Abstract:
:Alzheimer's disease (AD) is the most prevalent form of neurodegeneration; however, therapies to prevent or treat AD are inadequate. Amyloid-beta (Abeta) protein accrues in cortical senile plaques, one of the key neuropathological hallmarks of AD, and is elevated in brains of early onset AD patients in a small number of families that bear certain genetic mutations, further implicating its role in this devastating neurological disease. In addition, soluble Abeta oligomers have been shown to be detrimental to neuronal function. Therapeutic strategies aimed at lowering cerebral Abeta levels are currently under development. One strategy is to immunize AD patients with Abeta peptides so that they will generate antibodies that bind to Abeta protein and enhance its clearance. As of 1999, Abeta immunotherapy, either through active immunization with Abeta peptides or through passive transfer of Abeta-specific antibodies, has been shown to reduce cerebral Abeta levels and improve cognitive deficits in AD mouse models and lower plaque load in nonhuman primates. However, a Phase II clinical trial of active immunization using full-length human Abeta1-42 peptide and a strong Th1-biased adjuvant, QS-21, ended prematurely in 2002 because of the onset of meningoencephalitis in approximately 6% of the AD patients enrolled in the study. It is possible that T cell recognition of the human full-length Abeta peptide as a self-protein may have induced an adverse autoimmune response in these patients. Although only approximately 20% of immunized patients generated anti-Abeta titers, responders showed some general slowing of cognitive decline. Focal cortical regions devoid of Abeta plaques were observed in brain tissues of several immunized patients who have since come to autopsy. In order to avoid a deleterious immune response, passive Abeta immunotherapy is under investigation by administering monthly intravenous injections of humanized Abeta monoclonal antibodies to AD patients. However, a safe and effective active Abeta vaccine would be more cost-effective and more readily available to a larger AD population. We have developed several novel short Abeta immunogens that target the Abeta N-terminus containing a strong B cell epitope while avoiding the Abeta mid-region and C-terminus containing T cell epitopes. These immunogens include dendrimeric Abeta1-15 (16 copies of Abeta1-15 on a lysine antigen tree), 2xAbeta1-15 (a tandem repeat of two lysine-linked Abeta1-15 peptides), and 2xAbeta1-15 with the addition of a three amino acid RGD motif (R-2xAbeta1-15). Intranasal immunization with our short Abeta fragment immunogens and a mucosal adjuvant, mutant Escherichia coli heat-labile enterotoxin LT(R192G), resulted in reduced cerebral Abeta levels, plaque deposition, and gliosis, as well as increased plasma Abeta levels and improved cognition in a transgenic mouse model of AD. Preclinical trials in nonhuman primates, and human clinical trials using similar Abeta immunogens, are now underway. Abeta immunotherapy looks promising but must be made safer and more effective at generating antibody titers in the elderly. It is hoped that these novel immunogens will enhance Abeta antibody generation across a broad population and avoid the adverse events seen in the earlier clinical trial.
journal_name
Prog Brain Resjournal_title
Progress in brain researchauthors
Lemere CAdoi
10.1016/S0079-6123(09)17506-4subject
Has Abstractpub_date
2009-01-01 00:00:00pages
83-93eissn
0079-6123issn
1875-7855pii
S0079-6123(09)17506-4journal_volume
175pub_type
杂志文章,评审abstract::Saccadic oscillations are unwanted back-to-back saccades occurring one upon the other that produce a high-frequency oscillation of the eyes (usually 15-30 Hz). These may occur transiently in normal subjects, for example, around the orthogonal axis of a purely horizontal or vertical saccade, during combined saccade-ver...
journal_title:Progress in brain research
pub_type: 杂志文章
doi:10.1016/S0079-6123(08)00616-X
更新日期:2008-01-01 00:00:00
abstract::Three rhythmic movements, breathing, walking, and chewing, are considered from the perspective of the emerging factors that control their coordination. This takes us beyond the concept of a core excitatory kernel and into the common principles that govern the interaction between components of the neural networks that ...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/B978-0-444-53825-3.00017-6
更新日期:2011-01-01 00:00:00
abstract::The subiculum gives rise to the majority of hippocampal projections to various telencephalic and diencephalic structures. Previously, these projections have been described using anterograde tracing with radioactively labeled amino acids. As part of an ongoing detailed analysis of the connectivity of the hippocampal re...
journal_title:Progress in brain research
pub_type: 杂志文章
doi:10.1016/s0079-6123(08)61240-6
更新日期:1990-01-01 00:00:00
abstract::Quantitative models of the oculomotor plant and control of the saccadic eye movement system are presented in this chapter. Oculomotor plant models described here are linear, including a second-order model by Westheimer (1954), Bahill et al. (1980) and Enderle et al. (2000). The model of the saccade generator is initia...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/S0079-6123(02)40040-4
更新日期:2002-01-01 00:00:00
abstract::Human evolution was marked by an extraordinary increase in total brain size relative to body size. While it is certain that increased encephalization is an important factor contributing to the origin of our species-specific cognitive abilities, it is difficult to disentangle which aspects of human neural structure and...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/B978-0-444-53860-4.00011-8
更新日期:2012-01-01 00:00:00
abstract::The aim of this experiment was to investigate whether there were differences in decision-making skills between different age groups (Under 16, 18 and 23) of elite academy footballers on a video-based task of real-life football scenarios. It also explored the relationship between individual performance on the task and ...
journal_title:Progress in brain research
pub_type: 杂志文章
doi:10.1016/bs.pbr.2020.06.015
更新日期:2020-01-01 00:00:00
abstract::Oxidative stress is known to play a key role in the initiation and promotion of the neurodegeneration that characterizes the pathogenesis of Alzheimer disease (AD). An accumulation of redox active transition metals, including iron and copper, is likely a major generator of reactive oxidative species and other free rad...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/S0079-6123(08)80005-2
更新日期:2009-01-01 00:00:00
abstract::The epileptologically informed in-depth analysis of auto- and heteroanamnestic historical sources supports the hypothesis that Hector Berlioz (1803-1869) might have suffered from a photosensitive idiopathic generalized epilepsy syndrome with absences, absence status, myoclonic seizures, and bilateral tonic-clonic seiz...
journal_title:Progress in brain research
pub_type: 传,历史文章,杂志文章
doi:10.1016/bs.pbr.2014.11.007
更新日期:2015-01-01 00:00:00
abstract::The organization of key molecules at glutamatergic synapses in the rat cerebellar cortex as analyzed by high resolution immunocytochemical techniques using gold particles as markers. The distinct compartmentation of glutamate and glutamine was consistent with biochemical data indicating an active role of glia in the r...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/s0079-6123(08)63360-9
更新日期:1997-01-01 00:00:00
abstract::Migraine is among the most common and disabling neurological diseases in the world. Cortical spreading depression (CSD) is a wave of near-complete depolarization of neurons and glial cells that slowly propagates along the cortex creating the perception of aura. Evidence suggests that CSD can trigger migraine headache....
journal_title:Progress in brain research
pub_type: 杂志文章
doi:10.1016/bs.pbr.2020.05.009
更新日期:2020-01-01 00:00:00
abstract::The present study involves the effects on corticotropin (ACTH) release of neuro- and thymoleptic tricyclic antidepressant compounds (TrcACs: chlorpromazine, promethazine, haloperidol, imipramine, amitriptyline) and their interactions with lysine-8-vasopressin (LVP) and corticosterone (B). As an in vitro model, 14-day ...
journal_title:Progress in brain research
pub_type: 杂志文章
doi:10.1016/s0079-6123(08)62322-5
更新日期:1992-01-01 00:00:00
abstract::The main topic of this overview is an analysis of the concepts of phase and synchrony, as used in neurophysiology, in their various meanings. A number of notions related to the concepts of phase and synchrony, which are incorporated in contemporary neurophysiology, particularly in the domain of neuro-cognitive physiol...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/S0079-6123(06)59001-6
更新日期:2006-01-01 00:00:00
abstract::Miniature eye movements occur involuntarily during visual fixation. The most prominent contribution to these fixational eye movements is generated by microsaccades, which are rapid small-amplitude saccades with a rate of about one per second. Recent work demonstrates that microsaccades are optimized to counteract perc...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/S0079-6123(06)54009-9
更新日期:2006-01-01 00:00:00
abstract::The results from the language studies taken as a whole point to different developmental time courses and developmental vulnerabilities of aspects of grammatical and semantic/lexical processing. They thus provide support for conceptions of language that distinguish these subprocesses within language. Similarly, followi...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/S0079-6123(02)38078-6
更新日期:2002-01-01 00:00:00
abstract::Motor control of different segments of the body with multiple degrees of freedom appears to be coordinated by utilizing preferred axes of motor activity. This hypothesis may also be applied to vestibular control of posture. To explore this question we studied the anatomical relationship between the head and the cervic...
journal_title:Progress in brain research
pub_type: 杂志文章
doi:10.1016/s0079-6123(08)62282-7
更新日期:1993-01-01 00:00:00
abstract::Individual differences in cognitive functioning during extended work hours and shift work are of considerable magnitude, and observed both in the laboratory and in the workplace. These individual differences have a biological basis in trait-like, differential vulnerability to fatigue from sleep loss and circadian misa...
journal_title:Progress in brain research
pub_type: 杂志文章
doi:10.1016/B978-0-444-53817-8.00009-8
更新日期:2011-01-01 00:00:00
abstract::Sub-lethal exposure to practically any harmful stimulus has been shown to induce consequent protection against more severe stress. This preconditioning (PC) effect may be achieved by exposure to different stressors, indicating that the induction of tolerance involves activation of common protective pathways. Chronic e...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/S0079-6123(06)61025-X
更新日期:2007-01-01 00:00:00
abstract::This chapter reviews research that focuses on the effects of emotionality of single words, and of simple phrases, on event-related brain potentials when these are presented visually in various tasks. In these studies, presentation of emotionally evocative language material has consistently elicited a late (c. 300-600 ...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/S0079-6123(06)56009-1
更新日期:2006-01-01 00:00:00
abstract::During walking, an increase in speed is accompanied by a decrease in the stance phase duration while the swing phase remains relatively invariant. By definition, the rhythm generator in the lumbar spinal cord controls cycle period, phase durations, and phase transitions. Our first aim was to determine if this asymmetr...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/B978-0-444-53825-3.00007-3
更新日期:2011-01-01 00:00:00
abstract::Unraveling the mysteries of consciousness, lost and regained, and perhaps even intervening so as to prompt recovery are advances for which neither the clinical nor the lay community are prepared. These advances will shake existing expectations about severe brain damage and will find an unprepared clinical context, per...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/S0079-6123(05)50040-2
更新日期:2005-01-01 00:00:00
abstract::Selective attention is an important aspect of brain function that we need in coping with the immense and constant barrage of sensory information. One model of attention (Feature Integration Theory) that suggests an early selection of spatial locations of objects via an attentional spotlight would also solve the 'bindi...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/s0079-6123(01)34020-7
更新日期:2001-01-01 00:00:00
abstract::Glial scar encapsulation is thought to be one of the major reasons for the failure of chronic brain-machine interfaces. Many strategies, including modification of the probe surface chemistry, delivery of anti-inflammatory drugs, and changes of probe geometry, have been employed to reduce glial scar formation. We have ...
journal_title:Progress in brain research
pub_type: 杂志文章
doi:10.1016/B978-0-444-53815-4.00001-7
更新日期:2011-01-01 00:00:00
abstract::Nerve growth factor (NGF) is required for the survival of developing sympathetic and sensory neurons. In the absence of NGF, these neurons undergo protein synthesis-dependent apoptosis. Ten years have gone by since the first reports of specific genes being upregulated during NGF deprivation-induced cell death. Over th...
journal_title:Progress in brain research
pub_type: 历史文章,杂志文章,评审
doi:10.1016/S0079-6123(03)46008-1
更新日期:2004-01-01 00:00:00
abstract::The receptor tyrosine kinase B, TrkB, is the high-affinity receptor for brain-derived neurotrophic factor (BDNF). Much evidence supports a role for TrkB signaling in excitatory synapse formation. There have been a number of recent advances in understanding the cell biology of TrkB-mediated excitatory synaptogenesis. T...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/s0079-6123(06)57002-5
更新日期:2006-01-01 00:00:00
abstract::Retinal ganglion cell axons within the globe are functionally specialized being richly provided with many mitochondria. The mitochondria produce the high energy requirement for nerve conduction in the unmyelinated part of the ganglion cell axons. We have proposed that in the initiation of glaucoma, an alteration in th...
journal_title:Progress in brain research
pub_type: 杂志文章
doi:10.1016/S0079-6123(08)01124-2
更新日期:2008-01-01 00:00:00
abstract::Orienting one's gaze towards a peripheral target is usually composed of a hypometric primary saccade followed by a secondary 'corrective saccade' triggered automatically (without conscious perception) by the retinal error at the end of the primary saccade and characterised by a short latency. Due to visual suppression...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/S0079-6123(03)42012-8
更新日期:2003-01-01 00:00:00
abstract::The success of axon regeneration in the adult mammalian brain depends on the presence of growth-permissive environmental conditions as well as on specific properties of the affected neurons. To investigate the relative contribution of extrinsic cues and intrinsic determinants to reparative processes we have investigat...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/s0079-6123(08)63370-1
更新日期:1997-01-01 00:00:00
abstract::The capacity to sustain high-intensity aerobic exercise is essential for endurance performance. Therefore, it is important to understand what is the factor limiting time to exhaustion (TTE) in healthy and fit adults. In Study 1, maximal voluntary cycling power (MVCP) was measured in 11 volunteers before and immediatel...
journal_title:Progress in brain research
pub_type: 杂志文章
doi:10.1016/bs.pbr.2018.09.012
更新日期:2018-01-01 00:00:00
abstract::The Tibetan Buddhist classification of mind, its divisions and the system of meditation practices aimed at achieving ideal states of being are a complex presentation of psychological, behavioral and spiritual concepts and processes that demand thorough understanding before assessing their value and outcome (Yeshe, 199...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/s0079-6123(08)62160-3
更新日期:2000-01-01 00:00:00
abstract::The idea of the dentate gyrus as a gate or filter at the entrance to the hippocampus, blocking or filtering incoming excitation from the entorhinal cortex, has been an intriguing one. Here we review the historical development of the idea, and discuss whether it may be possible to be more specific in defining this gate...
journal_title:Progress in brain research
pub_type: 杂志文章,评审
doi:10.1016/S0079-6123(07)63032-5
更新日期:2007-01-01 00:00:00