Abstract：
:Twenty years ago, Wolfe, Xia, and Selkoe identified two aspartate residues in Alzheimer's presenilin protein that constitute the active site of the γ-secretase complex. Mutations in the genes encoding amyloid precursor protein (APP) or presenilin (PS) cause early onset familial Alzheimer's disease (AD), and sequential cleavages of the APP by β-secretase and γ-secretase/presenilin generate amyloid β protein (Aβ), the major component of pathological hallmark, neuritic plaques, in brains of AD patients. Therapeutic strategies centered on targeting γ-secretase/presenilin to reduce amyloid were implemented and led to several high profile clinical trials. This review article focuses on the studies of γ-secretase and its inhibitors/modulators since the discovery of presenilin as the γ-secretase. While a lack of complete understanding of presenilin biology renders failure of clinical trials, the lessons learned from some γ-secretase modulators, while premature for human testing, provide new directions to develop potential therapeutics. Imbalanced Aβ homeostasis is an upstream event of neurodegenerative processes. Exploration of γ-secretase modulators for their roles in these processes is highly significant, e.g., decreasing neuroinflammation and levels of phosphorylated tau, the component of the other AD pathological hallmark, neurofibrillary tangles. Agents with excellent human pharmacology hold great promise in suppressing neurodegeneration in pre-symptomatic or early stage AD patients.
journal_name
Neurosci Lettjournal_title
Neuroscience lettersauthors
Xia Wdoi
10.1016/j.neulet.2019.02.011subject
Has Abstractpub_date
2019-05-14 00:00:00pages
162-169eissn
0304-3940issn
1872-7972pii
S0304-3940(19)30094-1journal_volume
701pub_type
杂志文章,评审abstract：:Fish glial cells were obtained from cultivated segments of the optic nerve and raised in vitro. Two types of cells were identified as astrocyte- and oligodendrocyte-like glia by the monoclonal antibody Mab O1 (specific for oligodendrocytes) and the rabbit serum anti-goldfish glial fibrillary acidic protein (anti-G-GFA...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/0304-3940(89)90518-1
更新日期：1989-06-19 00:00:00
abstract：:Cholinergic amacrine cells in the rabbit retina have been detected by localizing choline acetyltransferase-like immunoreactivity. The characteristic array of normally placed and displaced amacrine cells was detected, as were two major synaptic plexuses in the inner plexiform layer. At the ultrastructural level, the mo...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/0304-3940(87)90310-7
更新日期：1987-03-09 00:00:00
abstract：:Although metabolic syndrome (MS) is recognized as a risk factor for ischemic stroke, little is known about genetic variants that confer susceptibility to ischemic stroke among individuals with or without MS. This study was completed to investigate whether the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorp...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/j.neulet.2012.11.031
更新日期：2013-01-15 00:00:00
abstract：:6-hydroxydopamine (6-OHDA) is usually thought to cross cell membrane through dopamine uptake transporters, to inhibit mitochondrial respiration and to generate intracellular reactive oxygen species. In this study, we show that the anti-oxidants catalase, glutathione and N-acetyl-cysteine are able to reverse the toxic ...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/s0304-3940(00)00948-4
更新日期：2000-04-14 00:00:00
abstract：:An analysis was made of primary afferent and dorsal horn neuron responses to stimulation of genitalia of female cats. Three types of primary afferents responded to vaginal probing. The most common type responded maximally to the on- and off-ramps of non-noxious pressure applied directly to the clitoris. A second type ...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/0304-3940(81)90427-4
更新日期：1981-10-01 00:00:00
abstract：:We report a sporadic case of tauopathy with unusual clinical and neuropathological features. The patient presented with progressive symmetric rigid-akinetic parkinsonism and dementia of the subcortical type. Magnetic resonance imaging of the brain revealed atrophy resembling multiple system atrophy. The level of cereb...
journal_title：Neuroscience letters
pub_type： 杂志文章,评审
doi：10.1016/s0304-3940(02)00616-x
更新日期：2002-09-13 00:00:00
abstract：:Local cerebral glucose utilization (LCGU) was measured during spontaneous waking and slow wave sleep (SWS) by an adaptation of the [14C]deoxyglucose method to the free moving cat. In awake animals heterogeneous rates of LCGU were observed throughout the brain with values extending from 8 mumol x 100 g-1 x min-1 for wh...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/0304-3940(82)90235-x
更新日期：1982-09-20 00:00:00
abstract：:Effects of anxiety on perceptual-motor organisation of rhythmical forearm movements were examined using an interrupted time series design with staggered baselines. Participants were exposed to repeated baseline sessions interrupted with two anxiety-inducing sessions. Results showed that under moderate levels of anxiet...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/j.neulet.2005.04.036
更新日期：2005-08-12 00:00:00
abstract：:The present study was designed to test the hypothesis that alpha-tocopherol (Vit. E) and pyrrolidine dithiocarbamate (PDTC) might exert direct effects on alcohol-induced contractions of canine basilar cerebral arteries. After precontraction of arterial ring segments with ethanol, PDTC (10(-8)-10(-6) M) and Vit. E (10(...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/s0304-3940(01)01588-9
更新日期：2001-03-30 00:00:00
abstract：:Striatal neurons containing acetylcholine and somatostatin were examined using a pharmacohistochemical procedure for acetylcholinesterase and NADPH-diaphorase histochemistry respectively. The use of these two histochemical procedures allowed both cholinergic and somatostatin cells to be visualized simultaneously in si...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/0304-3940(83)90536-0
更新日期：1983-02-21 00:00:00
abstract：:Intracellular recordings were performed in a midpontine slice preparation of the rat brain containing the mesencephalic trigeminal nucleus (MTN). In spite of the previous demonstration of an adenosine deaminase-containing plexus terminating on this nucleus, adenosine, adenosine 5'-triphosphate (ATP), alpha,beta-methyl...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/0304-3940(88)90615-5
更新日期：1988-10-17 00:00:00
abstract：:In vitro studies suggest that insulin-like growth factor (IGF)-I is a mitogen for microglia/macrophages. The actions of IGF-I are mediated by IGF-I receptors and modulated by IGF binding proteins (IGFBPs). The aim of this study was to investigate IGF-I receptors and IGFBPs in human microglia in normal brain white matt...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/j.neulet.2004.01.039
更新日期：2004-05-13 00:00:00
abstract：:The role of the lateral hypothalamus (LHT) in the regulation of feeding behavior has long been established. The major contribution of LHT glucose-sensitive neurons, activated by low glucose concentration, is well accepted. Two peptidergic neuron populations, whose perikarya are exclusively located within this area, ha...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/0304-3940(94)90404-9
更新日期：1994-02-28 00:00:00
abstract：:Prophylaxis of posttraumatic epilepsy will require a detailed knowledge of the epileptogenic pathophysiological processes that follow brain injury. Results from studies of experimental models and human epilepsy highlight alterations in GABAergic interneurons and formation of excessive new excitatory synaptic connectiv...
journal_title：Neuroscience letters
pub_type： 杂志文章,评审
doi：10.1016/j.neulet.2011.02.042
更新日期：2011-06-27 00:00:00
abstract：:Although the guinea pig is used widely in experimental medical research, including in studies on micturition control, the spinal origin of preganglionic parasympathetic bladder and somatic external urethral sphincter motoneurons is not known. In the male guinea pig using wheat germ agglutinin-conjugated horseradish pe...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/j.neulet.2004.02.051
更新日期：2004-05-13 00:00:00
abstract：:Buyang Huanwu Decoction (BYHWD), a traditional Chinese medicine, has been developed as a drug to be used for treatment of stroke for hundreds of years. However, the underlying mechanisms remain unknown. In the present study, the effects of BYHWD on delayed neuronal death of hippocampus after transient forebrain ischem...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/s0304-3940(03)00522-6
更新日期：2003-07-31 00:00:00
abstract：:To study zinc (Zn) mobility in the rat olfactory tract, brain distribution of 65Zn after injection into the olfactory bulb or amygdaloid nuclei was analyzed by autoradiography. Twenty-four hours after 65Zn injection into the olfactory bulb, 65Zn was distributed in the ipsilateral piriform cortex, amygdaloid nuclei and...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/s0304-3940(97)00181-x
更新日期：1997-03-28 00:00:00
abstract：:Dehydroepiandrosterone sulfate (DHEAS) dose-dependently inhibited [3H]norepinephrine (NE) secretion and the corresponding [Ca2+]i rise induced by the nicotinic receptor agonist 1,1-dimethyl-4-phenylpoperazimium (DMPP) in bovine chromaffin cells. DHEAS at 10 microM, the physiological concentration in human serum, signi...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/0304-3940(96)12350-8
更新日期：1996-02-09 00:00:00
abstract：:Using an antiserum (AS) raised against dynorphin B (DYN B), we revealed immunoreactive neurons in different nuclei of the rat hypothalamus as well as a population of neurons scattered in the lateral areas of the posterior hypothalamus. This population corresponds to that previously shown to be specifically recognized ...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/0304-3940(93)90447-s
更新日期：1993-06-25 00:00:00
abstract：:The reactivity of different narrow electroencephalographic (EEG) frequencies (4-6, 6-8, 8-10 and 10-12 Hz) to three types of emotionally laden film clips (aggressive, sad, neutral) were examined. We observed that different EEG frequency bands responded differently to the three types of film content. In the 4-6 Hz freq...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/s0304-3940(00)01092-2
更新日期：2000-05-26 00:00:00
abstract：:Release of endogenous polyamines may contribute to neuronal loss in ischemia and related conditions. Primary cortical neurons were exposed to spermine and spermidine and subsequently assayed for [3H]ouabain binding to quantify neuronal loss. Neuronal survival was significantly decreased in the presence of spermine at ...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/0304-3940(93)90152-b
更新日期：1993-10-14 00:00:00
abstract：:The origin of nerve fibers projecting to the guinea pig heart that contain nitric oxide synthase (NOS) were studied by unilateral cervical vagotomy. Three kinds of NOS-immunoreactive (NOS-ir) nerve fibers are distributed in the control guinea pig heart: the sparse network covering the right atrium, the basket-like end...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/s0304-3940(98)00568-0
更新日期：1998-08-14 00:00:00
abstract：:We examined whether the mGluR1 and mGluR5 were involved in development and maintenance of behavioral signs of non-evoked pain and secondary mechanical hyperalgesia induced by knee joint inflammation. Selective mGluR1 antagonist, (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA: 50, 100, 200 microM/25 microl, n=10 per gro...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/j.neulet.2007.01.063
更新日期：2007-04-12 00:00:00
abstract：:Restoration of autophagy represents a potential therapeutic target for neurodegenerative disorders, but factors that regulate autophagic flux are largely unknown. When deprived of trophic factors, cultured Purkinje neurons die by an autophagy associated cell death mechanism. The accumulation of autophagic vesicles and...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/j.neulet.2010.09.018
更新日期：2011-01-20 00:00:00
abstract：:Changes in the activity of gamma-glutamyl transpeptidase (GGTP) and the effects of a subacute dose (150 mg/kg b.wt.) of methionine sulfoximine (MSO) on its activity were studied in cerebral cortex, cerebellum and brainstem of rats of 4 different age groups. GGTP activity increased with increasing age between days 10 a...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/0304-3940(91)90359-2
更新日期：1991-05-13 00:00:00
abstract：:In the present study, we demonstrate that the histopathologic features of myelin oligodendrocyte glycoprotein (MOG) peptide 35-55-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice closely mirror the hallmarks of MS pathology. On the one hand, we depict a time-dependent transition from acute infla...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/j.neulet.2011.03.021
更新日期：2011-05-02 00:00:00
abstract：:Previous pharmacokinetics and electrophysiological results indicated an important role of nicotine in the modulation of dopamine transporter (DAT). To elucidate the expression changes of DAT on chronic nicotine and smoke administration, the effects of nicotine and passive cigarette smoke on DAT mRNA expression in the ...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/j.neulet.2004.03.053
更新日期：2004-06-03 00:00:00
abstract：:The localization of amyloid beta protein (A beta), A beta 40, A beta 42, and transthyretin (TTR) was investigated immunohistochemically in the autopsied human kidney, using polyclonal antibodies against TTR, A beta and C-terminal end-specific antibodies against A beta 40 and 42. Immunoreactivities of A beta and A beta...
journal_title：Neuroscience letters
pub_type： 临床试验,杂志文章
doi：10.1016/s0304-3940(97)13369-9
更新日期：1997-02-07 00:00:00
abstract：:We previously reported that the amyloid-beta protein (Abeta) reduces the synthesis of acetylcholine (ACh) in a mouse septal cell line, SN56, without causing death of the cells. Here, we report that the ACh-reducing effect of either Abeta 1-28 or Abeta 1-42 (100 nM; 48 h) in SN56 cells can be prevented by a co-treatmen...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/s0304-3940(97)00913-0
更新日期：1997-12-19 00:00:00
abstract：:Neural cell adhesion molecules (NCAMs) are members of the immunoglobulin superfamily and are involved in synaptic rearrangements in the mature brain. There are three major NCAM forms: NCAM 180, NCAM 140 and NCAM 120. Several studies report that NCAMs play a central role in memory. In the present study we investigated ...
journal_title：Neuroscience letters
pub_type： 杂志文章
doi：10.1016/s0304-3940(02)00328-2
更新日期：2002-06-28 00:00:00
