Kaufer D


Full name : Kaufer Daniela

First name : Daniela

Mail : Hebrew University of Jerusalem, Biological-Chemistry Dept, Life Sciences Institute, 91904 Jerusalem

Zip Code :

City :

Country : Israel

Email : danielak@leonardo.ls.huji.ac.i1

Phone : 972 26585454

Fax : 972 26520258

Website :

Directory :

References (19)

Title : Challenges and opportunities for improving the landscape for Lewy body dementia clinical trials - Goldman_2020_Alzheimers.Res.Ther_12_137
Author(s) : Goldman JG , Forsberg LK , Boeve BF , Armstrong MJ , Irwin DJ , Ferman TJ , Galasko D , Galvin JE , Kaufer D , Leverenz J , Lippa CF , Marder K , Abler V , Biglan K , Irizarry M , Keller B , Munsie L , Nakagawa M , Taylor A , Graham T
Ref : Alzheimers Res Ther , 12 :137 , 2020
Abstract : Lewy body dementia (LBD), including dementia with Lewy bodies and Parkinson's disease dementia, affects over a million people in the USA and has a substantial impact on patients, caregivers, and society. Symptomatic treatments for LBD, which can include cognitive, neuropsychiatric, autonomic, sleep, and motor features, are limited with only two drugs (cholinesterase inhibitors) currently approved by regulatory agencies for dementia in LBD. Clinical trials represent a top research priority, but there are many challenges in the development and implementation of trials in LBD. To address these issues and advance the field of clinical trials in the LBDs, the Lewy Body Dementia Association formed an Industry Advisory Council (LBDA IAC), in addition to its Research Center of Excellence program. The LBDA IAC comprises a diverse and collaborative group of experts from academic medical centers, pharmaceutical industries, and the patient advocacy foundation. The inaugural LBDA IAC meeting, held in June 2019, aimed to bring together this group, along with representatives from regulatory agencies, to address the topic of optimizing the landscape of LBD clinical trials. This review highlights the formation of the LBDA IAC, current state of LBD clinical trials, and challenges and opportunities in the field regarding trial design, study populations, diagnostic criteria, and biomarker utilization. Current gaps include a lack of standardized clinical assessment tools and evidence-based management strategies for LBD as well as difficulty and controversy in diagnosing LBD. Challenges in LBD clinical trials include the heterogeneity of LBD pathology and symptomatology, limited understanding of the trajectory of LBD cognitive and core features, absence of LBD-specific outcome measures, and lack of established standardized biologic, imaging, or genetic biomarkers that may inform study design. Demands of study participation (e.g., travel, duration, and frequency of study visits) may also pose challenges and impact trial enrollment, retention, and outcomes. There are opportunities to improve the landscape of LBD clinical trials by harmonizing clinical assessments and biomarkers across cohorts and research studies, developing and validating outcome measures in LBD, engaging the patient community to assess research needs and priorities, and incorporating biomarker and genotype profiling in study design.
ESTHER : Goldman_2020_Alzheimers.Res.Ther_12_137
PubMedSearch : Goldman_2020_Alzheimers.Res.Ther_12_137
PubMedID: 33121510

Title : Plasma acetylcholinesterase activity correlates with intracerebral beta-amyloid load - Alkalay_2013_Curr.Alzheimer.Res_10_48
Author(s) : Alkalay A , Rabinovici GD , Zimmerman G , Agarwal N , Kaufer D , Miller BL , Jagust WJ , Soreq H
Ref : Curr Alzheimer Res , 10 :48 , 2013
Abstract : BACKGROUND: Previous studies have demonstrated alterations in the peripheral cholinergic system in Alzheimer's disease (AD), though results have been inconsistent and not linked to in vivo biomarkers of pathology. We examined the relationship between amyloid-beta (Abeta) plaques and plasma cholinesterase activity in a heterogeneous dementia population.
METHODS: 29 participants with clinical AD and 35 with non-AD diagnoses underwent positron emission tomography (PET) with the amyloid ligand [11C] PIB and plasma measurements of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity. Multi-linear regression was used to evaluate the relationship between AChE or BChE activity and PIB binding (adjusted for age, sex, apolipoprotein E4 and vascular risk), applying voxel-wise and region of interest (ROI) approaches. AChE activity was further adjusted for cholinesterase inhibitor (ChE-I) use. Global amyloid load was measured using a PIB Index, representing mean tracer binding in frontal, parietal, lateral temporal and cingulate cortex.
RESULTS: AChE activity was correlated with PIB Index (beta=0.39, p < 0.001) and with regional PIB binding in frontal, temporal, parietal and occipital lobes, precuneus and posterior cingulate on both voxel-wise (p < 0.001 uncorrected) and ROI (beta=0.26-0.41, p < 0.005) analysis. Correlations remained significant after covarying clinical diagnosis (beta=0.42, p=0.001), and among participants naive to ChE-I (beta=0.51, p=0.005). No correlation was found between BChE activity and PIB. Among AD participants, disease severity was not correlated with AChE, BChE or PIB Index. CONCLUSION: AChE activity in plasma is correlated with brain Abeta load. Activation of the 'anti-inflammatory cholinergic pathway' may provide the link between Abeta plaques and peripheral cholinergic measures.
ESTHER : Alkalay_2013_Curr.Alzheimer.Res_10_48
PubMedSearch : Alkalay_2013_Curr.Alzheimer.Res_10_48
PubMedID: 23157337

Title : Changes in brain MicroRNAs contribute to cholinergic stress reactions - Meerson_2010_J.Mol.Neurosci_40_47
Author(s) : Meerson A , Cacheaux L , Goosens KA , Sapolsky RM , Soreq H , Kaufer D
Ref : Journal of Molecular Neuroscience , 40 :47 , 2010
Abstract : Mental stress modifies both cholinergic neurotransmission and alternative splicing in the brain, via incompletely understood mechanisms. Here, we report that stress changes brain microRNA (miR) expression and that some of these stress-regulated miRs regulate alternative splicing. Acute and chronic immobilization stress differentially altered the expression of numerous miRs in two stress-responsive regions of the rat brain, the hippocampal CA1 region and the central nucleus of the amygdala. miR-134 and miR-183 levels both increased in the amygdala following acute stress, compared to unstressed controls. Chronic stress decreased miR-134 levels, whereas miR-183 remained unchanged in both the amygdala and CA1. Importantly, miR-134 and miR-183 share a common predicted mRNA target, encoding the splicing factor SC35. Stress was previously shown to upregulate SC35, which promotes the alternative splicing of acetylcholinesterase (AChE) from the synapse-associated isoform AChE-S to the, normally rare, soluble AChE-R protein. Knockdown of miR-183 expression increased SC35 protein levels in vitro, whereas overexpression of miR-183 reduced SC35 protein levels, suggesting a physiological role for miR-183 regulation under stress. We show stress-induced changes in miR-183 and miR-134 and suggest that, by regulating splicing factors and their targets, these changes modify both alternative splicing and cholinergic neurotransmission in the stressed brain.
ESTHER : Meerson_2010_J.Mol.Neurosci_40_47
PubMedSearch : Meerson_2010_J.Mol.Neurosci_40_47
PubMedID: 19711202

Title : Behavioral effects of current Alzheimer's disease treatments: a descriptive review - Cummings_2008_Alzheimers.Dement_4_49
Author(s) : Cummings JL , Mackell J , Kaufer D
Ref : Alzheimers Dement , 4 :49 , 2008
Abstract : BACKGROUND: Behavioral abnormalities and neuropsychiatric symptoms are common manifestations of Alzheimer's disease (AD). Many clinical trials of cholinesterase inhibitors (ChE-Is) and memantine have included behavioral measures as primary or secondary outcomes, and most have observed behavioral benefits in conjunction with treatment. The purpose of this review was to determine the frequency of positive behavioral outcomes in AD clinical trials and clinical reports, to determine the symptoms most responsive to antidementia agents, and to explore factors that correlate with negative outcomes in clinical trials of antidementia agents with regard to behavioral measures.
METHODS: We performed a computerized search of randomized clinical trials and open-label studies of ChE-Is and memantine for AD including a behavioral outcome measure. Studies involving 10 or more patients using therapeutic doses of the target agents and including a behavioral measure as a primary or secondary outcome were included in this review.
RESULTS: One hundred fifty-seven peer-reviewed articles and 68 publicly presented abstracts were identified in the literature search. Subsequent review established that 15 publications arising from 13 randomized, double-blind, placebo-controlled AD trials met the review inclusion criteria. Positive outcomes on behavioral measures were reported in 8 of 15 publications as a primary or secondary outcome. In most blinded AD clinical trials, behavioral measures were secondary outcomes. Mood symptoms and apathy have most commonly responded to ChE-Is, whereas memantine has been associated with a reduction in irritability and agitation. However, there is substantial variability among trials in terms of behavioral outcomes. Studies that assessed patients with more severe dementia, included patients with less severe behavioral disturbances at baseline, involved institutionalized patients, or were international in scope tended to have negative outcomes. In institutionalized patients there is commonly an improvement in the placebo group that confounds the observation of any drug-placebo difference.
CONCLUSIONS: Antidementia agents have been associated with beneficial behavioral outcomes in many randomized clinical trials and open-label studies. Most studies are not designed to test the psychotropic properties of antidementia drugs. Trials with negative behavioral outcomes are most likely to involve patients who are institutionalized and have few behavioral disturbances at baseline. Clinical trials designed to assess behavioral effects of antidementia agents should anticipate these factors.
ESTHER : Cummings_2008_Alzheimers.Dement_4_49
PubMedSearch : Cummings_2008_Alzheimers.Dement_4_49
PubMedID: 18631950

Title : Cognitive performance in Alzheimer's disease patients receiving rivastigmine for up to 5 years - Small_2005_Int.J.Clin.Pract_59_473
Author(s) : Small GW , Kaufer D , Mendiondo MS , Quarg P , Spiegel R
Ref : Int J Clin Pract , 59 :473 , 2005
Abstract : This analysis aimed to assess mini-mental state examination (MMSE) scores in patients with Alzheimer's disease who received rivastigmine, an inhibitor of acetylcholinesterase and butyrylcholinesterase, for up to 5 years. Rivastigmine data came from two pooled open-label extensions of four 6-month, randomised, placebo-controlled trials. Projections of decline, had the same patients not been treated, were made using a baseline-dependent mathematical model. MMSE data were available for 1998 rivastigmine-treated patients and 657, 298 and 83 were still on treatment at 3, 4 and 5 years, respectively. The mean (+/-SD) baseline MMSE score was 19.3 (+/-4.9). Projected mean scores in model-based untreated patients declined below 10 points on the MMSE at about 3 years, while the mean MMSE score of patients who remained on rivastigmine stayed above 10 points for 5 years.
ESTHER : Small_2005_Int.J.Clin.Pract_59_473
PubMedSearch : Small_2005_Int.J.Clin.Pract_59_473
PubMedID: 15853867

Title : Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium - McKeith_2005_Neurology_65_1863
Author(s) : McKeith IG , Dickson DW , Lowe J , Emre M , O'Brien JT , Feldman H , Cummings J , Duda JE , Lippa C , Perry EK , Aarsland D , Arai H , Ballard CG , Boeve B , Burn DJ , Costa D , Del Ser T , Dubois B , Galasko D , Gauthier S , Goetz CG , Gomez-Tortosa E , Halliday G , Hansen LA , Hardy J , Iwatsubo T , Kalaria RN , Kaufer D , Kenny RA , Korczyn A , Kosaka K , Lee VM , Lees A , Litvan I , Londos E , Lopez OL , Minoshima S , Mizuno Y , Molina JA , Mukaetova-Ladinska EB , Pasquier F , Perry RH , Schulz JB , Trojanowski JQ , Yamada M
Ref : Neurology , 65 :1863 , 2005
Abstract : The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.
ESTHER : McKeith_2005_Neurology_65_1863
PubMedSearch : McKeith_2005_Neurology_65_1863
PubMedID: 16237129

Title : Alternative splicing and neuritic mRNA translocation under long-term neuronal hypersensitivity - Meshorer_2002_Science_295_508
Author(s) : Meshorer E , Erb C , Gazit R , Pavlovsky L , Kaufer D , Friedman A , Glick D , Ben-Arie N , Soreq H
Ref : Science , 295 :508 , 2002
Abstract : To explore neuronal mechanisms underlying long-term consequences of stress we studied stress-induced changes in the neuritic translocation of acetylcholinesterase AChE splice variants Under normal conditions we found the synaptic AChE-S mRNA and protein in neurites Corticosterone anticholinesterases and forced swim each facilitated a rapid minutes yet long-lasting weeks shift from AChE-S to the normally rare AChE-R mRNA promoted AChE-R mRNA translocation into neurites and induced enzyme secretion Weeks after stress electrophysiological measurements in hippocampus slices displayed apparently normal evoked synaptic responses but extreme hypersensitivity to both anticholinesterases and atropine Our findings suggest that neuronal hypersensitivity under stress involves neuritic replacement of AChE-S with AChE-R
ESTHER : Meshorer_2002_Science_295_508
PubMedSearch : Meshorer_2002_Science_295_508
PubMedID: 11799248

Title : [Treatment of neuropsychiatric symptoms in Alzheimer s disease] - Kaufer_2002_Rev.Neurol_35_846
Author(s) : Kaufer D
Ref : Rev Neurol , 35 :846 , 2002
Abstract : The overall goal of all therapeutic interventions in Alzheimer s disease (AD) is the optimisation of the adaptive functions and quality of life of these patients. The general strategy for the use of pharmacological interventions in the treatment of neuropsychiatric manifestations of AD includes the following: 1) An exhaustive evaluation of the psychiatric symptomatology; 2) Establish a hierachy of the simptoms to treat based on their severity of symptoms and on their impact on the caregiver; 3) The identification of an adequate agent based on the type of symptoms and subject s characteristics; 4) The initial use of low doses with gradual titration, and 5) Changing one drug at a time. Regarding psychotic symptons, the introduction of new agents (e.g., risperidone) has replaced the use of traditional treatments (e.g., thioridazine) in patients with AD. The presence of psychomotor agitation and aggression can be treated with great variety of drugs, such as antipsychotics, anticonvulsants, antidepressants, and sedatives. Selective serotonine re uptake inhibitors are the treatment of choice for depressive symptomatology. The cholinesterase inhibitors have shown to be useful in the treatment of hallucinations, anxiety and apathy.
ESTHER : Kaufer_2002_Rev.Neurol_35_846
PubMedSearch : Kaufer_2002_Rev.Neurol_35_846
PubMedID: 12436383

Title : Frequent blood-brain barrier disruption in the human cerebral cortex - Tomkins_2001_Cell.Mol.Neurobiol_21_675
Author(s) : Tomkins O , Kaufer D , Korn A , Shelef I , Golan H , Reichenthal E , Soreq H , Friedman A
Ref : Cellular Molecular Neurobiology , 21 :675 , 2001
Abstract : 1. The blood-brain barrier (BBB) protects the brain from circulating xenobiotic agents. The pathophysiology, time span, spatial pattern, and pathophysiological consequences of BBB disruptions are not known. 2. Here, we report the quantification of BBB disruption by measuring enhancement levels in computerized tomography brain images. 3. Pathological diffuse enhancement associated with elevated albumin levels in the cerebrospinal fluid (CSF) was observed in the cerebral cortex of 28 out of 43 patients, but not in controls. Four patients displayed weeks-long focal BBB impairment. In 19 other patients, BBB disruption was significantly associated with elevated blood pressure, body temperature, serum cortisol, and stress-associated CSF 'readthrough" acetylcholinesterase. Multielectrode electroencephalography revealed enhanced slow-wave activities in areas of focal BBB disruption. Thus, quantification of BBB disruption using minimally invasive procedures, demonstrated correlations with molecular, clinical, and physiological stress-associated indices. 4. These sequelae accompany a wide range of neurological disorders, suggesting that persistent, detrimental BBB disruption is considerably more frequent than previously assumed.
ESTHER : Tomkins_2001_Cell.Mol.Neurobiol_21_675
PubMedSearch : Tomkins_2001_Cell.Mol.Neurobiol_21_675
PubMedID: 12043841

Title : Antisense prevention of neuronal damages following head injury in mice - Shohami_2000_J.Mol.Med.(Berl)_78_228
Author(s) : Shohami E , Kaufer D , Chen Y , Seidman S , Cohen O , Ginzberg D , Melamed-Book N , Yirmiya R , Soreq H
Ref : J Mol Med (Berl) , 78 :228 , 2000
Abstract : Closed head injury (CHI) is an important cause of death among young adults and a prominent risk factor for nonfamilial Alzheimer's disease. Emergency intervention following CHI should therefore strive to improve survival, promote recovery, and prevent delayed neuropathologies. We employed high-resolution nonradioactive in situ hybridization to determine whether a single intracerebro-ventricular injection of 500 ng 2'-O-methyl RNA-capped antisense oligonucleotide (AS-ODN) against acetylcholinesterase (AChE) mRNA blocks overexpression of the stress-related readthrough AChE (AChE-R) mRNA splicing variant in head-injured mice. Silver-based Golgi staining revealed pronounced dendrite outgrowth in somatosensory cortex of traumatized mice 14 days postinjury that was associated with sites of AChE-R mRNA overexpression and suppressed by anti-AChE AS-ODNs. Furthermore, antisense treatment reduced the number of dead CA3 hippocampal neurons in injured mice, and facilitated neurological recovery as determined by performance in tests of neuromotor coordination. In trauma-sensitive transgenic mice overproducing AChE, antisense treatment reduced mortality from 50% to 20%, similar to that displayed by head-injured control mice. These findings demonstrate the potential of antisense therapeutics in treating acute injury, and suggest antisense prevention of AChE-R overproduction to mitigate the detrimental consequences of various traumatic brain insults.
ESTHER : Shohami_2000_J.Mol.Med.(Berl)_78_228
PubMedSearch : Shohami_2000_J.Mol.Med.(Berl)_78_228
PubMedID: 10933585

Title : Anticholinesterases induce multigenic transcriptional feedback response suppressing cholinergic neurotransmission - Kaufer_1999_Chem.Biol.Interact_119-120_349
Author(s) : Kaufer D , Friedman A , Seidman S , Soreq H
Ref : Chemico-Biological Interactions , 119-120 :349 , 1999
Abstract : Cholinesterase inhibitors (anti-ChEs) include a wide range of therapeutic, agricultural and warfare agents all aimed to inhibit the catalytic activity of the acetylcholine (ACh) hydrolysing enzyme acetylcholinesterase (AChE). In addition to promoting immediate excitation of cholinergic neurotransmission through transient elevation of synaptic ACh levels, anti-ChEs exposure is associated with long-term effects reminiscent of post-traumatic stress disorder. This suggested that exposure to anti-ChEs leads to persistent changes in brain proteins and called for exploring the mechanism(s) through which such changes could occur. For this purpose, we established an in vitro system of perfused, sagittal mouse brain slices which sustains authentic transcriptional responses for over 10 h and enables the study of gene regulation under controlled exposure to anti-ChEs. Slices were exposed to either organophosphate or cabamate anti-ChEs, both of which induced within 10 min excessive overexpression of the mRNA encoding the immediate early response transcription factor c-Fos. Twenty minutes later we noted 8-fold increases over control levels in AChE mRNA, accompanied by a 3-fold decrease in the mRNAs encoding for the ACh synthesizing enzyme choline acetyltransferase (ChAT) and the vesicular ACh transporter (VAChT). No changes were detected in synaptophysin mRNA levels. These modulations in gene expression paralleled those taking place under in vivo exposure. Of particular concern is the possibility that feedback processes leading to elevated levels of brain AChE may be similarly associated with low-level exposure to common organophosphorous anti-cholinesterases, and lead to long-term deleterious changes in cognitive functions.
ESTHER : Kaufer_1999_Chem.Biol.Interact_119-120_349
PubMedSearch : Kaufer_1999_Chem.Biol.Interact_119-120_349
PubMedID: 10421471

Title : Tracking cholinergic pathways from psychological and chemical stressors to variable neurodeterioration paradigms - Kaufer_1999_Curr.Opin.Neurol_12_739
Author(s) : Kaufer D , Soreq H
Ref : Curr Opin Neurol , 12 :739 , 1999
Abstract : Cholinergic hyperexcitation can be induced by both acute psychological stress and exposure to acetylcholinesterase inhibitors. Both factors are known risk factors for delayed neurodeterioration processes such as Alzheimer's disease and Parkinson's disease. Recent publications on the involvement of cholinergic pathways in these and other neurodeterioration syndromes are reviewed.
ESTHER : Kaufer_1999_Curr.Opin.Neurol_12_739
PubMedSearch : Kaufer_1999_Curr.Opin.Neurol_12_739
PubMedID: 10676758

Title : Differential neuropsychiatric symptom responses to tacrine in Alzheimer's disease: relationship to dementia severity - Kaufer_1998_J.Neuropsychiatry.Clin.Neurosci_10_55
Author(s) : Kaufer D , Cummings JL , Christine D
Ref : J Neuropsychiatry Clin Neurosci , 10 :55 , 1998
Abstract : Neuropsychiatric symptom responses to tacrine were investigated in an open-label study of Alzheimer's outpatients. Forty subjects were stratified into three groups (Mild, Moderate, and Severe) based on Mini-Mental State Examination scores. A significant reduction in total Neuropsychiatric Inventory score across all subjects was principally attributable to changes in the Moderate group. Apathy and disinhibition symptoms were significantly reduced overall. Whereas other symptoms showed differential responses in Mild and Severe subjects, all symptoms improved in Moderate subjects. These findings suggest that disease severity may significantly influence neuropsychiatric symptom responses to tacrine. Putative mechanisms underlying the observed pattern of responses are explored.
ESTHER : Kaufer_1998_J.Neuropsychiatry.Clin.Neurosci_10_55
PubMedSearch : Kaufer_1998_J.Neuropsychiatry.Clin.Neurosci_10_55
PubMedID: 9547467

Title : Beyond the cholinergic hypothesis: the effect of metrifonate and other cholinesterase inhibitors on neuropsychiatric symptoms in Alzheimer's disease - Kaufer_1998_Dement.Geriatr.Cogn.Disord_2_8
Author(s) : Kaufer D
Ref : Dementia & Geriatric Cognitive Disorders , 2 :8 , 1998
Abstract : Preliminary studies suggest that non-cognitive behavioural and personality alterations in Alzheimer's disease may benefit from agents which inhibit central acetylcholinesterase (AChE). A double-blind, placebo-controlled, 26-week study of the AChE inhibitor metrifonate using the NeuroPsychiatric Inventory (NPI) to assess the effects of treatment on neuropsychiatric symptoms observed statistically significant mean change differences favouring treatment in the total NPI score and in symptoms of depression, apathy and hallucinations, as well as a nearly significant difference in aberrant motor behaviours. These data are consistent with previous studies and are believed to represent the first large prospective, controlled study demonstrating a beneficial effect of AChE inhibitor therapy on neuropsychiatric symptoms in Alzheimer's disease. The nature of non-cognitive symptom responses to AChE inhibitor therapy and their potential impact on caregivers is discussed.
ESTHER : Kaufer_1998_Dement.Geriatr.Cogn.Disord_2_8
PubMedSearch : Kaufer_1998_Dement.Geriatr.Cogn.Disord_2_8
PubMedID: 9718229

Title : Acute stress facilitates long-lasting changes in cholinergic gene expression - Kaufer_1998_Nature_393_373
Author(s) : Kaufer D , Friedman A , Seidman S , Soreq H
Ref : Nature , 393 :373 , 1998
Abstract : Acute traumatic stress may lead to post-traumatic stress disorder (PTSD), which is characterized by delayed neuropsychiatric symptoms including depression, irritability, and impaired cognitive performance. Curiously, inhibitors of the acetylcholine-hydrolysing enzyme acetylcholinesterase may induce psychopathologies that are reminiscent of PTSD. It is unknown how a single stressful event mediates long-term neuronal plasticity. Moreover, no mechanism has been proposed to explain the convergent neuropsychological outcomes of stress and of acetylcholinesterase inhibition. However, acute stress elicits a transient increase in the amounts released of the neurotransmitter acetylcholine and a phase of enhanced neuronal excitability. Inhibitors of acetylcholinesterase also promote enhanced electrical brain activity, presumably by increasing the survival of acetylcholine at the synapse. Here we report that there is similar bidirectional modulation of genes that regulate acetylcholine availability after stress and blockade of acetylcholinesterase. These calcium-dependent changes in gene expression coincide with phases of rapid enhancement and delayed depression of neuronal excitability. Both of these phases are mediated by muscarinic acetylcholine receptors. Our results suggest a model in which robust cholinergic stimulation triggers rapid induction of the gene encoding the transcription factor c-Fos. This protein then mediates selective regulatory effects on the long-lasting activities of genes involved in acetylcholine metabolism.
ESTHER : Kaufer_1998_Nature_393_373
PubMedSearch : Kaufer_1998_Nature_393_373
PubMedID: 9620801

Title : Long-term modulations of cholinergic neurotransmission following chronic stress -
Author(s) : Kaufer D , Friedman A , Pavlovsky L , Soreq H
Ref : Journal de Physiologie (Paris) , 92 :446 , 1998

Title : Pyridostigmine brain penetration under stress enhances neuronal excitability and induces early immediate transcriptional response [see comments] - Friedman_1996_Nature.Med_2_1382
Author(s) : Friedman A , Kaufer D , Shemer J , Hendler I , Soreq H , Tur-Kaspa I
Ref : Nature Medicine , 2 :1382 , 1996
Abstract : Pyridostigmine, a carbamate acetylcholinesterase (AChE) inhibitor, is routinely employed in the treatment of the autoimmune disease myasthenia gravis. Pyridostigmine is also recommended by most Western armies for use as pretreatment under threat of chemical warfare, because of its protective effect against organophosphate poisoning. Because of this drug's quaternary ammonium group, which prevents its penetration through the blood-brain barrier, the symptoms associated with its routine use primarily reflect perturbations in peripheral nervous system functions. Unexpectedly, under a similar regimen, pyridostigmine administration during the Persian Gulf War resulted in a greater than threefold increase in the frequency of reported central nervous system symptoms. This increase was not due to enhanced absorption (or decreased elimination) of the drug, because the inhibition efficacy of serum butyryl-cholinesterase was not modified. Because previous animal studies have shown stress-induced disruption of the blood-brain barrier, an alternative possibility was that the stress situation associated with war allowed pyridostigmine penetration into the brain. Here we report that after mice were subjected to a forced swim protocol (shown previously to simulate stress), an increase in blood-brain barrier permeability reduced the pyridostigmine dose required to inhibit mouse brain AChE activity by 50% to less than 1/100th of the usual dose. Under these conditions, peripherally administered pyridostigmine increased the brain levels of c-fos oncogene and AChE mRNAs. Moreover, in vitro exposure to pyridostigmine increased both electrical excitability and c-fos mRNA levels in brain slices, demonstrating that the observed changes could be directly induced by pyridostigmine. These findings suggest that peripherally acting drugs administered under stress may reach the brain and affect centrally controlled functions.
ESTHER : Friedman_1996_Nature.Med_2_1382
PubMedSearch : Friedman_1996_Nature.Med_2_1382
PubMedID: 8946841

Title : Alternative Exon 6 Directs Synaptic Localization of Recombinant Human Acetylcholinesterase in Neuromuscular Junctions of Xenopus laevis Embryos -
Author(s) : Sternfeld M , Seidman S , Ben Aziz-Aloya R , Shapira M , Timberg R , Kaufer D , Soreq H
Ref : In Enzyme of the Cholinesterase Family - Proceedings of Fifth International Meeting on Cholinesterases , (Quinn, D.M., Balasubramanian, A.S., Doctor, B.P., Taylor, P., Eds) Plenum Publishing Corp. :45 , 1995

Title : Transgenic engineering of neuromuscular junctions in Xenopus laevis embryos transiently overexpressing key cholinergic proteins - Shapira_1994_Proc.Natl.Acad.Sci.U.S.A_91_9072
Author(s) : Shapira M , Seidman S , Sternfeld M , Timberg R , Kaufer D , Patrick J , Soreq H
Ref : Proceedings of the National Academy of Sciences of the United States of America , 91 :9072 , 1994
Abstract : To examine the role of key cholinergic proteins in the formation of neuromuscular junctions (NMJs), we expressed DNAs encoding the mouse muscle nicotinic acetylcholine receptor (nAChR) or human brain and muscle acetylcholinesterase (hAChE) in developing Xenopus laevis embryos. Acetylthiocholine hydrolysis and alpha-bungarotoxin binding in homogenates of transgenic embryos revealed transient overexpression of the respective proteins for at least 4 days postfertilization. Moreover, hAChE injection induced an approximately 2-fold increase in endogenous Xenopus nAChR. Electron microscopy coupled with cytochemical staining for AChE activity revealed that AChE-stained areas, which reached 0.17 microns2 in NMJs of control embryos raised at 21 degrees C, increased up to 0.53 and 0.60 microns2 in nAChR and hAChE transgenics, respectively. These increases coincided with the appearance of a class of large NMJs with average postsynaptic lengths up to 1.8-fold greater than controls. As much as 57% and 34% of the NMJs in animals transgenic for nAChR and hAChE, respectively, displayed AChE activity in nerve terminals in addition to muscle labeling, as compared with 10% nerve-labeled NMJs in control animals. Moreover, area, but not length values, were > 2-fold larger in hAChE-expressing NMJs labeled in their nerve terminals than in those labeled in muscle alone, reflecting a hAChE-induced increase in synaptic cleft width. These findings indicate that modulation of cholinergic neurotransmission in NMJs modifies the features of nerve-muscle connections.
ESTHER : Shapira_1994_Proc.Natl.Acad.Sci.U.S.A_91_9072
PubMedSearch : Shapira_1994_Proc.Natl.Acad.Sci.U.S.A_91_9072
PubMedID: 8090771