bluuebunny/crossref_metadata_2025_split huggingface dataset:
SCG10‐related neuronal growth‐associated proteins in neural development, plasticity, degeneration, and aging
Authors: Mori Nozomu , Morii Hiroshi 
Published: October 2002

AbstractNeuronal growth‐associated proteins (nGAPs) are in general neuron‐specific gene products whose expression correlates tightly with neuronal process outgrowth and/or regeneration, and are mostly good downstream targets of neurotrophin stimulation. Expression of genes encoding nGAPs such as GAP‐43, SCG10, and stathmin is upregulated following lesioning of cortical and hippocampal regions of the adult rat brain. In the brains of aged animals, however, the magnitude of the response is reduced, whereas the time course of the response is mostly unchanged when compared with that for brains of young ones. Expression of GAP‐43 and stathmin is reduced by aging, and is also changed in age‐related neurodegenerative conditions such as Alzheimer's disease in humans. Certain nGAPs are induced during long‐term potentiation (LTP) and also during critical periods of song‐learning and ocular dominance column formation in birds and cats, respectively. Recent evidence further supports the idea that functional synaptic modulation is often associated with remodeling of synaptic structures. These results suggest that neurotrophin‐responsive nGAPs serve as molecular markers of neuronal plasticity during development and aging, and that the neuronal plasticity decreases, at least in certain neuronal circuits, in the aged brain and neurodegenerative diseases. Recent findings on the roles of stathmin and SCG10‐related proteins in microtubule destabilization and its functional block by phosphorylation further support the importance of the SCG10 family proteins in neuronal cytoskeletal regulation, particularly as to microtubule dynamics. We summarize here a decade of research on SCG10 and its related molecules with special interests to brain aging and disease. © 2002 Wiley‐Liss, Inc.
Death and survival of neuronal cells exposed to Alzheimer's insults
Authors: Niikura Takako , Hashimoto Yuichi , Tajima Hirohisa , Nishimoto Ikuo 
Published: October 2002

AbstractNeuronal cell death is the central abnormality occurring in brains suffering from Alzheimer's disease (AD). The notion that AD is a disease caused by loss of neurons points toward suppression of neuronal death as the most important therapeutic target. Nevertheless, the mechanisms for neuronal death in AD are still relatively unclear. Three known mutant genes cause familial AD (FAD): amyloid precursor protein, presenilin 1, and presenilin 2. Detailed analysis of cytotoxic mechanisms of the FAD‐linked mutant genes reveals that they cause neuronal cell death at physiologically low expression levels. Unexpectedly, cytotoxic mechanisms vary depending on the type of mutations and genes, suggesting that various mechanisms for neuronal cell death are involved in AD patients. In support of this, activity‐dependent neurotrophic factor, basic fibroblast growth factor, and insulin‐like growth factor‐I can completely protect neurons from β‐amyloid (Aβ) cytotoxicity but exhibit incomplete or little effect on cytotoxicity by FAD mutant genes. By contrast, Humanin, a newly identified 24‐residue peptide, suppresses neuronal cell death by various FAD mutants and Aβ, whereas this factor has no effect on cytotoxicity from AD‐irrelevant insults. Studies investigating death and survival of neuronal cells exposed to AD insults will open a new horizon in developing therapy aimed at neuroprotection. © 2002 Wiley‐Liss, Inc.
Alzheimer's disease: β‐Amyloid protein and tau
Authors: Morishima‐Kawashima Maho , Ihara Yasuo 
Published: October 2002

AbstractResearch on the molecular pathogenesis of Alzheimer's disease (AD) has made great strides over the last decade. This progress is the result of protein chemical analysis of two extracellular and intracellular fibrillary lesions in AD brain conducted during the 1980s, which identified β‐amyloid protein (Aβ) and tau as their major components, respectively. Linkage analysis of familial AD identified four responsible genes: three causative genes (β‐amyloid precursor protein, presenilin 1, and presenilin 2) and one susceptibility gene (apolipoprotein E ϵ4). All those genes causing and predisposing to AD exhibit a common phenotype: an increased production of Aβ42, a longer, more amyloidogenic Aβ species, and/or its enhanced deposition. This observation was substantiated when presenilins were shown to be directly involved in Aβ production. Whereas Aβ deposition is relatively specific for AD, tau deposition is observed in various neurodegenerative diseases and is assumed to be intimately associated with neuronal loss. The genetic analysis of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP‐17) revealed the presence of mutations in the tau gene in affected members. Thus, tau can lead to intracellular tau deposits and neuronal loss, although the mechanism remains to be clarified. Taken together, Aβ might exert neurotoxicity through tau, leading to neuronal loss in the AD brain. © 2002 Wiley‐Liss, Inc.
Age‐related changes in central nervous system phosphatidylserine decarboxylase activity
Authors: Salvador Gabriela A. , López Frederico M. , Giusto Norma M. 
Published: October 2002

AbstractA significant portion of brain phosphatidylethanolamine (PE) is synthesized by a pathway involving the mitochondrial enzyme phosphatidylserine decarboxylase (PSDC), in a process by which phosphatidylserine (PS) is transferred from the endoplasmic reticulum to mitochondria. Aging changes the fatty acid composition of brain phospholipids, PS and PE being the most affected. The present study was carried out to determine PSDC activity in cerebral cortex (CC) and cerebellum (CRBL) mitochondrial fraction from adult (4‐month‐old) and aged (30‐month‐old) rats and to compare these activities with that found in liver. To study the effect of 22:6n‐3 content on the PSDC activity, PSs from different sources were prepared: rPS (from bovine retina, containing 36 mol % of 22:6n‐3); adPS (from adult rat CC microsomal membranes, with 25 mole % 22:6n‐3 content) and agPS (from aged rat CC microsomal membranes, with 21 mole % 22:6n‐3 content). For aged CC PSDC, the preferred substrate was agPS (the physiological substrate for aged animals), whereas in adult CC PSDC the substrate preference was inverse (rPS > adPS > agPS). Furthermore, CRBL PSDC does not show any substrate preference based on 22:6n‐3 content. CRBL PSDC activity in aged membranes using agPS as substrate is lower than PSDC activity in adult membranes in the presence of adPS. These results indicate that under physiological conditions, cerebellar PSDC is inhibited during aging. Liver PSDC activity showed the same substrate preference in adult and aged rats as adult CC PSDC. These findings lead us to conclude that PSDC activity has a differential tissue‐dependent substrate preference characteristic of the aging process. © 2002 Wiley‐Liss, Inc.
Ultrastructural analysis of the paranodal junction of myelinated fibers in 31‐month‐old‐rats
Authors: Sugiyama Ichiro , Tanaka Kayoko , Akita Masumi , Yoshida Kazunari , Kawase Takeshi , Asou Hiroaki 
Published: October 2002

AbstractRecent studies have revealed a significant decrease in white matter volume, including loss of myelin, with age but minimal decrease in gray matter volume (Guttmann et al., [1998] Neurology 50:972–978). Myelin is necessary for the rapid conduction of impulses along axons. Myelinated nerve includes various domains, the node of Ranvier, the paranodal region, the juxtaparanodal region and the internode. The paranodal junction may serve to anchor the myelin sheath to the axon. We analyzed the ultrastructure of the paranodal region in myelinated fibers from the aged rat brain. Severe alterations of myelinated fibers were observed in 31‐month‐old rats, resulting in the appearance of macrophages, splitting of the myelin sheath, myelin balloon formation and separation from the axon. Many paranodal retractions of myelinated axons occurred in the aged rats. It should be noted that the paranodal junction is functionally important, serving to anchor the myelin to the axon and that there is a diffusion barrier in the paranodal region. We analyzed myelin‐related proteins from young and aged rat brains. The 21.5‐kDa isoform of myelin basic protein (MBP) almost disappeared in the 31‐month‐old rats, whereas other myelin proteins were not significantly changed between young and aged rats. These results suggest that this isoform, a highly cationic charged major dense component protein that binds lipid bilayer in the membrane, may participate in the formation of a paranodal diffusion barrier at the myelin/noncompact membrane border. © 2002 Wiley‐Liss, Inc.
Expression patterns of immature neuronal markers PSA‐NCAM, CRMP‐4 and NeuroD in the hippocampus of young adult and aged rodents
Authors: Seki Tatsunori 
Published: October 2002

AbstractNeurogenesis is known to continue in the adult hippocampus of mammals, including humans. The present experiments were undertaken to examine the nature of developing neurons generated in the dentate gyrus of young and older rodents using immature neuronal markers such as highly polysialylated neural cell adhesion molecules (PSA‐NCAM), collapsin response‐mediated protein‐4 (CRMP‐4) and NeuroD. Most PSA‐expressing cells are simultaneously positive for CRMP‐4 and NeuroD in young rats. More than half of the PSA‐positive cells were also positive for mature neuronal markers such as NeuN and MAP2, although the intensity of the immunoreactivities was relatively weak. BrdU analysis revealed that CRMP‐4 is expressed for a longer period than PSA in BrdU‐labeled neurons. The number of immature neurons expressing PSA, NeuroD or CRMP‐4 decreased in older rodents, but no qualitative difference was found in the expression patterns of these molecular markers between young and older rodents. These results suggest not only that immunohistochemistry, using a combination of these immature and mature neuronal markers, is helpful for clarifying the developmental state of newly generated neurons, but also that newly generated neurons in young adult and older rodents have similar properties. © 2002 Wiley‐Liss, Inc.
Role of mitochondrial dysfunction in Alzheimer's disease
Authors: Castellani Rudy , Hirai Keisuke , Aliev Gjumrakch , Drew Kelly L. , Nunomura Akihiko , Takeda Atsushi , Cash Adam D. , Obrenovich Mark E. , Perry George , Smith Mark A. 
Published: October 2002

AbstractAbnormalities in mitochondrial function relate to the spectrum of pathological changes seen in Alzheimer's disease. Here we review the causes and consequences of mitochondrial disturbances in Alzheimer's disease as well as how this information might impact on therapeutic approaches to this disease. © 2002 Wiley‐Liss, Inc.
Region‐specific reduction of Aβ‐degrading endopeptidase, neprilysin, in mouse hippocampus upon aging
Authors: Iwata Nobuhisa , Takaki Yoshie , Fukami Shinjiro , Tsubuki Satoshi , Saido Takaomi C. 
Published: October 2002

AbstractMetabolism of amyloid‐β peptide (Aβ) is closely associated with the pathology and etiology of Alzheimer's disease (AD). Neprilysin is the only rate‐limiting catabolic peptidase proven by means of reverse genetics to participate in Aβ metabolism in vivo. The aim of the present study is to assess whether possible spatial changes in neprilysin level in the brain with aging correlate to AD‐vulnerable regions. When neprilysin levels in various brain regions of 10‐, 80‐ and 132‐week‐old mice were evaluated by neprilysin‐dependent endopeptidase activity assay and Western blot‐based quantitative analysis, a clear change in neprilysin level with aging was observed in the hippocampal formation, in which the level was reduced by 20% at 132 weeks, compared to the 10‐week group. Quantitative immunohistochemical analysis confirmed a marked local reduction of neprilysin levels with aging at the outer molecular layer and polymorphic layer of the dentate gyrus, and the stratum lucidum of the hippocampus, where the densities were reduced by 56%, 82% and 83%, respectively, at 132 weeks compared to the 10‐week group. Thus, neprilysin was decreased selectively at the terminal zones and on axons of the lateral perforant path and the mossy fibers. These are the sites that show Aβ pathology in mutant amyloid precursor protein (APP) transgenic mice, and that show synaptic loss in AD. The immunoreactivities to synaptic vesicle protein‐2 and synaptophysin in the stratum lucidum and the dentate gyrus were unchanged, suggesting that a loss or decrease of synapses was not responsible for the decrease in the neprilysin levels. These observations suggest that downregulation of neprilysin is likely to be related to AD pathology and to the Aβ deposition associated with normal aging in humans. © 2002 Wiley‐Liss, Inc.
In vivo conversion of racemized β‐amyloid ([D‐Ser26]Aβ1–40) to truncated and toxic fragments ([D‐Ser26]Aβ25–35/40) and fragment presence in the brains of Alzheimer's patients
Authors: Kubo Takekazu , Nishimura Satoko , Kumagae Yoshihiro , Kaneko Isao 
Published: October 2002

AbstractThe lag between β‐amyloid (Aβ) deposition and neurodegeneration in Alzheimer's disease (AD) suggests that age‐dependent factors are involved in the pathogenesis. Racemization of Ser and Asp in Aβ is a typical age‐dependent modification in AD. We have shown recently that Aβ1–40 racemized at Ser26 ([D‐Ser26]Aβ1–40) is soluble and non‐toxic to neuronal cells, but is easily converted by brain proteases to truncated toxic fragments, [D‐Ser26]Aβ25–35/40. Furthermore, [D‐Ser26]Aβ1–40 in vivo, produced a drastic and synergistic neuronal loss by enhancing the excitotoxicity when co‐injected into rat hippocampus with ibotenic acid, an excitatory amino acid, suggesting an in vivo conversion of non‐toxic [D‐Ser26]Aβ1–40 to toxic fragments including [D‐Ser26]Aβ25–35/40. In this study, we further investigated the mechanism behind the in vivo neuronal loss by [D‐Ser26]Aβ1–40 and ibotenic acid in rats, and also searched for the presence of [D‐Ser26]Aβ25–35/40 antigens in AD brains. Quantitative analyses of the damaged area indicate clearly that non‐toxic [D‐Ser26]Aβ1–40 caused as much neurodegeneration as toxic [D‐Ser26]Aβ25–35/40. MK‐801, an NMDA receptor antagonist, completely inhibited the neurodegeneration. The immunohistochemical analyses using anti‐[D‐Ser26]Aβ25–35/40‐specific antibodies demonstrated the presence of [D‐Ser26]Aβ25–35/40 antigens in senile plaques and in degenerating hippocampal CA1 neurons in AD brains, but not in age‐matched control brains. These results strengthen our hypothesis that soluble [D‐Ser26]Aβ1–40, possibly produced during aging, is released from plaques and converted by proteolysis to toxic [D‐Ser26]Aβ25–35/40, which damage hippocampal CA1 neurons by enhancing excitotoxicity in AD. This may account for the lag between Aβ deposition and neurodegeneration in AD. © 2002 Wiley‐Liss, Inc.
Alzheimer's disease with spastic paresis and cotton wool type plaques
Authors: Tabira Takeshi , Chui De Hua , Nakayama Hiroshi , Kuroda Shigetoshi , Shibuya Makoto 
Published: October 2002

AbstractWe reviewed Alzheimer's cases with spastic paresis and cotton wool type plaques in five Japanese and nine Caucasian cases. Most were early onset familial Alzheimer's disease with presenilin 1 mutations. The cotton wool type plaques were related to extremely high production of Aβ42, due mainly to presenilin 1 mutations and low immune responses. Cotton wool plaques were numerous in the entire central nervous system, including basal ganglia, brainstem and even in spinal cord. Cotton wool type plaques were composed of slightly electron dense synaptic structures, but amyloid fibrils were rarely found. Such a high accumulation of Aβ42 may cause degeneration of the pyramidal tract and basal ganglia from an early stage of Alzheimer's disease. © 2002 Wiley‐Liss, Inc.
β‐secretase as a target for the treatment of Alzheimer's disease
Authors: Citron Martin 
Published: October 2002

AbstractFinding inhibitors of the first step of the amyloid cascade, Aβ42 generation, is a major goal of Alzheimer's disease drug development. Two target protease activities, β‐and γ‐secretase, were detected more than 10 years ago but progress in this area has been slow because the enzymes were not identified. Using an expression cloning strategy we have identified a novel membrane bound aspartic protease, BACE1, as β‐secretase. The enzyme has been characterized in detail. The X‐ray crystal structure, which is critical for rational inhibitor design, has been solved and shown to be similar to that of other pepsin family members. Our recent knockout studies show that BACE1 is critical for Aβ generation, but the knockout mice show an otherwise normal phenotype, raising the possibility that therapeutic BACE1 inhibition could be accomplished without major mechanism based toxicity. Target‐mediated toxicity of β‐secretase inhibition cannot be ruled out, however, as long as the major substrates of this enzyme are unknown. Although various peptidic β‐secretase inhibitors have been published, the key challenge now is the generation of more drug‐like compounds that could be developed for therapeutic purposes. The focus of this review is progress in the β‐secretase field from the identification of the enzyme in 1999 to the most recent publications. © 2002 Wiley‐Liss, Inc.
Protective effect of dopamine D2 agonists in cortical neurons via the phosphatidylinositol 3 kinase cascade
Authors: Kihara Takeshi , Shimohama Shun , Sawada Hideyuki , Honda Kazuhiro , Nakamizo Tomoki , Kanki Rie , Yamashita Hiroshi , Akaike Akinori 
Published: October 2002

AbstractGlutamate, one of the excitatory neurotransmitters, contributes to the neuronal death associated with neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, and with ischemia. In Alzheimer's disease brains, there is a decreased number of dopamine D2 receptors, which might cause neuronal dysfunction or death. In the present study, bromocriptine exerted a protective effect against glutamate‐induced cytotoxicity in rat cortical neurons. This neuroprotective effect was mediated via D2 receptors, because it was attenuated by domperidone, a D2 dopaminergic receptor antagonist. Another dopamine D2 agonist, quinpirole, also protected cells against glutamate toxicity. D2 agonists protected cells from calcium influx, nitric oxide, and peroxynitrite toxicity, which are thought to be the mediators of glutamate toxicity. The phosphatidylinositol 3 kinase (PI3K) inhibitor (LY294002) inhibited this neuroprotective effect of bromocriptine, in contrast to the mitogen‐activated protein kinase kinase (MAPKK) inhibitor (PD98059), which did not counter the protective effect. Furthermore, Akt protein kinase, which is an effector of PI3K, was activated by bromocriptine, and the antiapoptotic protein Bcl‐2 was up‐regulated by bromocriptine treatment. These results suggest that D2 dopaminergic receptor activation plays an important role in neuroprotection against glutamate cytotoxicity and that the up‐regulation of Bcl‐2 expression via the PI3K cascade is, at least partially, involved in this effect. © 2002 Wiley‐Liss, Inc.
Age‐related deficits in long‐term potentiation are insensitive to hydrogen peroxide: Coincidence with enhanced autophosphorylation of Ca2+/calmodulin‐dependent protein kinase II
Authors: Watson J.B. , Khorasani H. , Persson A. , Huang K‐P. , Huang F.L. , O'Dell T.J. 
Published: October 2002

AbstractReactive oxygen species (ROS) can have deleterious effects for both normal aging and Alzheimer's disease (AD). We examined the hypothesis that synapses undergoing long‐term potentiation (LTP) are preferentially at risk for ROS‐mediated oxidative stress during aging. We observed age‐dependent deficits in LTP induced by a high‐frequency stimulation (HFS) protocol in the CA1 region of hippocampus from C57BL/6 mice. There was a significant difference between LTP measured over 60 min in young (1–2 months) and old (23–26 months) mice. In oxidative stress studies, exogenous H2O2 (580 μM) significantly inhibited LTP in young mice; a similar dose of H2O2 failed to inhibit LTP in slices from adult (2–4 months) or from old mice. The results show that there are significant deficits in LTP in aging mice, but such deficits are insensitive to H2O2. Western immunoblotting studies in young mice show that the relative levels of autophosphorylated α‐Ca2+/calmodulin‐dependent protein kinase II (CaMKII) are unchanged in hippocampal CA1 treated with H2O2 relative to untreated controls. However with aging, there is a significant enhancement in the levels of autophosphorylated CaMKII in H2O2‐treated CA1 of older mice. Phosphorylation of RC3/neurogranin (Ng) by protein kinase C (PKC) is decreased in CA1 in response to H2O2 treatment, irrespective of age. We propose that, during aging, enhanced local release of H2O2 from mitocohondria may induce a compensatory “ceiling” effect at synapses, so that the levels of autophosphorylated αCaMKII are aberrantly saturated, leading to alterations in synaptic plasticity. © 2002 Wiley‐Liss, Inc.
Attenuated transcriptional responses to oxidative stress in the aged rat brain
Authors: Tong LiQi , Toliver‐Kinsky Tracy , Edwards Michael , Rassin David K. , Werrbach‐Perez Karin , Perez‐Polo J. Regino 
Published: October 2002

AbstractThe aged nervous system displays impaired cognitive functions, and these impairments are exacerbated in several neurodegenerative diseases. A role for oxidative stress has been suggested for several of these age‐associated dysfunctions. In addition, recovery from more acute traumatic insults that also generate oxidative stress is impaired in the aged. Here we examine the response of aged rat hippocampi to normobaric hyperoxia treatments and demonstrate an attenuation in the DNA binding activity of the AP‐1 and nuclear factor‐κB transcription factors, which are important components of stress response signal transduction pathways and can determine shifts in cellular commitments to necrosis, apoptosis, or functional recovery in the central nervous system. © 2002 Wiley‐Liss, Inc.
Novel cognitive improving and neuroprotective activities of Polygala tenuifolia Willdenow extract, BT‐11
Authors: Park Cheol Hyoung , Choi Se Hoon , Koo Ja‐Wook , Seo Ji‐Heui , Kim Hye‐Sun , Jeong Sung‐Jin , Suh Yoo‐Hun 
Published: October 2002

AbstractWe carried out this study to search a new active constituent that had cognitive enhancing activity and low side effects from natural source. We found that the extract of dried root of Polygala tenuifolia Willdenow (BT‐11, 10 mg/kg, i.p.) could significantly reverse scopolamine‐induced cognitive impairments in rat, using a passive avoidance and a water maze test. We also investigated the effects of BT‐11 on neurotoxicity induced by glutamate (Glu) and toxic metabolites of amyloid precursor protein (APP) such as amyloid β protein (Aβ) and C‐terminal fragment of APP (CT) in primary cultured neurons of rat. The pretreatment of BT‐11 (0.5, 3, and 5 μg/ml) significantly reduced cell death induced by Glu (1 mM), Aβ (10 μM) and CT105 (10 μM) in a dose‐dependent manner. In addition, BT‐11 inhibited acetylcholinesterase (AChE) activity in a dose‐dependent and non‐competitive manner (IC50 value; 263.7 μg/ml). Our novel findings suggest the possibility that this extract may have some protective effects against neuronal death and cognitive impairments in Alzheimer's disease (AD), or other neurodegenerative diseases related to excitotoxicity and central cholinergic dysfunction. © 2002 Wiley‐Liss, Inc.