losartan-potassium and Alzheimer-Disease

During the last three decades, recombinant DNA technology has produced a wide range of hematopoietic and neurotrophic growth factors, including erythropoietin (EPO), which has emerged as a promising protein drug in the treatment of several diseases. Cumulative studies have recently indicated the neuroprotective role of EPO in preclinical models of acute and chronic neurodegenerative disorders, including Alzheimer's disease (AD). AD is one of the most prevalent neurodegenerative illnesses in the elderly, characterized by the accumulation of extracellular amyloid-ß (Aß) plaques and intracellular neurofibrillary tangles (NFTs), which serve as the disease's two hallmarks. Unfortunately, AD lacks a successful treatment strategy due to its multifaceted and complex pathology. Various clinical studies, both in vitro and in vivo, have been conducted to identify the various mechanisms by which erythropoietin exerts its neuroprotective effects. The results of clinical trials in patients with AD are also promising. Herein, it is summarized and reviews all such studies demonstrating erythropoietin's potential therapeutic benefits as a pleiotropic neuroprotective agent in the treatment of Alzheimer's disease.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Erythropoietin; Humans; Neuroprotective Agents; Plaque, Amyloid

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the world, and intracellular neurofibrillary tangles and extracellular amyloid-beta protein deposits represent the major pathological hallmarks of the disease. Currently available treatments provide some symptomatic relief but fail to modify primary pathological processes that underlie the disease. Erythropoietin (EPO), a hematopoietic growth factor, acts primarily to stimulate erythroid cell production, and is clinically used to treat anemia. EPO has evolved as a therapeutic agent for neurodegeneration and has improved neurological outcomes and AD pathology in rodents. However, penetration of the blood-brain barrier (BBB) and negative hematopoietic effects are the two major challenges for the therapeutic development of EPO for chronic neurodegenerative diseases like AD. The transferrin receptors at the BBB, which are responsible for transporting transferrin-bound iron from the blood into the brain parenchyma, can be used to shuttle therapeutic molecules across the BBB. In this review, we discuss the role of EPO as a potential neurotherapeutic for AD, challenges associated with EPO development for AD, and targeting the BBB transferrin receptor for EPO brain delivery.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Cognition; Erythropoietin; Gene Expression Regulation; Genetic Predisposition to Disease; Humans; Inflammation; Mice; Microglia; Mitochondria; Models, Neurological; Neuroprotective Agents; Neurotransmitter Agents; Oxidative Stress; Protein Transport; Rats; Receptors, Erythropoietin; Receptors, Transferrin; Transcytosis

Hemoglobins (Hbs) are heme-containing proteins binding oxygen, carbon monoxide, and nitric oxide. While erythrocytes are the most well-known location of Hbs, Hbs also exist in neurons, glia and oligodendroglia and they are primarily localized in the inner mitochondrial membrane of neurons with likely roles in cellular respiration and buffering protons. Recently, studies have suggested links between hypoxia and neurodegenerative disorders such as Alzheimer Disease (AD) and furthermore suggested involvement of Hbs in the pathogenesis of AD. While cellular immunohistochemical studies on AD brains have observed reduced levels of Hb in the cytoplasm of pre-tangle and tangle-bearing neurons, other studies on homogenates of AD brain samples observed increased Hb levels. This potential discrepancy may result from differential presence and function of intracellular versus extracellular Hbs. Intracellular Hbs may protect neurons against hypoxia and hyperoxia. On the other hand, extracellular free Hb and its degradation products may trigger inflammatory immune and oxidative reactions against neural macromolecules and/or damage the blood-brain barrier. Therefore, biological processes leading to reduction of Hb transcription (including clinically silent Hb mutations) may influence intra-erythrocytic and neural Hbs, and reduce the transport of oxygen, carbon monoxide and nitric oxide which may be involved in the (patho)physiology of neurodegenerative disorders such as AD. Agents such as erythropoietin, which stimulate both erythropoiesis, reduce eryptosis and induce intracellular neural Hbs may exert multiple beneficial effects on the onset and course of AD. Thus, evidence accumulates for a role of Hbs in the central nervous system while Hbs deserve more attention as possible candidate molecules involved in AD.

Topics: Alzheimer Disease; Animals; Blood-Brain Barrier; Brain; Cell Hypoxia; Disease Models, Animal; Erythropoietin; Hemoglobins; Humans; Mutation; Neurons; Thalassemia

Diabetes mellitus (DM) is a significant healthcare concern worldwide that affects more than 165 million individuals leading to cardiovascular disease, nephropathy, retinopathy, and widespread disease of both the peripheral and central nervous systems. The incidence of undiagnosed diabetes, impaired glucose tolerance, and impaired fasting glucose levels raises future concerns in regards to the financial and patient care resources that will be necessary to care for patients with DM. Interestingly, disease of the nervous system can become one of the most debilitating complications and affect sensitive cognitive regions of the brain, such as the hippocampus that modulates memory function, resulting in significant functional impairment and dementia. Oxidative stress forms the foundation for the induction of multiple cellular pathways that can ultimately lead to both the onset and subsequent complications of DM. In particular, novel pathways that involve metabotropic receptor signaling, protein-tyrosine phosphatases, Wnt proteins, Akt, GSK-3beta, and forkhead transcription factors may be responsible for the onset and progression of complications form DM. Further knowledge acquired in understanding the complexity of DM and its ability to impair cellular systems throughout the body will foster new strategies for the treatment of DM and its complications.

Topics: Alzheimer Disease; Animals; Apoptosis; Blood Glucose; Diabetes Mellitus; Erythropoietin; Glycogen Synthase Kinases; GTP-Binding Proteins; Humans; Insulin Resistance; Mitochondria; Models, Biological; Oxidative Stress; Phosphatidylinositol 3-Kinases; Wnt Proteins

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by memory impairment in patients. Erythropoietin (EPO) has been reported to stimulate neurogenesis. This study was conducted to determine the regenerative effects of EPO in an AD model and to assess its underlying mechanism. Recombinant human EPO was intraperitoneally administered to AD mice induced by intracerebroventricular Aβ oligomer injection. Behavioral assessments with novel object recognition test and passive avoidance task showed improvement in memory function of the EPO-treated AD mice compared to that of the saline-treated AD mice (p < 0.0001). An in vivo protein assay for the hippocampus and cortex tissue indicated that EPO treatment modulated neurotransmitters, including dopamine, serotonin, and adrenaline. EPO treatment also restored the activity of serotonin receptors, including 5-HT4R, 5-HT7R, and 5-HT1aR (p < 0.01), at mRNA levels. Furthermore, EPO seemed to exert an anti-inflammatory influence by downregulating TLR4 at mRNA and protein levels (p < 0.05). Finally, an immunohistochemical assay revealed increments of Nestin(+) and NeuN(+) neuronal cells in the CA3 region in the EPO-treated AD mice compared to those in the saline-treated AD mice. The conclusion is that EPO administration might be therapeutic for AD by activating the serotonergic pathway, anti-inflammatory action, and neurogenic characteristics.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Epoetin Alfa; Erythropoietin; Hippocampus; Humans; Mice; Neurodegenerative Diseases; Recombinant Proteins; RNA, Messenger; Serotonin

Impaired clearance of beta-amyloid (Aβ) is a primary cause of sporadic Alzheimer's disease (AD). Aβ clearance in the periphery contributes to reducing brain Aβ levels and preventing Alzheimer's disease pathogenesis. We show here that erythropoietin (EPO) increases phagocytic activity, levels of Aβ-degrading enzymes, and Aβ clearance in peripheral macrophages via PPARγ. Erythropoietin is also shown to suppress Aβ-induced inflammatory responses. Deletion of EPO receptor in peripheral macrophages leads to increased peripheral and brain Aβ levels and exacerbates Alzheimer's-associated brain pathologies and behavioral deficits in AD-model mice. Moreover, erythropoietin signaling is impaired in peripheral macrophages of old AD-model mice. Exogenous erythropoietin normalizes impaired EPO signaling and dysregulated functions of peripheral macrophages in old AD-model mice, promotes systemic Aβ clearance, and alleviates disease progression. Erythropoietin treatment may represent a potential therapeutic approach for Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Disease Models, Animal; Erythropoietin; Macrophages; Mice; Mice, Transgenic

Intracerebroventricular (icv) administration of streptozotocin (STZ) has been used as a metabolic model of sporadic Alzheimer's disease (AD). Erythropoietin (EPO) possesses neuroprotective and memory-improving effects, which might be advantageous in treating different characteristics of AD. Nevertheless, the hematopoietic effect of EPO has hindered its application as a neuroprotective agent. Previous studies have shown that a new Epo derivative called carbamylated Erythropoietin-Fc (CEPO-Fc), yield noticeable neuroprotective effects without affecting hematopoiesis. In this study, the neuroprotective effects of CEPO-Fc on icv-STZ induced memory impairment and hippocampal apoptosis were examined. Adult male Wistar rats weighing 250-300 g were used. STZ was administered on days 1 and 3 (3 mg/kg in divided doses/icv), and CEPO-Fc was administered at the dose of 5000 IU/ip/daily during days 4-14. The animals were trained in Morris water maze during days 15-17, and the memory retention test was performed on the 18th day. Following behavioral studies, the animals were sacrificed and their hippocampi isolated to determine the amounts of cleaved caspase-3 (the landmark of apoptosis). The results showed that CEPO-Fc treatment at the dose of 5000 IU/kg/ip was able to prevent the learning and memory deficit induced by icv-STZ. Western blot analysis revealed that STZ prompted the cleavage of caspase-3 in the hippocampus while pretreatment with CEPO-Fc significantly reduced the cleavage of this protein. Collectively, our findings suggest that CEPO-Fc could restore STZ-induced learning and memory impairment as well as apoptosis in the hippocampal region in a rat model of sporadic AD induced by icv-STZ.

Topics: Alzheimer Disease; Animals; Antibiotics, Antineoplastic; Apoptosis; Behavior, Animal; Brain; Caspase 3; Disease Models, Animal; Erythropoietin; Hippocampus; Immunoglobulin Fc Fragments; Injections, Intraventricular; Learning; Memory; Morris Water Maze Test; Neuroprotective Agents; Rats; Recombinant Fusion Proteins; Streptozocin

Alzheimer's Disease (AD) features the accumulation of β-amyloid in erythrocytes. The subsequent red cell damage may well affect their oxygen-carrying capabilities. 2,3- diphosphoglycerate (2,3-DPG) binds to the hemoglobin thereby promoting oxygen release. It is theorized that 2,3-DPG is reduced in AD and that the resulting hypoxia triggers erythropoietin (EPO) release.. To explore this theory, we analyzed red cell 2,3-DPG content and EPO in AD, mild cognitive impairment, and the control group, subjective cognitive impairment.. We studied (i) 2,3-DPG in red cells, and (ii) circulating EPO in AD, and both markers were unaffected by dementia. Disturbances of these oxygen-regulatory pathways do not appear to participate in brain hypoxia in AD.

Topics: 2,3-Diphosphoglycerate; Aged; Alzheimer Disease; Biomarkers; Cognitive Dysfunction; Cohort Studies; Diagnostic Self Evaluation; Erythrocytes; Erythropoietin; Female; Humans; Male; Middle Aged

Erythropoietin (EPO) is a potential therapeutic for Alzheimer's disease (AD); however, limited blood-brain barrier (BBB) penetration reduces its applicability as a CNS therapeutic. Antibodies against the BBB transferrin receptor (TfRMAbs) act as molecular Trojan horses for brain drug delivery, and a fusion protein of EPO and TfRMAb, designated TfRMAb-EPO, is protective in a mouse model of AD. TfRMAbs have Fc effector function side effects, and removal of the Fc N-linked glycosylation site by substituting Asn with Gly reduces the Fc effector function. However, the effect of such Fc mutations on the pharmacokinetics (PK) of plasma clearance of TfRMAb-based fusion proteins, such as TfRMAb-EPO, is unknown. To examine this, the plasma PK of TfRMAb-EPO (wild-type), which expresses the mouse IgG1 constant heavy chain region and includes the Asn residue at position 292, was compared to the mutant TfRMAb-N292G-EPO, in which the Asn residue at position 292 is mutated to Gly. Plasma PK was compared following IV, IP, and SQ administration for doses between 0.3 and 3 mg/kg in adult male C57 mice. The results show a profound increase in clearance (6- to 8-fold) of the TfRMAb-N292G-EPO compared with the wild-type TfRMAb-EPO following IV administration. The clearance of both the wild-type and mutant TfRMAb-EPO fusion proteins followed nonlinear PK, and a 10-fold increase in dose resulted in a 7- to 11-fold decrease in plasma clearance. Following IP and SQ administration, the

Topics: Alzheimer Disease; Animals; Antibodies, Monoclonal; Blood-Brain Barrier; Cell Line; Endothelial Cells; Erythropoietin; Humans; Immunoconjugates; Immunoglobulin Constant Regions; Immunoglobulin G; Injections, Intravenous; Injections, Subcutaneous; Male; Mice; Mutation; Receptors, Transferrin; Recombinant Fusion Proteins; Reticulocytes

Cognitive dysfunction is reported to be a major cause of morbidity in chronic kidney disease (CKD). The senile plaques (SPs) in the brain are one of the most pathophysiological characteristics of cognitive dysfunction and its major constituent amyloid β (Aβ) released from amyloid precursor protein (APP) by β (BACE1) and γ (presenilin 1) secretases . Platelets contain more than 95% of the circulating APP and implicate as a candidate biomarker for cognitive decline. Recombinant human erythropoietin (rHuEPO) is a standard therapy for anemia in CKD and also acts as a neuroprotective agent. The aim of the study is to determine the impact of rHuEPO therapy on platelet APP processing in CKD with Cognitive Dysfunction.. A total of 60 subjects comprising of 30 CKD without cognitive dysfunction and 30 CKD with cognitive dysfunction based on neuropsychological assessment. APP, BACE1, Presenilin 1, ADAM 10 (α secretase) and Aβ expressions in platelets were determined by western blotting and lipid peroxidation (LPO) in platelet rich plasma (PRP) was done by spectrophotometrically. The parameters were statistically compared with Alzheimer's disease (AD), Normocytic normochromic anemic and healthy subjects.. Significantly (p < 0.05) decreased APP, ADAM 10 while increased BACE1, Presenilin 1, Aβ and LPO were observed in CKD with cognitive dysfunction like AD subjects compared to other groups. The parameters were reassessed in CKD with cognitive dysfunction subjects after rHuEPO (100 IU/ kg, weekly twice, 6 months) therapy. All the parameters were retrieved significantly (p < 0.05) along with improved neuropsychological tests scoring after rHuEPO therapy.. This study demonstrated that rHuEPO is an effective neuroprotective agent in the context of CKD associated cognitive dysfunction and proved its clinical usefulness.

Topics: ADAM10 Protein; Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Blood Platelets; Brain; Cognitive Dysfunction; Erythropoietin; Female; Humans; Male; Middle Aged; Neuroprotective Agents; Pilot Projects; Presenilin-1; Proteins; Recombinant Proteins; Renal Insufficiency, Chronic; Young Adult

Topics: Activities of Daily Living; Aged; Alzheimer Disease; Anemia; Erythropoietin; Female; Hip Fractures; Humans; Kidney Failure, Chronic

Erythropoietin (EPO), a glycoprotein cytokine essential to hematopoiesis, has neuroprotective effects in rodent models of Alzheimer's disease (AD). However, high therapeutic doses or invasive routes of administration of EPO are required to achieve effective brain concentrations due to low blood-brain barrier (BBB) penetrability, and high EPO doses result in hematopoietic side effects. These obstacles can be overcome by engineering a BBB-penetrable analog of EPO, which is rapidly cleared from the blood, by fusing EPO to a chimeric monoclonal antibody targeting the transferrin receptor (cTfRMAb), which acts as a molecular Trojan horse to ferry the EPO into the brain via the transvascular route. In the current study, we investigated the effects of the BBB-penetrable analog of EPO on AD pathology in a double transgenic mouse model of AD. Five and a half month old male APPswe/PSEN1dE9 (APP/PS1) transgenic mice were treated with saline ( n = 10) or the BBB-penetrable EPO ( n = 10) 3 days/week intraperitoneally for 8 weeks, compared to same-aged C57BL/6J wild-type mice treated with saline ( n = 8) with identical regiment. At 9 weeks following treatment initiation, exploration and spatial memory were assessed with the open-field and Y-maze test, mice were sacrificed, and brains were evaluated for Aβ peptide load, synaptic loss, BBB disruption, microglial activation, and microhemorrhages. APP/PS1 mice treated with the BBB-penetrable cTfRMAb-EPO fusion protein had significantly lower cortical and hippocampal Aβ peptide number ( p < 0.05) and immune-positive area ( p < 0.05), a decrease in hippocampal synaptic loss ( p < 0.05) and cortical microglial activation ( p < 0.001), and improved spatial memory ( p < 0.05) compared with APP/PS1 saline controls. BBB-penetrating EPO was not associated with microhemorrhage development. The cTfRMAb-EPO fusion protein offers therapeutic benefits by targeting multiple targets of AD pathogenesis and progression (Aβ load, synaptic loss, microglial activation) and improving spatial memory in the APP/PS1 mouse model of AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Blood-Brain Barrier; CHO Cells; Cricetulus; Disease Models, Animal; Erythropoietin; Humans; Immunoconjugates; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Permeability; Receptors, Transferrin; Recombinant Fusion Proteins; Treatment Outcome

Erythropoietin (EPO) is a cytokine known to have effective cytoprotective action in the brain, particularly in ischemic, traumatic, inflammatory, and neurodegenerative conditions. We previously reported the neuroprotective effect of a low sialic form of EPO, Neuro-EPO, applied intranasally in rodent models of stroke or cerebellar ataxia and in a non-transgenic mouse model of Alzheimer's disease (AD). Here we analyzed the protective effect of Neuro-EPO in APPSwe mice, a reference transgenic mouse model of AD. Mice were administered 3 times a day, 3 days in the week with Neuro-EPO (125, 250 μg/kg) intranasally, between 12 and 14 months of age. Motor responses, general activity, and memory responses were analyzed during and after treatment. The deficits in spontaneous alternation, place learning in the water-maze, and novel object recognition observed in APPSwe mice were alleviated by the low dose of Neuro-EPO. Oxidative stress, neuroinflammation, trophic factor levels, and a synaptic marker were analyzed in the hippocampus or cortex of the animals. The increases in lipid peroxidation or in GFAP and Iba-1 contents in APPSwe mice were significantly reduced after Neuro-EPO. Activation of intrinsic and extrinsic apoptotic pathways was analyzed. The increases in Bax/Bcl-2 ratio, TNFα, or Fas ligand levels observed in APPSwe mice were reduced by Neuro-EPO. Finally, immunohistochemical and ELISA analyses of Aβ1-42 levels in the APPSwe mouse cortex and hippocampus showed a marked reduction in Aβ deposits and in soluble and insoluble Aβ1-42 forms. This study therefore confirmed the neuroprotective activity of EPO, particularly for an intranasally deliverable formulation, devoid of erythropoietic side effects, in a transgenic mouse model of AD. Neuro-EPO alleviated memory alterations, oxidative stress, neuroinflammation, apoptosis induction, and amyloid load in 14-month-old APPSwe mice.

Topics: Administration, Intranasal; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cerebral Cortex; Disease Models, Animal; Erythropoietin; Hippocampus; Maze Learning; Memory; Memory Disorders; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity; N-Acetylneuraminic Acid; Neuroprotective Agents; Nootropic Agents

Erythropoietin and curcumin showed promising neuroprotective effects in various models of Alzheimer's dementia. This study was designed to compare the beneficial effects of erythropoietin and/or curcumin in intracerebro-ventricular (ICV) streptozotocin-induced Alzheimer's like disease in rats. Rats received ICV injection of either saline (control, n=8 rats), or streptozotocin. Three weeks following surgery, streptozotocin-injected rats were assigned into 4 groups (8 rats each); vehicle, curcumin (80mg/kg/day, orally), erythropoietin (500 IU/kg every other day, intraperitoneally) and combined (curcumin and erythropoietin)-treated groups. After 3 months of treatment, rats were subjected to neurobehavioral testing, and then killed for biochemical and histological assessment of hippocampus. Fas ligand protein and caspase-8 activity as mediators of extrinsic apoptotic pathway, oxidative stress markers (malondialdehyde and reduced glutathione) and β-amyloid (1-40 and 1-42) peptides were measured. The results showed that administration of erythropoietin suppressed extrinsic apoptosis better than curcumin, while curcumin was more effective in combating oxidative stress in ICV-streptozotocin injected rats. Both erythropoietin and curcumin treatments (individually or combined) equally reduced the hippocampal β-amyloid accumulation and improved cognitive impairment in Morris water maze and passive avoidance tasks. The combined treatment was the most effective in ameliorating apoptosis and oxidative stress rather than behavioral responses or β-amyloid burden. In conclusion, ICV-streptozotocin-induced Alzheimer's dementia activates hippocampal Fas ligand-mediated apoptosis, which could be reduced by erythropoietin and/or curcumin treatment. Curcumin supplementation alone could ameliorate cognitive deficits and reverse biochemical alterations in ICV-streptozotocin Alzheimer's rat model without the hazardous polycythemic effect of long-term erythropoietin injection.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Apoptosis; Behavior, Animal; Curcumin; Erythropoietin; Hematocrit; Hippocampus; Male; Oxidative Stress; Rats; Rats, Wistar; Retention, Psychology; Signal Transduction; Spatial Learning; Streptozocin

Several studies indicate erythropoietin (Epo) to have remarkable neuroprotection in various central nervous system disorders, including Alzheimer's disease (AD). Amyloid beta (Aβ) is believed to be responsible for the synaptic dysfunction that occurs in AD. Therefore, the present study is aimed to investigate the effects of Epo on the Aβ-induced impairments in learning-memory and hippocampal synaptic plasticity.. Male Sprague-Dawley rats (200-250 g) were used in this study. After the injection of Aβ, they were injected intra-peritoneal with Epo in the Aβ+Epo group or its vehicle in the Aβ+V group every other day for 12 days. A shuttle box apparatus was used for the passive avoidance learning and memory study. Moreover, paired-pulse ratio (PPR) was monitored before and after tetanic stimulation.. Bilateral injection of Aβ decreased step-through latency (STL), whereas the 12 day administration of Epo significantly improved memory performance in Aβ+Epo group. The field potential recording demonstrated that the in vivo administration of Aβ25-35 led to extreme inhibition in long-term potentiation, this inhibition was accompanied by a significant increase of the normalized PPR (PPR after HFS/PPR before HFS) as an index for release probability. However, administration of Epo recovers the magnitude of the LTP and the extent of normalized PPR.. The results of this study demonstrated that the injection of Aβ25-35 resulted in impaired LTP and the memory process, which is likely mediated through increasing the release probability of neurotransmitter vesicles. In addition, treatment with Epo improved the Aβ-induced deficits in memory and LTP induction, probably via recovering the release probability.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Avoidance Learning; Disease Models, Animal; Erythropoietin; Excitatory Postsynaptic Potentials; Glutamic Acid; Hematocrit; Hippocampus; Long-Term Potentiation; Male; Memory Disorders; Neuronal Plasticity; Neuroprotective Agents; Peptide Fragments; Rats

Neuroprotection of erythropoietin (EPO) following long-term administration is hampered by the associated undesirable effects on hematopoiesis and body weight. For this reason, we tested carbamylated-EPO (CEPO), which has no effect on erythropoiesis, and compared it with EPO in the AβPP/PS1 mouse model of familial Alzheimer’s disease. Groups of 5-month old wild type (WT) and transgenic mice received chronic treatment consisting of CEPO (2,500 or 5,000 UI/kg) or EPO (2,500 U I/kg) 3 days/week for 4 weeks. Memory at the end of treatment was assessed with the object recognition test. Microarray analysis and quantitative-PCR were used for gene expression studies. No alterations in erythropoiesis were observed in CEPO-treated WT and AβPP/PS1 transgenic mice. EPO and CEPO improved memory in AβPP/PS1 animals. However, only EPO decreased amyloid-β (Aβ)plaque burden and soluble Aβ(40). Microarray analysis of gene expression revealed a limited number of common genes modulated by EPO and CEPO. CEPO but not EPO significantly increased gene expression of dopamine receptors 1 and 2, and adenosine receptor 2a, and significantly down-regulated adrenergic receptor 1D and gastrin releasing peptide. CEPO treatment resulted in higher protein levels of dopamine receptors 1 and 2 in WT and AβPP/PS1 animals, whereas the adenosine receptor 2a was reduced in WT animals. The present results suggest that the improved behavior observed in AβPP/PS1 transgenic mice after CEPO treatment may be mediated, at least in part, by the observed modulation of the expression of molecules involved in neurotransmission.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Body Weight; Disease Models, Animal; Erythropoietin; Gastrin-Releasing Peptide; Gene Expression Regulation; Humans; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Peptide Fragments; Presenilin-1; Receptors, Catecholamine; Synapses; Time Factors

Alzheimer's disease is a neurodegenerative disorder clinically characterized by cognitive dysfunction and by deposition of amyloid plaques, neurofibrillary tangles in the brain. The study investigated the therapeutic effect of combined mesenchymal stem cells and erythropoietin on Alzheimer's disease. Five groups of mice were used: control group, Alzheimer's disease was induced in four groups by a single intraperitoneal injection of 0.8 mg kg(-1) lipopolysaccharide and divided as follows: Alzheimer's disease group, mesenchymal stem cells treated group by injecting mesenchymal stem cells into the tail vein (2 x 10(6) cells), erythropoietin treated group (40 microg kg(-1) b.wt.) injected intraperitoneally 3 times/week for 5 weeks and mesenchymal stem cells and erythropoietin treated group. Locomotor activity and memory were tested using open field and Y-maze. Histological, histochemical, immunohistochemical studies, morphometric measurements were examined in brain sections of all groups. Choline transferase activity, brain derived neurotrophic factor expression and mitochondrial swellings were assessed in cerebral specimens. Lipopolysaccharide decreased locomotor activity, memory, choline transferase activity and brain derived neurotrophic factor. It increased mitochondrial swelling, apoptotic index and amyloid deposition. Combined mesenchymal stem cells and erythropoietin markedly improved all these parameters. This study proved the effective role of mesenchymal stem cells in relieving Alzheimer's disease symptoms and manifestations; it highlighted the important role of erythropoietin in the treatment of Alzheimer's disease.

Topics: Alzheimer Disease; Animals; Brain; Brain-Derived Neurotrophic Factor; Choline O-Acetyltransferase; Cognition; Endoglin; Erythropoietin; Gene Expression Regulation; Intracellular Signaling Peptides and Proteins; Lipopolysaccharides; Locomotion; Male; Maze Learning; Mesenchymal Stem Cell Transplantation; Mice; Mitochondrial Size; Organic Chemicals; Treatment Outcome

Long noncoding RNA (lncRNA) within mRNA sequences of Alzheimer's disease genes, namely, APP, APOE, PSEN1, and PSEN2, has been analyzed using fractal dimension (FD) computation and correlation analysis. We examined lncRNA by comparing mRNA FD to corresponding coding DNA sequences (CDSs) FD. APP, APOE, and PSEN1 CDSs select slightly higher FDs compared to the mRNA, while PSEN2 CDSs FDs are lower. The correlation coefficient for these sequences is 0.969. A comparative study of differentially expressed MAPK signaling pathway lncRNAs in pancreatic cancer cells shows a correlation of 0.771. Selection of higher FD CDSs could indicate interaction of Alzheimer's gene products APP, APOE, and PSEN1. Including hypocretin sequences (where all CDSs have higher fractal dimensions than mRNA) in the APP, APOE, and PSEN1 sequence analyses improves correlation, but the inclusion of erythropoietin (where all CDSs have higher FD than mRNA) would suppress correlation, suggesting that HCRT, a hypothalamus neurotransmitter related to the wake/sleep cycle, might be better when compared to EPO, a glycoprotein hormone, for targeting Alzheimer's disease drug development. Fractal dimension and entropy correlation have provided supporting evidence, consistent with evolutionary studies, for using a zebrafish model together with a mouse model, in HCRT drug development.

Topics: 5'-Nucleotidase; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Apolipoproteins E; Computational Biology; Disease Models, Animal; Drug Discovery; Erythropoietin; Fractals; Glycoproteins; Humans; Intracellular Signaling Peptides and Proteins; Mice; Neuropeptides; Orexin Receptors; Orexins; Presenilin-2; Receptors, Erythropoietin; RNA, Long Noncoding; RNA, Messenger; Sequence Analysis, RNA; Zebrafish

Erythropoietin (EPO) promotes neurogenesis and neuroprotection. We here compared the protection induced by two EPO formulations in a rodent model of Alzheimer's disease (AD): rHu-EPO and a low sialic form, Neuro-EPO. We used the intracerebroventricular administration of aggregated Aβ₂₅₋₃₅ peptide, a non-transgenic AD model. rHu-EPO was tested at 125-500 µg/kg intraperitoneally and Neuro-EPO at 62-250 µg/kg intranasally (IN). Behavioural procedures included spontaneous alternation, passive avoidance, water-maze and object recognition, to address spatial and non-spatial, short- and long-term memories. Biochemical markers of Aβ₂₅₋₃₅ toxicity in the mouse hippocampus were examined and cell loss in the CA1 layer was determined. rHu-EPO and Neuro-EPO led to a significant prevention of Aβ₂₅₋₃₅-induced learning deficits. Both EPO formulations prevented the induction of lipid peroxidation in the hippocampus, showing an antioxidant activity. rHu-EPO (250 µg/kg) or Neuro-EPO (125 µg/kg) prevented the Aβ₂₅₋₃₅-induced increase in Bax level, TNFα and IL-1β production and decrease in Akt activation. A significant prevention of the Aβ₂₅₋₃₅-induced cell loss in CA1 was also observed. EPO is neuroprotective in the Aβ₂₅₋₃₅ AD model, confirming its potential as an endogenous neuroprotection system that could be boosted for therapeutic efficacy. We here identified a new IN formulation of EPO showing high neuroprotective activity. Considering its efficacy, ease and safety, IN Neuro-EPO is a new promising therapeutic agent in AD.

Topics: Administration, Intranasal; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Count; Chemistry, Pharmaceutical; Disease Models, Animal; Dose-Response Relationship, Drug; Erythropoietin; Hippocampus; Humans; Interleukin-1beta; Lipid Peroxidation; Male; Maze Learning; Mice; Neuroprotective Agents; Peptide Fragments; Receptors, Erythropoietin; Recognition, Psychology; Recombinant Proteins; Retention, Psychology; Signal Transduction; Tumor Necrosis Factor-alpha

Central nervous system microglia promote neuronal regeneration and sequester toxic β-amyloid (Aβ) deposition during Alzheimer's disease. We show that the cytokine erythropoietin (EPO) decreases the toxic effect of Aβ on microgliain vitro. EPO up-regulates the cysteine-rich glycosylated wingless protein Wnt1 and activates the PI 3-K/Akt1/mTOR/ p70S6K pathway. This in turn increases phosphorylation and cytosol trafficking of Bad, reduces the Bad/Bcl-xL complex and increases the Bcl-xL/Bax complex, thus preventing caspase 1 and caspase 3 activation and apoptosis. Our data may foster development of novel strategies to use cytoprotectants such as EPO for Alzheimer's disease and other degenerative disorders.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Apoptosis; bcl-Associated Death Protein; bcl-X Protein; Caspases; Cell Line; Cytoprotection; Dose-Response Relationship, Drug; Enzyme Activation; Erythropoietin; Humans; Membrane Potential, Mitochondrial; Microglia; Mitochondria; Neuroprotective Agents; Peptide Fragments; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Recombinant Proteins; Ribosomal Protein S6 Kinases, 70-kDa; RNA Interference; Signal Transduction; Time Factors; TOR Serine-Threonine Kinases; Transfection; Wnt1 Protein

Topics: Alzheimer Disease; Erythropoietin; Humans; Recombinant Proteins

Observational studies have consistently documented independent, strong associations of anemia--even if not severe--with major adverse functional outcomes in older adults. In this chapter, recent epidemiologic evidence linking mild anemia with decline in physical and cognitive function, frailty, and disability in community-dwelling older adults is reviewed. Altogether, these biologically plausible associations provide empirical, though not conclusive, support for the notion of mild anemia as a cause of adverse functional outcomes in older adults. Randomized clinical trial data assessing the impact of anemia correction on functional outcomes are lacking at this time.

Topics: Activities of Daily Living; Adult; Aged; Aging; Alzheimer Disease; Anemia; Cognition; Epoetin Alfa; Erythropoietin; Female; Frail Elderly; Hematinics; Hemoglobins; Humans; Male; Physical Fitness; Recombinant Proteins

We aimed to establish age-related reference values for Erythropoietin (EPO) in cerebrospinal fluid (CSF) and to evaluate concentrations in neurological diseases. CSF and serum EPO was measured in controls with tension-type headache (CTTH), in patients with ALS, dementia and depression using ELISA technique. Stability experiments showed CSF EPO to be stable for two and a half months and over two thaw/freeze cycles. A positive correlation of CSF EPO with age was found (P<0.01). We found a CSF/serum EPO concentration ratio of 0.126, pointing towards an intrathecal synthesis of EPO. The ALS group showed significantly lowered CSF EPO compared to age-matched CTTH (P<0.012), whereas the dementia and depression group showed no significant differences compared to CTTH.The establishment of age-related reference values in a large cohort of controls will improve the interpretation of future CSF EPO evaluations in neurological diseases.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aging; Alzheimer Disease; Depression; Erythropoietin; Humans; Middle Aged; Nervous System Diseases; Reference Values; Tension-Type Headache

Erythropoietin (EPO) and its specific receptor (EPOR) have been proposed to act as an endogenous system protecting against neuronal injury and neurodegeneration. We measured EPO in cerebrospinal fluid (CSF) of patients with neurodegenerative diseases, and tested for a correlation with an established biomarker of neuro-axonal damage, tau protein. Patients with Alzheimer's disease (AD, N=40), vascular dementia (VD, N=19), frontotemporal lobe dementia (FTLD, N=5), ALS (N=30) and controls (N=49) were included. Cerebrospinal fluid and serum levels of EPO and tau were measured using ELISA techniques. We found CSF EPO in ALS to be lower than in controls (p=0.04), while no difference between patients with AD, VD, FTLD and controls was detectable. CSF EPO correlated with age (p<0.001) as well as with tau protein (p=0.002) in all patients pooled. In contrast to the upregulation of the EPO/EPOR system in brain tissue upon various conditions of neuronal distress, CSF EPO concentrations in neurodegenerative disease were found in the same range or even reduced as compared to controls. This may be due to a relative deficiency of endogenous CNS EPO in these conditions and/or to a more efficient extraction of free EPO molecules from brain intercellular fluid by increased numbers of EPOR.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyotrophic Lateral Sclerosis; Biomarkers; Dementia; Dementia, Vascular; Erythropoietin; Female; Humans; Male; Middle Aged; Neurodegenerative Diseases; tau Proteins

No longer considered exclusive for the function of the hematopoietic system, erythropoietin (EPO) is now considered as a viable agent to address central nervous system injury in a variety of cellular systems that involve neuronal, vascular, and inflammatory cells. Yet, it remains unclear whether the protective capacity of EPO may be effective for chronic neurodegenerative disorders such as Alzheimer's disease (AD) that involve beta-amyloid (Abeta) apoptotic injury to hippocampal neurons. We therefore investigated whether EPO could prevent both early and late apoptotic injury during Abeta exposure in primary hippocampal neurons and assessed potential cellular pathways responsible for this protection. Primary hippocampal neuronal injury was evaluated by trypan blue dye exclusion, DNA fragmentation, membrane phosphatidylserine (PS) exposure, and nuclear factor-kappaB (NF-kappaB) expression with subcellular translocation. We show that EPO, in a concentration specific manner, is able to prevent the loss of both apoptotic genomic DNA integrity and cellular membrane asymmetry during Abeta exposure. This blockade of Abeta generated neuronal apoptosis by EPO is both necessary and sufficient, since protection by EPO is completely abolished by co-treatment with an anti-EPO neutralizing antibody. Furthermore, neuroprotection by EPO is closely linked to the expression of NF-kappaB p65 by preventing the degradation of this protein by Abeta and fostering the subcellular translocation of NF-kappaB p65 from the cytoplasm to the nucleus to allow the initiation of an anti-apoptotic program. In addition, EPO intimately relies upon NF-kappaB p65 to promote neuronal survival, since gene silencing of NF-kappaB p65 by RNA interference removes the protective capacity of EPO during Abeta exposure. Our work illustrates that EPO is an effective entity at the neuronal cellular level against Abeta toxicity and requires the close modulation of the NF-kappaB p65 pathway, suggesting that either EPO or NF-kappaB may be used as future potential therapeutic strategies for the management of chronic neurodegenerative disorders, such as AD.

Topics: Active Transport, Cell Nucleus; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antibodies; Apoptosis; Cell Nucleus; Cells, Cultured; Dose-Response Relationship, Drug; Erythropoietin; Hippocampus; Male; Nerve Degeneration; Neurons; Phosphatidylserines; Protein Transport; Rats; RNA Interference; Transcription Factor RelA