanted iNOS−/− mice (24 ± 3 mm3; n = 10; p < 0.01), implicating blood-borne leukocytes in the damage. Furthermore, iNOS+/+ mice transplanted with iNOS−/− BM had large infarcts (39 ± 6 mm3; n = 13), similar to those of autologous transplanted iNOS+/+ mice (39 ± 4 mm3; n = 14), indicating the resident brain cells also play a role. Flow cytometry and cell sorting revealed that iNOS is highly expressed in neutrophils and endothelium but not microglia. Surprisingly, postischemic iNOS expression was enhanced in the endothelium of iNOS+/+ mice transplanted with iNOS−/− BM and in leukocytes of iNOS−/− mice with iNOS+/+ BM, suggesting that endothelial iNOS suppresses iNOS expression in leukocytes and vice versa. To provide independent evidence that neutrophils mediate brain injury, neutrophils were isolated and transferred to mice 24 h after stroke. Consistent with the result in chimeric mice, transfer of iNOS+/+, but not iNOS−/−, neutrophils into iNOS−/− mice increased infarct volume. The findings establish that iNOS in both neutrophils and endothelium mediates tissue damage and identify these cell types as putative therapeutic targets for stroke injury.
110 citations
TL;DR: T-SwDI mice exhibit a profound age-dependent cerebrovascular dysfunction, involving multiple regulatory mechanisms, and early therapeutic interventions are likely to have the best chance to counteract the deleterious vascular effects of cerebral amyloid angiopathy.
Abstract: Background and Purpose—Accumulation of amyloid-β in cerebral blood vessels occurs in familial and sporadic forms of cerebral amyloid angiopathy and is a prominent feature of Alzheimer disease. However, the functional correlates of the vascular pathology induced by cerebral amyloid angiopathy and the mechanisms involved have not been fully established. Methods—We used male transgenic mice expressing the Swedish, Iowa, and Dutch mutations of the amyloid precursor protein (Tg-SwDI) to examine the effect of cerebral amyloid angiopathy on cerebrovascular structure and function. Somatosensory cortex cerebral blood flow was monitored by laser-Doppler flowmetry in anesthetized Tg-SwDI mice and wild-type littermates equipped with a cranial window. Results—Tg-SwDI mice exhibited reductions in cerebral blood flow responses to whisker stimulation, endothelium-dependent vasodilators, or hypercapnia at 3 months when compared with wild-type mice, whereas the response to adenosine was not attenuated. However, at 18 and 2...
104 citations
TL;DR: It is reported that the cerebrovascular dysfunction induced by Aβ is mediated by DNA damage caused by vascular oxidative-nitrosative stress in cerebral endothelial cells, which, in turn, activates the DNA repair enzyme poly(ADP)-ribose polymerase.
Abstract: Alzheimer's dementia is a devastating and incurable disease afflicting over 35 million people worldwide. Amyloid-β (Aβ), a key pathogenic factor in this disease, has potent cerebrovascular effects that contribute to brain dysfunction underlying dementia by limiting the delivery of oxygen and glucose to the working brain. However, the downstream pathways responsible for the vascular alterations remain unclear. Here we report that the cerebrovascular dysfunction induced by Aβ is mediated by DNA damage caused by vascular oxidative-nitrosative stress in cerebral endothelial cells, which, in turn, activates the DNA repair enzyme poly(ADP)-ribose polymerase. The resulting increase in ADP ribose opens transient receptor potential melastatin-2 (TRPM2) channels in endothelial cells leading to intracellular Ca(2+) overload and endothelial dysfunction. The findings provide evidence for a previously unrecognized mechanism by which Aβ impairs neurovascular regulation and suggest that TRPM2 channels are a potential therapeutic target to counteract cerebrovascular dysfunction in Alzheimer's dementia and related pathologies.
95 citations
01 Jan 2014
TL;DR: In this article, evidence-based recommendations are provided for the control of risk factors, interventional approaches to atherosclerotic disease of the cervicocephalic circulation, and antithrombotic treatments for preventing thrombosis and thromboembolic stroke.
Abstract: The aim of this updated statement is to provide comprehensive and timely evidence-based recommendations on the prevention of stroke among individuals who have not previously experienced a stroke or transient ischemic attack. Evidence-based recommendations are included for the control of risk factors, interventional approaches to atherosclerotic disease of the cervicocephalic circulation, and antithrombotic treatments for preventing thrombotic and thromboembolic stroke. Further recommendations are provided for genetic and pharmacogenetic testing and for the prevention of stroke in a variety of other specific circumstances, including sickle cell disease and patent foramen ovale. (Strok e. 2014;45:00-00.)
92 citations
TL;DR: The results indicate that excess Aβ can potentially disrupt hypothalamic arcuate NPY neurons leading to weight loss and a pathologically low leptin state early in the disease process that progressively worsens as the amyloid burden increases.
Abstract: Weight loss is a prominent early feature of Alzheimer's disease (AD) that often precedes the cognitive decline and clinical diagnosis. While the exact pathogenesis of AD remains unclear, accumulation of amyloid-β (Aβ) derived from the amyloid precursor protein (APP) in the brain is thought to lead to the neuronal dysfunction and death underlying the dementia. In this study, we examined whether transgenic mice overexpressing the Swedish mutation of APP (Tg2576), recapitulating selected features of AD, have hypothalamic leptin signaling dysfunction leading to early body weight deficits. We found that 3-month-old Tg2576 mice, before amyloid plaque formation, exhibit decreased weight with markedly decreased adiposity, low plasma leptin levels, and increased energy expenditure without alterations in feeding behavior. The expression of the orexigenic neuropeptide Y (NPY) in the hypothalamus to the low leptin state was abnormal at basal and fasting conditions. In addition, arcuate NPY neurons exhibited abnormal electrophysiological responses to leptin in Tg2576 hypothalamic slices or wild-type slices treated with Aβ. Finally, the metabolic deficits worsened as Tg2576 mice aged and amyloid burden increased in the brain. These results indicate that excess Aβ can potentially disrupt hypothalamic arcuate NPY neurons leading to weight loss and a pathologically low leptin state early in the disease process that progressively worsens as the amyloid burden increases. Collectively, these findings suggest that weight loss is an intrinsic pathological feature of Aβ accumulation and identify hypothalamic leptin signaling as a previously unrecognized pathogenic site of action for Aβ.
75 citations
TL;DR: A retrospectively analyzed all adult patients with active systemic cancer diagnosed with acute ischemic stroke at a tertiary care cancer center from 2005 through 2009 to find out whether cryptogenic stroke is independently associated with reduced survival in patients withactive cancer and isChemic stroke.
Abstract: Background and Purpose—Cryptogenic stroke is common in patients with cancer. Autopsy studies suggest that many of these cases may be because of marantic endocarditis, which is closely linked to cancer activity. We, therefore, hypothesized that among patients with cancer and ischemic stroke, those with cryptogenic stroke would have shorter survival. Methods—We retrospectively analyzed all adult patients with active systemic cancer diagnosed with acute ischemic stroke at a tertiary care cancer center from 2005 through 2009. Two neurologists determined stroke mechanisms by consensus. Patients were diagnosed with cryptogenic stroke if no specific mechanism could be determined. The diagnosis of marantic endocarditis was restricted to patients with cardiac vegetations on echocardiography or autopsy and negative blood cultures. Patients were followed until July 31, 2012, for the primary outcome of death. Kaplan–Meier statistics and the log-rank test were used to compare survival between patients with cryptogenic...
72 citations
TL;DR: It is demonstrated that after focal cerebral ischemia in vivo or oxygen–glucose deprivation in organotypic hippocampal slices or neurons, p75NTR is rapidly induced, and overexpression of miR-592 in neurons decreases the level of ischemic injury-induced p 75NTR and attenuates activation of pro-apoptotic signaling and cell death.
Abstract: The neurotrophin receptor p75NTR has been implicated in mediating neuronal apoptosis after injury to the CNS. Despite its frequent induction in pathologic states, there is limited understanding of the mechanisms that regulate p75NTR expression after injury. Here, we show that after focal cerebral ischemia in vivo or oxygen–glucose deprivation in organotypic hippocampal slices or neurons, p75NTR is rapidly induced. A concomitant induction of proNGF, a ligand for p75NTR, is also observed. Induction of this ligand/receptor system is pathologically relevant, as a decrease in apoptosis, after oxygen–glucose deprivation, is observed in hippocampal neurons or slices after delivery of function-blocking antibodies to p75NTR or proNGF and in p75NTR and ngf haploinsufficient slices. Furthermore, a significant decrease in infarct volume was noted in p75NTR−/− mice compared with the wild type. We also investigated the regulatory mechanisms that lead to post-ischemic induction of p75NTR. We demonstrate that induction of p75NTR after ischemic injury is independent of transcription but requires active translation. Basal levels of p75NTR in neurons are maintained in part by the expression of microRNA miR-592, and an inverse correlation is seen between miR-592 and p75NTR levels in the adult brain. After cerebral ischemia, miR-592 levels fall, with a corresponding increase in p75NTR levels. Importantly, overexpression of miR-592 in neurons decreases the level of ischemic injury-induced p75NTR and attenuates activation of pro-apoptotic signaling and cell death. These results identify miR-592 as a key regulator of p75NTR expression and point to a potential therapeutic candidate to limit neuronal apoptosis after ischemic injury.
72 citations
TL;DR: The components of the immune system required for induction of IT are described and the mechanisms by which a reprogrammed immune response contributes to the neuroprotection observed after preconditioning are reviewed.
Abstract: Stressor-induced tolerance is a central mechanism in the response of bacteria, plants, and animals to potentially harmful environmental challenges This response is characterized by immediate changes in cellular metabolism and by the delayed transcriptional activation or inhibition of genetic programs that are not generally stressor specific (cross-tolerance) These programs are aimed at countering the deleterious effects of the stressor While induction of this response (preconditioning) can be established at the cellular level, activation of systemic networks is essential for the protection to occur throughout the organs of the body This is best signified by the phenomenon of remote ischemic preconditioning, whereby application of ischemic stress to one tissue or organ induces ischemic tolerance in remote organs through humoral, cellular and neural signaling The immune system is an essential component in cerebral ischemic tolerance acting simultaneously both as mediator and target This dichotomy is based on the fact that activation of inflammatory pathways is necessary to establish ischemic tolerance and that ischemic tolerance can be, in part, attributed to a subdued immune activation after index ischemia Here we describe the components of the immune system required for induction of ischemic tolerance and review the mechanisms by which a reprogrammed immune response contributes to the neuroprotection observed after preconditioning Learning how local and systemic immune factors participate in endogenous neuroprotection could lead to the development of new stroke therapies
TL;DR: Findings show for the first time that dehydration alters critical mechanisms regulating the cerebral circulation through vasopressin and oxidative stress, which may alter cognitive function and increase the brain's susceptibility to cerebral ischemia.
Abstract: Adequate hydration is essential for normal brain function and dehydration induces cognitive deterioration. In addition, dehydration has emerged as a stroke risk factor. However, it is unknown whether alterations in cerebrovascular regulation are responsible for these effects. To address this issue, C57BI/6 mice were water deprived for 24 or 48 hours and somatosensory cortex blood flow was assessed by laser-Doppler flowmetry in a cranial window. Dehydration increased plasma osmolality and vasopressin levels, and suppressed the increase in blood flow induced by neural activity, by the endothelium-dependent vasodilator acetylcholine and the smooth muscle relaxant adenosine. The cerebrovascular dysfunction was associated with oxidative stress and cognitive deficits, assessed using the Y maze. The vasopressin la receptor antagonist SR49059 improved the dehydration-induced oxidative stress and vasomotor dysfunction. Dehydration upregulated endothelin-1 in cerebral blood vessels, an effect blocked by SR49059. Fu...
TL;DR: Correlations between baseline ChaCo and subsequent tissue loss suggest that the Network Modification Tool could be used to identify regions most susceptible to remote degeneration from acute infarcts, including those with sensorimotor, perception, learning, and memory functions.
Abstract: Background and Purpose— The Network Modification (NeMo) Tool uses a library of brain connectivity maps from normal subjects to quantify the amount of structural connectivity loss caused by focal brain lesions. We hypothesized that the Network Modification Tool could predict remote brain tissue loss caused by poststroke loss of connectivity. Methods— Baseline and follow-up MRIs (10.7±7.5 months apart) from 26 patients with acute ischemic stroke (age, 74.6±14.1 years, initial National Institutes of Health Stroke Scale, 3.1±3.1) were collected. Lesion masks derived from diffusion-weighted images were superimposed on the Network Modification Tool’s connectivity maps, and regional structural connectivity losses were estimated via the Change in Connectivity (ChaCo) score (ie, the percentage of tracks connecting to a given region that pass through the lesion mask). ChaCo scores were correlated with subsequent atrophy. Results— Stroke lesions’ size and location varied, but they were more frequent in the left hemisphere. ChaCo scores, generally higher in regions near stroke lesions, reflected this lateralization and heterogeneity. ChaCo scores were highest in the postcentral and precentral gyri, insula, middle cingulate, thalami, putamen, caudate nuclei, and pallidum. Moderate, significant partial correlations were found between baseline ChaCo scores and measures of subsequent tissue loss ( r =0.43, P =4.6×10 –9 ; r =0.61, P =1.4×10 –18 ), correcting for the time between scans. Conclusions— ChaCo scores varied, but the most affected regions included those with sensorimotor, perception, learning, and memory functions. Correlations between baseline ChaCo and subsequent tissue loss suggest that the Network Modification Tool could be used to identify regions most susceptible to remote degeneration from acute infarcts.
TL;DR: The hypothesis that the intensity of the hypoxic challenge determines the protective or destructive nature of CIH by modulating mitochondrial resistance to injury is tested and found that 10% CIH is neuroprotective, whereas 6%CIH exacerbates tissue damage.
Abstract: Background and Purpose—Obstructive sleep apnea, a condition associated with chronic intermittent hypoxia (CIH), carries an increased risk of stroke. However, CIH has been reported to either increase or decrease brain injury in models of focal cerebral ischemia. The factors determining the differential effects of CIH on ischemic injury and their mechanisms remain unclear. Here, we tested the hypothesis that the intensity of the hypoxic challenge determines the protective or destructive nature of CIH by modulating mitochondrial resistance to injury. Methods—Male C57Bl/6J mice were exposed to CIH with 10% or 6% O2 for ≤35 days and subjected to transient middle cerebral artery occlusion. Motor deficits and infarct volume were assessed 3 days later. Intraischemic cerebral blood flow was measured by laser-Doppler flowmetry and resting cerebral blood flow by arterial spin labeling MRI. Ca2+-induced mitochondrial depolarization and reactive oxygen species production were evaluated in isolated brain mitochondria. ...
TL;DR: Testing the hypothesis that changes in ovarian hormones with age promote susceptibility to AngII hypertension, and influence NMDA receptor NR1 subunit trafficking in ERβ‐containing PVN neurons suggests that, in young female mice, NR1 density is decreased in ER β‐PVN dendrites thus reducingNMDA receptor activity and preventing hypertension.
Abstract: The incidence of hypertension increases after menopause. Similar to humans, "slow-pressor" doses of angiotensin II (AngII) increase blood pressure in young males, but not in young female mice. However, AngII increases blood pressure in aged female mice, paralleling reproductive hormonal changes. These changes could influence receptor trafficking in central cardiovascular circuits and contribute to hypertension. Increased postsynaptic N-methyl-D-aspartate (NMDA) receptor activity in the hypothalamic paraventricular nucleus (PVN) is crucial for the sympathoexcitation driving AngII hypertension. Estrogen receptors β (ERβs) are present in PVN neurons. We tested the hypothesis that changes in ovarian hormones with age promote susceptibility to AngII hypertension, and influence NMDA receptor NR1 subunit trafficking in ERβ-containing PVN neurons. Transgenic mice expressing enhanced green fluorescent protein (EGFP) in ERβ-containing cells were implanted with osmotic minipumps delivering AngII (600 ng/kg/min) or saline for 2 weeks. AngII increased blood pressure in 2-month-old males and 18-month-old females, but not in 2-month-old females. By electron microscopy, NR1-silver-intensified immunogold (SIG) was mainly in ERβ-EGFP dendrites. At baseline, NR1-SIG density was greater in 2-month-old females than in 2-month-old males or 18-month-old females. After AngII infusion, NR1-SIG density was decreased in 2-month-old females, but increased in 2-month-old males and 18-month-old females. These findings suggest that, in young female mice, NR1 density is decreased in ERβ-PVN dendrites thus reducing NMDA receptor activity and preventing hypertension. Conversely, in young males and aged females, NR1 density is upregulated in ERβ-PVN dendrites and ultimately leads to the neurohumoral dysfunction driving hypertension.
TL;DR: It is demonstrated that prohibitin overexpression protects highly vulnerable CA1 neurons from ischemic injury in vivo and suggested that the effect is mediated by reduction of postischemic reactive oxygen species generation and preservation of mitochondrial outer membrane integrity that prevents activation of apoptosis.
Abstract: Background and Purpose—Prohibitin is a multi-functional protein involved in numerous cellular activities. Prohibitin overexpression protects neurons from injury in vitro, but it is unclear whether prohibitin can protect selectively vulnerable hippocampal CA1 neurons in a clinically relevant injury model in vivo and, if so, whether the salvaged neurons remain functional. Methods—A mouse model of transient forebrain ischemia that mimics the brain damage produced by cardiac arrest in humans was used to test whether prohibitin expression protects CA1 neurons from injury. Prohibitin-expressing viral vector was microinjected in mouse hippocampus to upregulate prohibitin. Results—Prohibitin overexpression protected CA1 neurons from transient forebrain ischemia. The protection was associated with dampened postischemic reactive oxygen species generation, reduced mitochondrial cytochrome c release, and decreased caspase-3 activation. Importantly, the improvement in CA1 neuronal viability translated into an improvem...
TL;DR: The pathobiology of CD36 is complex involving both tissue destruction, related mainly to oxidative stress and inflammation, and beneficial reparative effects due to the involvement ofCD36 in tissue repair and reorganization.
TL;DR: A 44-year-old man who presented with a first-time seizure but was otherwise neurologically intact and denied any headache is reported, demonstrating that ABRA can occur in young patients without headache or neurologic deficits, and should be considered in patients with new-onset seizures and mass lesions.
Abstract: Amyloid beta-related angiitis (ABRA) of the central nervous system (CNS) is a very rare inflammatory disorder that causes destruction of CNS arteries and subsequent neuronal injury. Most patients with ABRA are old and present with cognitive dysfunction and stroke; however, some patients may present atypically. In this article, we report a 44-year-old man who presented with a first-time seizure but was otherwise neurologically intact and denied any headache. Brain MRI showed right hemispheric and bilateral medial frontal lobe hyperintensities and microhemorrhages that were most suspicious for a mass lesion. An extensive diagnostic evaluation including CSF analysis and catheter angiography was unremarkable. A brain biopsy with specific stains for amyloid surprisingly demonstrated ABRA and led to immunosuppressive treatment. The patient has remained neurologically intact and seizure-free 1 year after presentation. This case demonstrates that ABRA can occur in young patients without headache or neurologic deficits, and should be considered in patients with new-onset seizures and mass lesions. It also reinforces the need to consider a brain biopsy in patients with idiopathic brain lesions and negative non-invasive testing, as it is virtually impossible to confirm the diagnosis of ABRA otherwise.
Patent•
31 Oct 2014TL;DR: In this article, the authors present compositions and methods to treat Alzheimer's disease and other neurodegenerative diseases and conditions by expressing exogenous prohibitin in the neurons of the brain of the subject.
Abstract: The present invention provides compositions and methods to treat Alzheimer's disease and other neurodegenerative diseases and conditions by expressing exogenous prohibitin in the neurons of the brain of the subject.
TL;DR: The body clears small clots from blood vessels through a process called angiophagy, opening up new approaches to combat cerebral and cardiac microvascular occlusive diseases.
Abstract: The body clears small clots from blood vessels through a process called angiophagy, opening up new approaches to combat cerebral and cardiac microvascular occlusive diseases (Grutzendler et al., this issue).
Journal Article•
TL;DR: The results suggest that early amyloid-beta excess may cause a low leptin state by disrupting specific hypothalamic neuronal populations in mice overexpressing the Swedish mutation of APP.
Abstract: OBJECTIVE: To determine whether excess amyloid-beta early in Alzheimer’s disease (AD) leads to reduced adiposity by disrupting hypothalamic leptin signals.
BACKGROUND: An early manifestation in preclinical AD is weight loss of unclear etiology. Low plasma levels of leptin, an adipocyte hormone acting on the hypothalamus to regulate body weight, have also been correlated with increased AD risk. Therefore, increased amyloid-beta levels derived from amyloid precursor protein (APP) may disrupt hypothalamic leptin signaling early in AD.
DESIGN/METHODS: Metabolic function (body weight, adiposity by MR spectroscopy, food intake, metabolic rate by indirect calorimetry, plasma insulin and leptin by ELISA, blood glucose by glucometer) was assessed in transgenic mice overexpressing the Swedish mutation of APP (Tg2576) prior to amyloid plaque formation (age 3 months) and wild-type littermates at baseline and after 48-hour fast. Gene expression was analyzed by quantitative RT-PCR.
RESULTS: Compared to wild-type littermates, Tg2576 mice had at baseline: (1) decreased body weight and adiposity, (2) reduced plasma leptin but normal insulin and glucose levels, (3) normal food intake but increased metabolic rate. In the hypothalamus of Tg2576 mice, anorexigenic proopiomelanocortin (POMC) mRNA levels were appropriately decreased, but orexigenic agouti-related protein (AgRP) levels were not elevated despite low leptin levels. Fasting led to similar weight loss and reduced glucose and insulin levels in both groups. However, while plasma leptin appropriately decreased in fasted wild-type mice, no difference was found in Tg2576 mice. Furthermore, fasted Tg2576 mice had a blunted hypothalamic AgRP response.
CONCLUSIONS: These results suggest that early amyloid-beta excess may cause a low leptin state by disrupting specific hypothalamic neuronal populations. The molecular bases of the leptin dysfunction in Tg2576 mice remain to be elucidated and may lead to the identification of novel preclinical biomarkers and therapeutic targets for AD.
Study Supported by: Leon Levy Neuroscience Fellowship (M.I.) and NS37853 (C.I.). Disclosure: Dr. Ishii has nothing to disclose. Dr. Iadecola has received personal compensation in an editorial capacity for the Journal of Neuroscience.