Alzheimer Disease: Wisniewski T

Wisniewski T. · New York University School of Medicine, Millhauser Laboratory, New York, NY 10016, USA. · CNS Neurol Disord Drug Targets. · Pubmed #19355935 No free full text.

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Wisniewski T, Sadowski M. · Department of Neurology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA. · BMC Neurosci. · Pubmed #19090993 links to  free full text

Abstract: Central to the pathogenesis of Alzheimer's disease (AD) is the conversion of normal, soluble beta-amyloid (sAbeta) to oligomeric, fibrillar Abeta. This process of conformational conversion can be influenced by interactions with other proteins that can stabilize the disease-associated state; these proteins have been termed 'pathological chaperones'. In a number of AD models, intervention that block soluble Abeta aggregation, including beta-sheet breakers, and compounds that block interactions with pathological chaperones, have been shown to be highly effective. When combined with early pathology detection, these therapeutic strategies hold great promise as effective and relatively toxicity free methods of preventing AD related pathology.

Wisniewski T, Konietzko U. · Department of Neurology, New York University School of Medicine, New York, NY 10016, USA. · Lancet Neurol. · Pubmed #18667360 No free full text.

Abstract: Alzheimer's disease is the main cause of dementia in elderly people and is becoming an ever greater problem as societies worldwide age. Treatments that stop or at least effectively modify disease course do not yet exist. In Alzheimer's disease, the conversion of the amyloid-beta peptide (Abeta) from a physiological water-soluble monomeric form into neurotoxic oligomeric and fibrillar forms rich in stable beta-sheet conformations is an important event. The most toxic forms of Abeta are thought to be oligomers, and dimers might be the smallest neurotoxic species. Numerous immunological approaches that prevent the conversion of the normal precursor protein into pathological forms or that accelerate clearance are in development. More than ten new approaches to active and passive immunotherapy are under investigation in clinical trials with the aim of producing safe methods for immunological therapy and prevention. A delicate balance between immunological clearance of an endogenous protein with acquired toxic properties and the induction of an autoimmune reaction must be found.

Sadowski M, Wisniewski T. · Department of Neurology, New York University School of Medicine, New York, NY 10016, USA. · Curr Pharm Des. · Pubmed #17627527 No free full text.

Abstract: Alzheimer's disease (AD) is the most common age-associated neurodegenerative disease in the world. The major neuropathological features of AD are synaptic loss, neuronal loss, neurofibrillary tangles and the deposition of amyloid-beta (Abeta) as plaques and in cerebral blood vessels. Numerous Abeta targeting therapeutic approaches have been shown to prevent amyloid deposition and resulting in cognitive improvement in transgenic mouse models of AD. Some of these approaches are currently in early clinical trials. It remains to be seen if these approaches will be proven effective in patients. Future anti-AD therapies will likely be multi-modal and individually tailored depending on the patient's immune status, genetic background and their amyloid burden, as determined by imaging studies using Abeta specific labeling ligands. Pre-clinical data suggests that it will be much more feasible to prevent AD related pathology, then to clear existing pathology, making early diagnosis critically important.

Wisniewski T, Sigurdsson EM. · Department of Neurology, New York University School of Medicine, NY 10016, USA. · FEBS J. · Pubmed #17617224 No free full text.

Abstract: Alzheimer's and prion diseases belong to a category of conformational neurodegenerative disorders [Prusiner SB (2001) N Eng J Med344, 1516-1526; Sadowski M & Wisniewski T (2007) Curr Pharm Des 13, 1943-1954; Beekes M (2007) FEBS J 274, 575]. Treatments capable of arresting or at least effectively modifying the course of disease do not yet exist for either one of these diseases. Alzheimer's disease is the major cause of dementia in the elderly and has become an ever greater problem with the aging of Western societies. Unlike Alzheimer's disease, prion diseases are relatively rare. Each year only approximately 300 people in the USA and approximately 100 people in the UK succumb to various forms of prion diseases [Beekes M (2007) FEBS J 274, 575; Sigurdsson EM & Wisniewski T (2005) Exp Rev Vaccines 4, 607-610]. Nevertheless, these disorders have received great scientific and public interest due to the fact that they can be transmissible among humans and in certain conditions from animals to humans. The emergence of variant Creutzfeld-Jakob disease demonstrated the transmissibility of the bovine spongiform encephalopathy to humans [Beekes M (2007) FEBS J 274, 575]. Therefore, the spread of bovine spongiform encephalopathy across Europe and the recently identified cases in North America have put a large human population at risk of prion infection. It is estimated that at least several thousand Britons are asymptomatic carriers of prion infections and may develop variant Creutzfeld-Jakob disease in the future [Hilton DA (2006) J Pathol 208, 134-141]. This delayed emergence of human cases following the near elimination of bovine spongiform encephalopathy in the UK may occur because prion disease have a very prolonged incubation period, ranging from months to decades, which depends on the amount of inoculum, the route of infection and the genetic predisposition of the infected subject [Hilton DA (2006) J Pathol 208, 134-141]. Therefore, there is a great need for effective therapies for both Alzheimer's disease and prion diseases.

Wisniewski T, Frangione B. · Department of Neurology, New York University School of Medicine, 550 First Avenue, NewYork, NY 10016, USA. · Brain Pathol. · Pubmed #15779239 No free full text.

Abstract: Alzheimer disease (AD) is the most common cause of dementia. Currently available therapies only provide symptomatic relief. A number of therapeutic approaches are under development that aim to increase the clearance of brain Abeta peptides. These include immune mediated clearance of Abeta and the inhibition of the interaction between Abeta and its pathological chaperones. Both active and passive immunization has been shown to have robust effects in transgenic mouse models of AD on amyloid reduction and behavioral improvements. However, a human trial of active immunization has been associated with significant toxicity in a minority of patients. New generation vaccines are being developed which likely will reduce the potential for cell-mediated toxicity. In addition, the recent development of anti-chaperone therapy opens a new therapeutic avenue which is unlikely to be associated with toxicity.

Sadowski M, Wisniewski T. · Department of Neurology, New York University School of Medicine, 550 First Avenue, MHL Rm. HN 419, New York, NY 10016, USA. · Expert Rev Vaccines. · Pubmed #15176944 No free full text.

Abstract: Neurodegenerative disorders are becoming increasingly common and an ever greater healthcare burden, as the average age in Western populations rises. Many of these are conformational disorders, which are characterized by the accumulation of a host protein that undergoes a structural change increasing its beta-sheet content, rendering it toxic. The most common of these illnesses is Alzheimer's disease. Prion diseases are also conformational disorders, which are currently less common than Alzheimer's disease, however, these illnesses have no treatment and are universally rapidly fatal. The emergence of new variant Creutzfeldt-Jakob disease has raised the possibility of a large population at risk for this illness, as well as causing great concern regarding the safety of blood bank supplies. Recently, immune modulation has emerged as a highly promising therapeutic strategy for both Alzheimer's and prion diseases. We and others have demonstrated in both Alzheimer's and prion disease animal models that vaccination can dramatically improve the course of the illness. A human trial of an Alzheimer's disease vaccine using A beta1-42 was halted due to toxicity in a minority of patients (6%). However, recent data suggests that patients with a humoral response to A beta benefited cognitively from the vaccine. Toxicity in this human trial has been linked to excessive cell-mediated immunity. Novel vaccine strategies are under development for both Alzheimer's disease and prionoses which are predicted to have few or no significant side effects, while being efficacious.

Sigurdsson EM, Wisniewski T, Frangione B. · Department of Psychiatry, School of Medicine, New York University, 550 First Avenue, New York 10016, USA. · Neurobiol Aging. · Pubmed #12470795 No free full text.

Abstract: Recent reports indicate that amyloid-beta (Abeta) vaccine-based therapy for Alzheimer's disease (AD) may be on the horizon. There are, however, concerns about the safety of this approach. Immunization with Abeta1-42 may not be appropriate in humans because it crosses the blood-brain barrier, can seed fibril formation, and is highly fibrillogenic. Abeta1-42 fibrils can in turn cause inflammation and neurotoxicity. This issue is of a particular concern in the elderly who often do not mount an adequate immune response to vaccines. Our findings show that vaccination with nonamyloidogenic/nontoxic Abeta derivative may be a safer therapeutic approach to impede the progression of Abeta-related histopathology in AD. Although the site of action of the anti-Abeta antibodies has been suggested to be within the brain, peripheral clearance of Abeta may have a greater role in reducing cerebral amyloid plaques in these animals and eventually in AD patients. Antibodies in general are predominantly found outside the central nervous system (CNS) and will, therefore, primarily clear systemic Abeta compared to brain Abeta. This disruption of the equilibrium between central and peripheral Abeta should then result in efflux of Abeta out of the brain, and subsequent removal of plaques. Abeta therapy can be targeted to the periphery, which may result in fewer CNS side effects, such as inflammation. Future Abeta derived vaccines should include T(h) epitopes, carriers and/or lipid moieties to enhance antibody production in the elderly, the population predominantly affected by AD.

Wisniewski T, Brown DR, Sigurdsson EM. · Department of Neurology, New York University Medical Center, 550 First Avenue TH 427, New York, NY 10016, USA. · Biochem Soc Trans. · Pubmed #12196140 No free full text.

Abstract: There is increasing recognition that numerous neurodegenerative conditions have the same underlying pathogenetic mechanism, namely a change in protein conformation, where the beta-sheet content is increased. In Alzheimer's disease, amyloid deposition in the form of neuritic plaques and congophilic angiopathy is driven by the conversion of normal soluble amyloid-beta peptide (sA beta) to A beta plaques; while in the prionoses the critical event is the conversion of normal prion protein, PrP(C), to the disease-associated form, PrP(Sc). This common theme in the pathogenesis of these disorders and the extracellular localization of the accumulating abnormal protein make them highly amenable to therapeutic approaches based on experimental manipulation of protein conformation and clearance. A number of different approaches under current development include drugs which affect the processing of the precursor proteins drugs the clearance of the amyloidogenic protein, and which inhibit or prevent the conformation change and immunological approaches. Particularly interesting are compounds termed 'beta-sheet breakers' that directly target the abnormal conformational change both for A beta- and PrP(Sc)-related deposits. In addition, immune system activation can serve as beta-sheet breakers and/or to increase the clearance of the disease-associated proteins. These conformation-based approaches appear to hold the best promise for therapies for this devastating group of disorders.

Wisniewski T, Sigurdsson EM. · Department of Neurology, New York University Medical Center, Millhauser Laboratory, HN419, 550 First Avenue, New York, NY 10016, USA. · Curr Neurol Neurosci Rep. · Pubmed #12169219 No free full text.

Abstract: There is growing realization that many neurodegenerative conditions have the same underlying pathogenetic mechanism: a change in protein conformation, where the beta-sheet content is increased. In Alzheimer's disease (AD), amyloid deposition in the form of neuritic plaques and congophilic angiopathy is driven by the conversion of normal soluble amyloid beta (sAbeta) to Abeta plaques, whereas in the prionoses the critical event is the conversion of normal prion protein, PrP(C), to PrP(Sc). This common theme in the pathogenesis of these disorders and the extracellular localization of the accumulating abnormal protein make them highly amenable to therapeutic approaches based on experimental manipulation of protein conformation and clearance. Different approaches under development include drugs that affect the processing of the precursor proteins, enhance clearance of the amyloidogenic protein, and inhibit or prevent the conformation change. Particularly interesting are recent studies of immune system activation, which appear to increase the clearance of the disease-associated protein. These immunologically based approaches are highly effective in animal models of these disorders, and in these model systems are associated with no obvious side effects. In transgenic mice with AD-related pathology, immunization has also been shown to prevent age-related cognitive impairment. However, the first clinical trial of this approach in AD patients was associated with unacceptable toxicity. These immune-based treatment approaches have great potential as rational therapies for this devastating group of disorders, but additional development is needed before they can be safely applied to humans.

Scholtzova H, Kascsak RJ, Bates KA, Boutajangout A, Kerr DJ, Meeker HC, Mehta PD, Spinner DS, Wisniewski T. · Department of Neurology, New York University School of Medicine, New York, New York 10016, USA. · J Neurosci. · Pubmed #19211891 links to  free full text

Abstract: The pathogenesis of Alzheimer's disease (AD) is thought to be related to the accumulation of amyloid beta (Abeta) in amyloid deposits and toxic oligomeric species. Immunomodulation is emerging as an effective means of shifting the equilibrium from Abeta accumulation to clearance; however, excessive cell mediated inflammation and cerebral microhemorrhages are two forms of toxicity which can occur with this approach. Vaccination studies have so far mainly targeted the adaptive immune system. In the present study, we have stimulated the innate immune system via the Toll-like receptor 9 (TLR9) with cytosine-guanosine-containing DNA oligodeoxynucleotides in Tg2576 AD model transgenic mice. This treatment produced a 66% and 80% reduction in the cortical (p = 0.0001) and vascular (p = 0.0039) amyloid burden, respectively, compared with nontreated AD mice. This was in association with significant reductions in Abeta42, Abeta40, and Abeta oligomer levels. We also show that treated Tg mice performed similarly to wild-type mice on a radial arm maze. Our data suggest that stimulation of innate immunity via TLR9 is highly effective at reducing the parenchymal and vascular amyloid burden, along with Abeta oligomers, without apparent toxicity.

Trouche SG, Asuni A, Rouland S, Wisniewski T, Frangione B, Verdier JM, Sigurdsson EM, Mestre-Francés N. · Université Montpellier II, Montpellier F-34095, France; INSERM, U-710, Montpellier F-34095, France. · Vaccine. · Pubmed #19114076 links to  free full text

Abstract: We have been developing Abeta derivative vaccines with the objective to improve the safety of Abeta targeting immunotherapy. Our Abeta homologs are designed to have less direct toxicity and to produce a modified immune response compared to Abeta. In extensive mouse studies, all our vaccines have improved cognition in transgenic mice while eliciting different immune responses and reducing brain amyloid burden to a variable degree. While we are continuing to characterize these vaccines in mice, in preparation for studies in old primates and for human trials we assessed their effect in young lemur primates (n=25) that with age develop Abeta plaques and tau aggregates as seen in Alzheimer's disease. In the primates, all the peptides administered with alum adjuvant elicited a moderate to robust anti-Abeta IgM response. Abeta1-42, K6Abeta1-30 and K6Abeta1-30[E(18)E(19)] resulted in a high anti-Abeta IgG response, whereas Abeta1-30[E(18)E(19)] produced a weaker more variable IgG titer. Notably, 22 weeks after the 3rd immunization, IgM and IgG levels in derivative-vaccinated primates were similar to preimmune values whereas Abeta1-42 treated primates maintained a moderate IgG titer. The increase in antibodies that recognized Abeta1-40 often correlated with increase in Abeta1-40 in plasma, which suggests that the antibodies were binding to Abeta in vivo. Interestingly, significant transient weight gain was observed (K6Abeta1-30-, Abeta1-30[E(18)E(19)]- and Abeta1-42-treated) or a trend in the same direction (K6Abeta1-30[E(18)E(19)]-treated, adjuvant controls) following the injections. Based on these findings, we have chosen K6Abeta1-30 for immunizations in old primates as the antibody response to this vaccine was less variable compared to other Abeta derivatives. Our present findings indicate that most of our Abeta derivatives elicit a substantial antibody response in primates, and importantly this effect is reversible which enhances the safety profile of our approach.

Cercy SP, Sadowski MJ, Wisniewski T. · Memory Disorders Clinic, Veterans Affairs New York Harbor Healthcare System, New York, NY 10010, USA. · Cogn Behav Neurol. · Pubmed #18797263 No free full text.

Abstract: OBJECTIVE: We describe atypical motor and cognitive features in a case of familial Alzheimer disease (FAD) due to presenilin-1 (PS-1) mutation. BACKGROUND: Extrapyramidal signs (EPS) typically are a late-presenting feature of sporadic Alzheimer disease (AD), but relatively little data are available regarding EPS in FAD. METHOD: A 59-year-old, right-handed man of Caribbean-Hispanic descent underwent brain imaging studies, laboratory tests for AD, and serial neurologic and neuropsychologic evaluations. RESULTS: The patient presented with recent-onset delusional ideation associated with cognitive decline. Prominent EPS developed soon after initiation of an atypical neuroleptic agent. Neuropsychologic evaluation revealed global cognitive deficits; he was found to be a carrier of a PS-1 point mutation at position G206A. EPS resolved completely after discontinuing the neuroleptic agent and coincided with improved motor speed, set initiation, and verbal fluency. CONCLUSIONS: Severe neuroleptic sensitivity and associated deficits of cognitive speed occurred in response to a dopaminergic antagonist agent; both responded readily to withdrawal of the offending agent. Patients with PS-1 AD may be at substantially increased risk of neuroleptic-induced EPS. That feature underscores the heterogeneity of the FAD clinical phenotype.

Wegiel J, Dowjat K, Kaczmarski W, Kuchna I, Nowicki K, Frackowiak J, Mazur Kolecka B, Wegiel J, Silverman WP, Reisberg B, Deleon M, Wisniewski T, Gong CX, Liu F, Adayev T, Chen-Hwang MC, Hwang YW. · Department of Developmental Neurobiology, NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA. · Acta Neuropathol. · Pubmed #18696092 links to  free full text

Abstract: The gene encoding the minibrain kinase/dual-specificity tyrosine phosphorylated and regulated kinase 1A (DYRK1A) is located in the Down syndrome (DS) critical region of chromosome 21. The third copy of DYRK1A is believed to contribute to abnormal brain development in patients with DS. In vitro studies showing that DYRK1A phosphorylates tau protein suggest that this kinase is also involved in tau protein phosphorylation in the human brain and contributes to neurofibrillary degeneration, and that this contribution might be enhanced in patients with DS. To explore this hypothesis, the brain tissue from 57 subjects including 16 control subjects, 21 patients with DS, and 20 patients with sporadic Alzheimer's disease (AD) was examined with two antibodies to the amino-terminus of DYRK1A (7F3 and G-19), as well as two polyclonal antibodies to its carboxy-terminus (X1079 and 324446). Western blots demonstrated higher levels of full-length DYRK1A in the brains of patients with DS when compared to control brains. Immunocytochemistry revealed that DYRK1A accumulates in neurofibrillary tangles (NFTs) in subjects with sporadic AD and in subjects with DS/AD. Overexpression of DYRK1A in patients with DS was associated with an increase in DYRK1A-positive NFTs in a gene dosage-dependent manner. Results support the hypothesis that overexpressed DYRK1A contributes to neurofibrillary degeneration in DS more significantly than in subjects with two copies of the DYRK1A gene and sporadic AD. Immunoreactivity with antibodies against DYRK1A not only in NFTs but also in granules in granulovacuolar degeneration and in corpora amylacea suggests that DYRK1A is involved in all three forms of degeneration and that overexpression of this kinase may contribute to the early onset of these pathologies in DS.

Scholtzova H, Wadghiri YZ, Douadi M, Sigurdsson EM, Li YS, Quartermain D, Banerjee P, Wisniewski T. · Department of Neurology, New York University School of Medicine, New York, New York 10016, USA. · J Neurosci Res. · Pubmed #18615702 No free full text.

Abstract: Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to improve learning and memory in several preclinical models of Alzheimer's disease (AD). Memantine has also been shown to reduce the levels of amyloid beta (A beta) peptides in human neuroblastoma cells as well as to inhibit A beta oligomer-induced synaptic loss. In this study, we assessed whether NMDA receptor inhibition by memantine in transgenic mice expressing human amyloid-beta precursor protein (APP) and presenilin 1 (PS1) is associated with cognitive benefit and amyloid burden reduction by using object recognition, micromagnetic resonance imaging (micro MRI), and histology. APP/PS1 Tg mice were treated either with memantine or with vehicle for a period of 4 months starting at 3 months of age. After treatment, the mice were subjected to an object recognition test and analyzed by ex vivo micro MRI, and histological examination of amyloid burden. micro MRI was performed following injection with gadolinium-DTPA-A beta(1-40). We found that memantine-treated Tg mice performed the same as wild-type control mice, whereas the performance of vehicle-treated Tg mice was significantly impaired (P = 0.0081, one-way ANOVA). Compared with vehicle-treated animals, memantine-treated Tg mice had a reduced plaque burden, as determined both histologically and by micro MRI. This reduction in amyloid burden correlates with an improvement in cognitive performance. Thus, our findings provide further evidence of the potential role of NMDA receptor antagonists in ameliorating AD-related pathology. In addition, our study shows, for the first time, the utility of micro MRI in conjunction with gadolinium-labeled A beta labeling agents to monitor the therapeutic response to amyloid-reducing agents.

Klyubin I, Betts V, Welzel AT, Blennow K, Zetterberg H, Wallin A, Lemere CA, Cullen WK, Peng Y, Wisniewski T, Selkoe DJ, Anwyl R, Walsh DM, Rowan MJ. · Institute of Neuroscience and Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland. · J Neurosci. · Pubmed #18417702 links to  free full text

Abstract: The current development of immunotherapy for Alzheimer's disease is based on the assumption that human-derived amyloid beta protein (Abeta) can be targeted in a similar manner to animal cell-derived or synthetic Abeta. Because the structure of Abeta depends on its source and the presence of cofactors, it is of great interest to determine whether human-derived oligomeric Abeta species impair brain function and, if so, whether or not their disruptive effects can be prevented using antibodies. We report that untreated ex vivo human CSF that contains Abeta dimers rapidly inhibits hippocampal long-term potentiation in vivo and that acute systemic infusion of an anti-Abeta monoclonal antibody can prevent this disruption of synaptic plasticity. Abeta monomer isolated from human CSF did not affect long-term potentiation. These results strongly support a strategy of passive immunization against soluble Abeta oligomers in early Alzheimer's disease.

Zhan J, Brys M, Glodzik L, Tsui W, Javier E, Wegiel J, Kuchna I, Pirraglia E, Li Y, Mosconi L, Saint Louis LA, Switalski R, De Santi S, Kim BC, Wisniewski T, Reisberg B, Bobinski M, de Leon MJ. · Department of Psychiatry, New York University School of Medicine, New York 10016, USA. · Hum Brain Mapp. · Pubmed #18381771 links to  free full text

Abstract: OBJECTIVES: Magnetic resonance (MRI) studies rely on sulcal boundaries to delineate the human entorhinal cortex (EC) and typically show that EC size is reduced in Alzheimer's disease (AD) and a predictor of future dementia. However, it is unknown if variations in the EC sulcal patterns are associated with AD. We classified the lateral EC sulcal boundary as either a rhinal or collateral pattern and tested the hypotheses that the rhinal pattern was (1) more common in AD and (2) associated with a smaller EC size. EXPERIMENTAL DESIGN: MRI was used to determine the prevalence of the rhinal and collateral EC patterns in 421 subjects (212 AD, 107 old normal (ONL), and 102 young NL (YNL). Anatomical validation studies of normal subjects were conducted at postmortem in 34 brain hemispheres and in vivo with 21 MRI volume studies. EC pattern reliability was studied with MRI in both cross-sectional and longitudinal designs. PRINCIPAL OBSERVATIONS: The rhinal pattern was more frequent in the right hemisphere in AD (47%) compared with ONL (28%, odds ratio = 2.25, P = 0.001). EC pattern was not related to ApoE genotype. The validations showed that the EC sulcal pattern was not associated with the neuronal number, surface area, or volume of the EC. In patients with antemortem MRI studied at postmortem it was equivalently determined, that EC patterns are reliably determined on MRI and do not change with the progressive atrophy of AD. CONCLUSIONS: The data indicate that the right hemisphere rhinal pattern is over represented in AD as compared with control. However, in normal subjects the EC rhinal pattern is not associated with a diminished EC tissue size. It remains to be demonstrated if the right EC rhinal sulcus pattern association with AD reflects genetic or developmental influences.

Firuzi O, Zhuo J, Chinnici CM, Wisniewski T, Praticò D. · Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA. · FASEB J. · Pubmed #17998412 links to  free full text

Abstract: 5-Lipoxygenase (5LO), by producing leukotrienes, is a proinflammatory enzyme, and there is evidence suggesting that it is up-regulated with aging and may be involved in Alzheimer's disease (AD). In this paper, we studied the effect of 5LO-targeted gene disruption on the amyloid phenotype of a transgenic mouse model of AD, the Tg2576. Amyloid-beta (Abeta) deposition in the brains of Tg2576 mice lacking 5LO was reduced by 64-80% compared with Tg2576 controls. This reduction was associated with a similar significant decrease in Abeta levels measured by sandwich ELISA. Absence of 5LO did not induce any significant change in amyloid-beta precursor protein (APP) levels and processing, or Abeta catabolic pathways. Furthermore, in vitro studies showed that 5LO activation or 5LO metabolites increase, whereas 5LO inhibition decreases, Abeta formation, secondary to correspondent changes in gamma-secretase activity. These data establish for the first time a novel functional role for 5LO in the pathogenesis of AD-like amyloidosis, thereby modulating gamma-secretase activity. Our work suggests that pharmacological inhibition of 5LO could provide a novel therapeutic tool for AD.

Li Q, Min J, Ahn YH, Namm J, Kim EM, Lui R, Kim HY, Ji Y, Wu H, Wisniewski T, Chang YT. · Department of Chemistry, New York University, School of Medicine, New York, NY 11219, USA. · Chembiochem. · Pubmed #17705341 No free full text.

Abstract: A group of styryl-based neutral compounds has been synthesized in this study for potential use as in vivo imaging agents for beta-amyloid plaques. Of 56 candidates, 14 compounds were found to label beta-amyloid plaques well on Alzheimer's disease (AD) human brain sections in vitro. The binding affinity to beta-amyloid fibrils was then determined by measuring the change in fluorescence intensity. Interestingly, we found that a class of quinaldine-styryl scaffold compounds displays specific binding to beta-amyloid fibrils. A representative compound, STB-8, was used in ex vivo and in vivo imaging experiments on an AD transgenic mouse model and demonstrated excellent blood-brain barrier (BBB) permeability and specific staining of the AD beta-amyloid plaques.

Litterst C, Georgakopoulos A, Shioi J, Ghersi E, Wisniewski T, Wang R, Ludwig A, Robakis NK. · Department of Psychiatry and Neuroscience, Mount Sinai School of Medicine New York University, New York, NY 10029, USA, and Institute for Molecular Cardiovascular Research, University Hospital Reinisch-West Faelische Technische Hochschule, Aachen, Germany. · J Biol Chem. · Pubmed #17428795 links to  free full text

Abstract: Binding of EphB receptors to ephrinB ligands on the surface of adjacent cells initiates signaling cascades that regulate angiogenesis, axonal guidance, and neuronal plasticity. These functions require processing of EphB receptors and removal of EphB-ephrinB complexes from the cell surface, but the mechanisms involved are poorly understood. Here we show that the ectodomain of EphB2 receptor is released to extracellular space following cleavage after EphB2 residue 543. The remaining membrane-associated fragment is cleaved by the presenilin-dependent gamma-secretase activity after EphB2 residue 569 releasing an intracellular peptide that contains the cytoplasmic domain of EphB2. This cleavage is inhibited by presenilin 1 familial Alzheimer disease mutations. Processing of EphB2 receptor depends on specific treatments: ephrinB ligand-induced processing requires endocytosis, and the ectodomain cleavage is sensitive to peptide inhibitor N-benzyloxycarbonyl-Val-Leu-leucinal but insensitive to metalloproteinase inhibitor GM6001. The ligand-induced processing takes place in endosomes and involves the rapid degradation of the extracellular EphB2. EphrinB ligand stimulates ubiquitination of EphB2 receptor. Calcium influx- and N-methyl-d-aspartic acid-induced processing of EphB2 is inhibited by GM6001 and ADAM10 inhibitors but not by N-benzyloxycarbonyl-Val-Leu-leucinal. This processing requires no endocytosis and promotes rapid shedding of extracellular EphB2, indicating that it takes place at the plasma membrane. Our data identify novel cleavages and modifications of EphB2 receptor and indicate that specific conditions determine the proteolytic systems and subcellular sites involved in the processing of this receptor.

Sigurdsson EM, Wadghiri YZ, Mosconi L, Blind JA, Knudsen E, Asuni A, Scholtzova H, Tsui WH, Li Y, Sadowski M, Turnbull DH, de Leon MJ, Wisniewski T. · Department of Psychiatry, New York University School of Medicine, New York, NY 10016, USA. · Neurobiol Aging. · Pubmed #17291630 links to  free full text

Abstract: Amyloid plaques are a characteristic feature in Alzheimer's disease (AD). A novel non-toxic contrast agent is presented, Gd-DTPA-K6Abeta1-30, which is homologous to Abeta, and allows plaque detection in vivo. microMRI was performed on AD model mice and controls prior to and following intracarotid injection with Gd-DTPA-K6Abeta1-30 in mannitol solution, to transiently open the blood-brain barrier. A gradient echo T2(*)-weighted sequence was used to provide 100 microm isotropic resolution with imaging times of 115 min. The scans were examined with voxel-based analysis (VBA) using statistical parametric mapping, for un-biased quantitative comparison of ligand-injected mice and controls. The results indicate that: (1) Gd-DTPA-K6Abeta1-30 is an effective, non-toxic, ligand for plaque detection when combined with VBA (p< or =0.01-0.001), comparing pre and post-ligand injection scans. (2) Large plaques can be detected without the use of a contrast agent and this detection co-localizes with iron deposition. (3) Smaller, earlier plaques require contrast ligand for MRI visualization. Our ligand when combined with VBA may be useful for following therapeutic approaches targeting amyloid in transgenic mouse models.

Wegiel J, Kuchna I, Nowicki K, Frackowiak J, Mazur-Kolecka B, Imaki H, Wegiel J, Mehta PD, Silverman WP, Reisberg B, Deleon M, Wisniewski T, Pirttilla T, Frey H, Lehtimäki T, Kivimäki T, Visser FE, Kamphorst W, Potempska A, Bolton D, Currie JR, Miller DL. · Department of Developmental Neurobiology, NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY, 10314, USA. · Acta Neuropathol. · Pubmed #17237937 links to  free full text

Abstract: Amyloid beta (Abeta) immunoreactivity in neurons was examined in brains of 32 control subjects, 31 people with Down syndrome, and 36 patients with sporadic Alzheimer's disease to determine if intraneuronal Abeta immunoreactivity is an early manifestation of Alzheimer-type pathology leading to fibrillar plaque formation and/or neurofibrillary degeneration. The appearance of Abeta immunoreactivity in neurons in infants and stable neuron-type specific Abeta immunoreactivity in a majority of brain structures during late childhood, adulthood, and normal aging does not support this hypothesis. The absence or detection of only traces of reaction with antibodies against 4-13 aa and 8-17 aa of Abeta in neurons indicated that intraneuronal Abeta was mainly a product of alpha- and gamma-secretases (Abeta(17-40/42)). The presence of N-terminally truncated Abeta(17-40) and Abeta(17-42) in the control brains was confirmed by Western blotting and the identity of Abeta(17-40) was confirmed by mass spectrometry. The prevalence of products of alpha- and gamma -secretases in neurons and beta- and gamma-secretases in plaques argues against major contribution of Abeta-immunopositive material detected in neuronal soma to amyloid deposit in plaques. The strongest intraneuronal Abeta(17-42) immunoreactivity was observed in structures with low susceptibility to fibrillar Abeta deposition, neurofibrillary degeneration, and neuronal loss compared to areas more vulnerable to Alzheimer-type pathology. These observations indicate that the intraneuronal Abeta immunoreactivity detected in this study is not a predictor of brain amyloidosis or neurofibrillary degeneration. The constant level of Abeta immunoreactivity in structures free from neuronal pathology during essentially the entire life span suggests that intraneuronal amino-terminally truncated Abeta represents a product of normal neuronal metabolism.

Sadowski MJ, Pankiewicz J, Scholtzova H, Mehta PD, Prelli F, Quartermain D, Wisniewski T. · Department of Neurology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA. · Proc Natl Acad Sci U S A. · Pubmed #17116874 links to  free full text

Abstract: The amyloid-beta (Abeta) cascade hypothesis of Alzheimer's disease (AD) maintains that accumulation of Abeta peptide constitutes a critical event in the early disease pathogenesis. The direct binding between Abeta and apolipoprotein E (apoE) is an important factor implicated in both Abeta clearance and its deposition in the brain's parenchyma and the walls of meningoencephalic vessels as cerebral amyloid angiopathy. With the aim of testing the effect of blocking the apoE/Abeta interaction in vivo as a potential novel therapeutic target for AD pharmacotherapy, we have developed Abeta12-28P, which is a blood-brain-barrier-permeable nontoxic, and nonfibrillogenic synthetic peptide homologous to the apoE binding site on the full-length Abeta. Abeta12-28P binds with high affinity to apoE, preventing its binding to Abeta, but has no direct effect on Abeta aggregation. Abeta12-28P shows a strong pharmacological effect in vivo. Its systemic administration resulted in a significant reduction of Abeta plaques and cerebral amyloid angiopathy burden and a reduction of the total brain level of Abeta in two AD transgenic mice models. The treatment did not affect the levels of soluble Abeta fraction or Abeta oligomers, indicating that inhibition of the apoE/Abeta interaction in vivo has a net effect of increasing Abeta clearance over deposition and at the same time does not create conditions favoring formation of toxic oligomers. Furthermore, behavioral studies demonstrated that treatment with Abeta12-28P prevents a memory deficit in transgenic animals. These findings provide evidence of another therapeutic approach for AD.

Asuni AA, Boutajangout A, Scholtzova H, Knudsen E, Li YS, Quartermain D, Frangione B, Wisniewski T, Sigurdsson EM. · Department of Psychiatry, New York University School of Medicine, Millhauser Laboratories, 560 First Avenue, New York, NY 10016, USA. · Eur J Neurosci. · Pubmed #17100841 links to  free full text

Abstract: Immunotherapy holds great promise for Alzheimer's disease (AD) and other conformational disorders but certain adverse reactions need to be overcome. The meningoencephalitis observed in the first AD vaccination trial was likely related to excessive cell-mediated immunity caused by the immunogen, amyloid-beta (Abeta) 1-42, and the adjuvant, QS-21. To avoid this toxicity, we have been using Abeta derivatives in alum adjuvant that promotes humoral immunity. Other potential side effects of immunotherapy are increased vascular amyloid and associated microhemorrhages that may be related to rapid clearance of parenchymal amyloid. Here, we determined if our immunization strategy was associated with this form of toxicity, and if the therapeutic effect was age-dependent. Tg2576 mice and wild-type littermates were immunized from 11 or 19 months and their behaviour evaluated prior to killing at 24 months. Subsequently, plaque- and vascular-Abeta burden, Abeta levels and associated pathology was assessed. The therapy started at the cusp of amyloidosis reduced cortical Abeta deposit burden by 31% and Abeta levels by 30-37%, which was associated with cognitive improvements. In contrast, treatment from 19 months, when pathology is well established, was not immunogenic and therefore did not reduce Abeta burden or improve cognition. Significantly, the immunotherapy in the 11-24 months treatment group, that reduced Abeta burden, did not increase cerebral bleeding or vascular Abeta deposits in contrast to several Abeta antibody studies. These findings indicate that our approach age-dependently improves cognition and reduces Abeta burden when used with an adjuvant suitable for humans, without increasing vascular Abeta deposits or microhemorrhages.

Leal MC, Dorfman VB, Gamba AF, Frangione B, Wisniewski T, Castaño EM, Sigurdsson EM, Morelli L. · Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas de Buenos Aires, CONICET, Ciudad de Buenos Aires, Argentina. · J Neuropathol Exp Neurol. · Pubmed #17021402 No free full text.

Abstract: It was proposed that insulin-degrading enzyme (IDE) participates in the clearance of amyloid beta (Abeta) in the brain, and its low expression or activity may be relevant for the progression of Alzheimer disease. We performed a longitudinal study of brain level, activity, and distribution of IDE in transgenic mice (Tg2576) expressing the Swedish mutation in human Abeta precursor protein. At 16 months of age, Tg2576 showed a significant 2-fold increment in IDE protein level as compared with 4.5- and 11-month-old animals. The peak of IDE was in synchrony with the sharp accumulation of sodium dodecyl sulfate-soluble Abeta and massive Abeta deposition into plaques. At this stage, IDE appeared surrounding Abeta fibrillar deposits within glial fibrillar acidic protein-positive astrocytes, suggesting that it was locally overexpressed during the Abeta-mediated inflammation process. When primary astrocytes were exposed to fibrillar Abeta in vitro, IDE protein level increased as compared with control, and this effect was reduced by the addition of U0126, a specific inhibitor of the ERK1/2 mitogen-activated protein kinase cascade. We propose that in Tg2576 mice and in contrast to its behavior in Alzheimer brains, active IDE increases with age around plaques as a component of astrocyte activation as a result of Abeta-triggered inflammation.