共查询到20条相似文献,搜索用时 15 毫秒
1.
Interest in the beta amyloid (Abeta) peptides continues to grow due to their known accumulation in the brains of patients with Alzheimer's disease and recent tantalising evidence that reducing such accumulations can reverse disease-associated functional deficits. Abeta peptides are naturally produced in every cell by proteolytic cleavage of the amyloid precursor protein with two main alloforms (40 or 42 amino acids) both of which are disease associated. The identification that genetic mutations causing Alzheimer's disease impact on Abeta production and clearance have allowed for the manipulation of these pathways in cellular and animal models. These studies show that the amount and type of Abeta in the brain has significant consequences on neural function. However, there have been significant difficulties in the conversion of these findings into successful treatments in humans. In this review we concentrate on data from human studies to determine any comparative differences in Abeta production and clearance that may assist with better treatment design and delivery. Abeta40 is the dominant peptide species in human cerebrospinal fluid accounting for approximately 90% of total Abeta under normal conditions. However, similar studies using disease free human brain tissue do not correlate with these findings. In these studies, concentrations of Abeta40 are low with Abeta42 often identified as the dominant species. The data suggest preferential brain tissue utilisation and/or clearance of Abeta40 compared with Abeta42, findings which may have been predicted by their physiochemical differences. In Alzheimer's disease this equilibrium is disrupted significantly increasing Abeta peptide levels in brain tissue. The disease-specific increase in Abeta40 brain tissue levels in Alzheimer's disease appears to be an important though overlooked pathological change compared with the well-documented Abeta42 change observed both in the aged and in Alzheimer's disease. These findings are discussed in association with Abeta peptide function and a model of toxicity developed. 相似文献
2.
Wang He-Cheng Zhang Tao Kuerban Bolati Jin Ying-Lan Le Weidong Hara Hideo Fan Dong-Sheng Wang Yan-Jiang Tabira Takeshi Chui De-Hua 《神经科学通报》2015,31(4):491-504
The imbalance between β-amyloid(Aβ) generation and clearance plays a fundamental role in the pathogenesis of Alzheimer 's disease(AD). The sporadic form of AD is characterized by an overall impairment in Aβ clearance. Immunotherapy targeting Aβ clearance is believed to be a promising approach and is under active clinical investigation. Autophagy is a conserved pathway for degrading abnormal protein aggregates and is crucial for Aβ clearance. We previously reported that oral vaccination with a recombinant AAV/Aβ vaccine increased the clearance of Aβ from the brain and improved cognitive ability in AD animal models, while the underlying mechanisms were not well understood. In this study, we first demonstrated that oral vaccination with rAAV/Aβ decreased the p62 level and up-regulated the LC3BII/LC3B-I ratio in APP/PS1 mouse brain, suggesting enhanced autophagy. Further, inhibition of the Akt/m TOR pathway may account for autophagy enhancement. We also found increased anti-Aβ antibodies in the sera of APP/PS1 mice with oralvaccination, accompanied by elevation of complement factors C1 q and C3 levels in the brain. Our results indicate that autophagy is closely involved in oral vaccination-induced Aβ clearance, and modulating the autophagy pathway may be an important strategy for AD prevention and intervention. 相似文献
3.
4.
Huttunen HJ Puglielli L Ellis BC MacKenzie Ingano LA Kovacs DM 《Journal of molecular neuroscience : MN》2009,37(1):6-15
A common pathogenic event that occurs in all forms of Alzheimer’s disease is the progressive accumulation of amyloid β-peptide
(Aβ) in brain regions responsible for higher cognitive functions. Inhibition of acyl-coenzyme A: cholesterol acyltransferase
(ACAT), which generates intracellular cholesteryl esters from free cholesterol and fatty acids, reduces the biogenesis of
the Aβ from the amyloid precursor protein (APP). Here we have used AC29 cells, defective in ACAT activity, to show that ACAT
activity steers APP either toward or away from a novel proteolytic pathway that replaces both α and the amyloidogenic β cleavages
of APP. This alternative pathway involves a novel cleavage of APP holoprotein at Glu281, which correlates with reduced ACAT
activity and Aβ generation in AC29 cells. This sterol-dependent cleavage of APP occurs in the endosomal compartment after
internalization of cell surface APP. The resulting novel C-terminal fragment APP-C470 is destined to proteasomal degradation
limiting the availability of APP for the Aβ generating system. The proportion of APP molecules that are directed to the novel
cleavage pathway is regulated by the ratio of free cholesterol and cholesteryl esters in cells. These results suggest that
subcellular cholesterol distribution may be an important regulator of the cellular fate of APP holoprotein and that there
may exist several competing proteolytic systems responsible for APP processing within the endosomal compartment. 相似文献
5.
Interleukin-1β is associated with depressive episode in major depression but not in bipolar disorder
Rosana Mota Marta Gazal Bruna A. Acosta Pâmela B. de Leon Karen Jansen Ricardo T. Pinheiro Luciano D. Souza Ricardo A. Silva Jean P. Oses Luciana Quevedo Diogo R. Lara Gabriele Ghisleni Manuella P. Kaster 《Journal of psychiatric research》2013
Our work was sought to investigate possible changes in peripheral levels of interleukin-1β (IL-1β) according to the diagnosis of major depression (MD) and bipolar disorder (BD) and in different mood episodes. This is a cross-sectional nested in a population-based study comparing 240 young adults (80 controls, 80 MD and 80 BD), balanced for age and gender. Serum levels of IL-1β were significantly higher in MD when compared to control or BD subjects. In addition, when divided by current mood episode, MD subjects in current depression presented higher IL-1β levels than controls. No differences in IL-1β levels were found between different episodes of BD (euthymic, depressed, mania or mixed). Moreover, the use of psychiatric medication was very low in our sample and not associated with changes in IL-1β levels. In conclusion, increased peripheral IL-1β might be a useful marker associated with a depressive episode in the context of MD. 相似文献
6.
7.
Multiple sclerosis (MS) is a central nervous system inflammatory disorder with evidence of peripheral immune dysregulation. Abnormalities of the immune suppressive cytokine TGF-β have been reported, but not fully defined, in MS. Through a pathway-focused expression profiling of the peripheral blood, we found abnormalities of TGF-βRII, SMAD4 and SMAD7 expression in subjects with MS, and reduction in the levels of TGF-β regulated genes, indicating an overall reduction in TGF-β signaling in MS. The response to exogenous TGF-β was intact, however, indicating an extrinsic defect of TGF-β signaling in MS. These results indicate that TGF-β control is diminished in MS. 相似文献
8.
Bleich S Wilhelm J Graesel E Degner D Sperling W Rössner V Javaheripour K Kornhuber J 《Journal of neural transmission (Vienna, Austria : 1996)》2003,110(4):401-411
Summary. There is evidence that a higher incidence of diverse neurodegenerative diseases is associated with the apolipoprotein E ε4
allele (ApoE4). Most recently it has been found that the ApoE4 allele is specifically related to an accelerated hippocampal
atrophy in patients with Alzheimer's disease. Therefore, the aim of the present study was to investigate the association between
ApoE4 genotypes and brain hippocampal volume reduction in alcoholics by using volumetric high-resolution MR imaging. In the
present study, female alcoholics with the ApoE4 genotype were found to have significantly smaller hippocampal volumes than
those not carrying an ε4 allele (ANOVA, p < 0.05), whereas no differences in hippocampal volume were seen in male alcoholics.
Since hippocampal volume reduction is lately discussed to be proportional to brain atrophy, we propose that the alcohol-related
brain atrophy in patients suffering from chronic alcoholism, is more pronounced in female carriers of the apoE ε4 allele.
These findings indicate a genetic disposition for alcohol related brain atrophy in female carrying the ApoE4 genotype, which
may also explain why female alcoholics are more susceptible to alcohol-induced brain damage.
Received June 21, 2002; accepted October 2, 2002 Published online December 20, 2002
Authors' address: Dr. S. Bleich, MD, Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of Erlangen-Nuremberg,
Schwabachanlage 6-10, D-91054 Erlangen, Federal Republic of Germany, e-mail: stefan.bleich@psych.imed.uni-erlangen.de 相似文献
9.
Alexandru A Jagla W Graubner S Becker A B?uscher C Kohlmann S Sedlmeier R Raber KA Cynis H R?nicke R Reymann KG Petrasch-Parwez E Hartlage-Rübsamen M Waniek A Rossner S Schilling S Osmand AP Demuth HU von H?rsten S 《The Journal of neuroscience》2011,31(36):12790-12801
Posttranslational amyloid-β (Aβ) modification is considered to play an important role in Alzheimer's disease (AD) etiology. An N-terminally modified Aβ species, pyroglutamate-amyloid-β (pE3-Aβ), has been described as a major constituent of Aβ deposits specific to human AD but absent in normal aging. Formed via cyclization of truncated Aβ species by glutaminyl cyclase (QC; QPCT) and/or its isoenzyme (isoQC; QPCTL), pE3-Aβ aggregates rapidly and is known to seed additional Aβ aggregation. To directly investigate pE3-Aβ toxicity in vivo, we generated and characterized transgenic TBA2.1 and TBA2.2 mice, which express truncated mutant human Aβ. Along with a rapidly developing behavioral phenotype, these mice showed progressively accumulating Aβ and pE3-Aβ deposits in brain regions of neuronal loss, impaired long-term potentiation, microglial activation, and astrocytosis. Illustrating a threshold for pE3-Aβ neurotoxicity, this phenotype was not found in heterozygous animals but in homozygous TBA2.1 or double-heterozygous TBA2.1/2.2 animals only. A significant amount of pE3-Aβ formation was shown to be QC-dependent, because crossbreeding of TBA2.1 with QC knock-out, but not isoQC knock-out, mice significantly reduced pE3-Aβ levels. Hence, lowering the rate of QC-dependent posttranslational pE3-Aβ formation can, in turn, lower the amount of neurotoxic Aβ species in AD. 相似文献
10.
Oculomotor dysfunction in Parkinson's disease (PD) is mainly characterized by a fragmentation of memory-guided gaze shifts
(target is reached by several hypometric saccades). Since this phenomenon can also be observed in normal subjects, we scrutinized
its pathophysiological significance in PD patients. We recorded horizontal eye movements in eleven mildly- or moderately-affected
PD patients and eleven control subjects. A quantitative assessment of gaze shift fragmentation was made possible by increasing
its incidence over a sequence of two visually- and two subsequent memory-guided gaze shifts. Basic saccade measures (latency,
velocity, etc.) were similar in the two subject groups as well as in fragmented versus non-fragmented gaze shifts. Fragmentation
probability is increased in the second memory-guided gaze shift, and this clearly more so in patients than in controls. The
fragmentation shows a typical gain pattern (uniform increase of gain of saccadic amplitudes across correction saccades towards
1.0 with the last saccade of the gaze shift) independent of subject group, stimulus mode, and fragmentation degree. Gaze shift
fragmentation represents a physiological phenomenon, which has thus far been overlooked. It reflects a robust correction mechanism,
which assures that target is reached even if the pre-oculomotor drive through the basal ganglia to the superior colliculus
becomes abnormally weak or under inadequately strong inhibition – as is postulated for PD. Thus, only the abnormally high
incidence of fragmentation, and of the associated amplitude reduction of the primary saccades, rather than the phenomenon
per se, can be used as a diagnostic criterion in early stages of PD.
Received: 19 June 2001, Received in revised form: 19 October 2001, Accepted: 24 October 2001 相似文献
11.
12.
13.
Krefft Maja Frydecka Dorota Zalsman Gil Krzystek-Korpacka Małgorzata Śmigiel Robert Gębura Katarzyna Bogunia-Kubik Katarzyna Misiak Błażej 《European child & adolescent psychiatry》2021,30(6):899-908
European Child & Adolescent Psychiatry - Several lines of evidence indicate that immune-inflammatory alterations are widely observed in various mental disorders. Genetic syndromes with high... 相似文献
14.
Patti F Nicoletti A Pappalardo A Castiglione A Lo Fermo S Messina S D'Amico E Cimino V Zappia M 《Acta neurologica Scandinavica》2012,125(2):91-95
Patti F, Nicoletti A, Pappalardo A, Castiglione A, Lo Fermo S, Messina S, D’Amico E, Cimino V, Zappia M. Frequency and severity of headache is worsened by Interferon‐β therapy in patients with multiple sclerosis. Acta Neurol Scand: 2012: 125: 91–95. © 2011 John Wiley & Sons A/S. Background – The relationship between multiple sclerosis (MS) and headache (HA) is not well known. It was reported that interferon‐beta (IFNβ) could induce or worsen HA. Objective – To evaluate the impact of IFNβ treatment on HA and the relationship between HA and the various commercial preparations of IFNβ in mildly disabled patients with MS. Methods – A specific questionnaire was administered to 357 relapsing‐remitting MS patients. Characteristics of HAs were considered, including the temporal relationships with IFNβ administration. Results – One hundred and seventeen patients were treated with weekly intramuscular injections of interferon IFNβ‐1a (Avonex®), 84 with subcutaneous injections of IFNβ‐1b (Betaferon®) every other day, 48 and 108 with three times weekly subcutaneous injections of IFNβ‐1a (Rebif®) 22 mcg or IFNβ‐1a (Rebif®) 44 mcg, respectively. Three hundred and fourteen patients were affected by HA, and among them, 219 patients suffered of pre‐existing HA. In this latter group, 121 subjects (55%) noted a worsening of their HA after starting IFNβ therapy; this was more frequently reported by patients treated with Avonex® and Rebif® 44. Ninety‐five patients experienced new HA. Conclusion – IFNβ treatment could worsen HA in patients with pre‐existing HA or cause the appearance of new HA. Among different IFNβ preparations, Rebif® 44 and Avonex® seemed to be more cephalalgic than the other drugs. 相似文献
15.
16.
17.
18.
19.
Contini V Victor MM Cerqueira CC Polina ER Grevet EH Salgado CA Karam RG Vitola ES Belmonte-de-Abreu P Bau CH 《European archives of psychiatry and clinical neuroscience》2011,261(3):205-211
Adrenergic α2A receptor gene (ADRA2A) is one of the most promising candidate genes for ADHD pharmacogenetics. Thus far, three studies have investigated the association
between the ADRA2A −1291 C>G polymorphism and the therapeutic response to methylphenidate (MPH) in children with ADHD, all of them with positive
results. The aim of this study is to investigate, for the first time, the association between three ADRA2A polymorphisms (−1291 C>G, −262 G>A, and 1780 C>T) and the response to MPH in adults with ADHD. The sample comprises 165 Brazilians
of European descent evaluated in the adult ADHD outpatient clinic of the Hospital de Clínicas de Porto Alegre. The diagnostic
procedures followed the DSM-IV criteria. Drug response was assessed by both categorical and dimensional approaches, through
the scales Swanson, Nolan, and Pelham Rating scale version IV and the Clinical Global Impression-Severity Scale, applied at
the beginning and after the 30th day of treatment. We found no evidence of association between the three ADRA2A polymorphisms and the therapeutic response to MPH treatment. Our findings do not support a significant role for the ADRA2A gene in ADHD pharmacogenetics, at least among adult patients. 相似文献
20.
Intraneuronal Aβ immunoreactivity is not a predictor of brain amyloidosis-β or neurofibrillary degeneration 总被引:3,自引:3,他引:0
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 《Acta neuropathologica》2007,113(4):389-402
Amyloid β (Aβ) 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 Aβ immunoreactivity is an early manifestation
of Alzheimer-type pathology leading to fibrillar plaque formation and/or neurofibrillary degeneration. The appearance of Aβ
immunoreactivity in neurons in infants and stable neuron-type specific Aβ 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 Aβ in neurons indicated that intraneuronal Aβ was mainly a product
of α- and γ-secretases (Aβ17–40/42). The presence of N-terminally truncated Aβ17–40 and Aβ17–42 in the control brains was confirmed by Western blotting and the identity of Aβ17–40 was confirmed by mass spectrometry. The prevalence of products of α- and γ -secretases in neurons and β- and γ-secretases
in plaques argues against major contribution of Aβ-immunopositive material detected in neuronal soma to amyloid deposit in
plaques. The strongest intraneuronal Aβ17–42 immunoreactivity was observed in structures with low susceptibility to fibrillar Aβ deposition, neurofibrillary degeneration,
and neuronal loss compared to areas more vulnerable to Alzheimer-type pathology. These observations indicate that the intraneuronal
Aβ immunoreactivity detected in this study is not a predictor of brain amyloidosis or neurofibrillary degeneration. The constant
level of Aβ immunoreactivity in structures free from neuronal pathology during essentially the entire life span suggests that
intraneuronal amino-terminally truncated Aβ represents a product of normal neuronal metabolism.
This study was supported in part by funds from the New York State Office of Mental Retardation and Developmental Disabilities
and grants from the National Institutes of Health (The National Institute of Child Health and Human Development R01 HD43960
and PO1 HD35897; and the National Institute of Aging P30 AG08051, AG03051, and PO1 AG11531). 相似文献