Xiao-xin Yan | Central South University (original) (raw)

papers by Xiao-xin Yan

Panels (A–D) shows BACE1 immunolabeled sections, c... more Panels (A–D) shows BACE1 immunolabeled sections, counterstained with cresyl violet, that reveal cell loss in CA1 and CA3 stratum pyramidale (s.p.) in a 14 month-old epileptic mouse (C, D) relative to an age-matched control (A, B). Arrows in A and C point to relatively large neuritic clusters. Mossy fiber sprouting (mfs) in the inner molecular layer is clear in D. Profound loss (green arrows) of immunoreactivity for neuron-specific nuclear antigen (NeuN IR) can be seen in CA1 and CA3, and to a lesser extent in the piriform cortex and amygdala in 11- (F, H) and 14- (K, L) month old epileptic mice relative to controls (E, G, I, J). Graph (M) summarizes normalized levels of densitometric data of NeuN IR in the hippocampal cell layers, amygdala and piriform cortex. The green line represents the mean density (defined as 100%) from all control animals (n = 12). Symbols (circle, triangle or diamond) in the graph represent normalized means from the 3 age groups of the epileptics (9-month: red; 11-month: green; 14-month: blue). NeuN density in somatosensory cortex is shown as negative assay control. Refer to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0048782#pone-0048782-g001" target="_blank">Fig. 1</a> for abbreviations. Scale bar in (A) = 1 mm in (A, C, E–H); equivalent to 250 µm for (B, D, I–L).</p

The Journal of Neuroscience, 1998

Febrile seizures are the most common seizure type in young children. Whether they induce death of... more Febrile seizures are the most common seizure type in young children. Whether they induce death of hippocampal and amygdala neurons and consequent limbic (temporal lobe) epilepsy has remained controversial, with conflicting data from prospective and retrospective studies. Using an appropriate-age rat model of febrile seizures, we investigated the acute and chronic effects of hyperthermic seizures on neuronal integrity and survival in the hippocampus and amygdala via molecular and neuroanatomical methods. Hyperthermic seizures-but not hyperthermia alone-resulted in numerous argyrophilic neurons in discrete regions of the limbic system; within 24 hr of seizures, a significant proportion of neurons in the central nucleus of the amygdala and in the hippocampal CA3 and CA1 pyramidal cell layer were affected. These physicochemical alterations of hippocampal and amygdala neurons persisted for at least 2 weeks but were not accompanied by significant DNA fragmentation, as determined by in situ end labeling. By 4 weeks after the seizures, no significant neuronal dropout in these regions was evident. In conclusion, in the immature rat model, hyperthermic seizures lead to profound, yet primarily transient alterations in neuronal structure.

Alzheimer's research & therapy, Jan 24, 2018

Alzheimer's disease (AD) is a devastating neurodegenerative disorder bearing multiple patholo... more Alzheimer's disease (AD) is a devastating neurodegenerative disorder bearing multiple pathological hallmarks suggestive of complex cellular/molecular interplay during pathogenesis. Transgenic mice and nonhuman primates are used as disease models for mechanistic and translational research into AD; the extent to which these animal models recapitulate AD-type neuropathology is an issue of importance. Putative C-terminal fragments from sortilin, a member of the vacuolar protein sorting 10 protein (Vps10p) family, have recently been shown to deposit in the neuritic β-amyloid (Aβ) plaques in the human brain. We set out to explore if extracellular sortilin neuropathology exists in AD-related transgenic mice and nonhuman primates. Brains from different transgenic strains and ages developed overt cerebral Aβ deposition, including the β-amyloid precursor protein and presenilin 1 double-transgenic (APP/PS1) mice at ~ 14 months of age, the five familial Alzheimer's disease mutations tra...

Frontiers in neuroanatomy, 2017

Genetic variations in the vacuolar protein sorting 10 protein (Vps10p) family have been linked to... more Genetic variations in the vacuolar protein sorting 10 protein (Vps10p) family have been linked to Alzheimer's disease (AD). Here we demonstrate deposition of fragments from the Vps10p member sortilin at senile plaques (SPs) in aged and AD human cerebrum. Sortilin changes were characterized in postmortem brains with antibodies against the extracellular and intracellular C-terminal domains. The two antibodies exhibited identical labeling in normal human cerebrum, occurring in the somata and dendrites of cortical and hippocampal neurons. The C-terminal antibody also marked extracellular lesions in some aged and all AD cases, appearing as isolated fibrils, mini-plaques, dense-packing or circular mature-looking plaques. Sortilin and β-amyloid (Aβ) deposition were correlated overtly in a region/lamina- and case-dependent manner as analyzed in the temporal lobe structures, with co-localized immunofluorescence seen at individual SPs. However, sortilin deposition rarely occurred around t...

Neuroscience, Jan 12, 2016

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by beta-amy... more Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by beta-amyloid (Aβ) deposition, neurofibrillary tangles and cognitive decline. Recent pharmacologic studies have found that ATP-sensitive potassium (KATP) channels may play a role in AD and could be a potential therapeutic target. Interestingly, these channels are found in both neurons and astrocytes. One of the hallmarks associated with AD is reactive gliosis and a change in astrocytic function has been identified in several neuropathological conditions including AD. Thus the goal of this study was to examine whether the pore-forming subunits of KATP channels, Kir6.1 and Kir6.2, are altered in the hippocampus in a cell type-specific manner of the 3xTg-AD mouse model of AD and in human AD tissue obtained from the Chinese brain bank. Specifically, in old 3xTg-AD mice, and age-matched controls, we examined glial fibrillary acidic protein (GFAP), glutamine synthetase (GS), Kir6.1 and Kir6.2 in hippoc...

Experimental Brain Research, 1997

The present study shows the distribution of calcitonin gene-related peptide (CGRP)-immunolabeled ... more The present study shows the distribution of calcitonin gene-related peptide (CGRP)-immunolabeled neuronal somata and fibers in the accessory optic system of adult rats. CGRP-immunoreactive cell bodies were small to medium-sized and mostly fusiform or oval-shaped. Both immunolabeled somata and fibers were found in the dorsal and lateral terminal nuclei as well as in the interstitial nucleus of the superior fasciculus

Experimental gerontology, Jan 4, 2015

Spectrins are a part of cytoskeletal platform that lines the intracellular side of plasma membran... more Spectrins are a part of cytoskeletal platform that lines the intracellular side of plasma membrane, which can be proteolyzed by calcium-sensitive enzymes including calpains and caspases. Caspase-3 mediated αII-spectrin proteolysis results in the release of a 120kDa spectrin breakdown product (SBDP120), known to occur in conditions with cell death. In rodents, intraneuronal SBDP120 accumulation in the forebrain develops with age, which is enhanced in transgenic models of Alzheimer's disease (AD). The present study was set to explore age-related SBDP120 formation and its relevance to AD-type hallmark lesions in the human brains. SBDP120 immunoreactivity (IR) was detected in neuronal somata and dendrites in the cortex and hippocampal formation in postmortem brains from aged (n=10, mean age=84.2) and AD (n=10, mean age=84.8) subjects, but not mid-aged controls (n=10, mean age=58.2). The overall density of SBDP120 IR quantified in the temporal neocortex was increased in the aged and ...

BMC Neurology, 2015

Background: Cerebral amyloid angiopathy (CAA) refers to the deposition of β-amyloid (Aβ) peptides... more Background: Cerebral amyloid angiopathy (CAA) refers to the deposition of β-amyloid (Aβ) peptides in the wall of brain vasculature, commonly involving capillaries and arterioles. Also being considered a part of CAA is the Aβ deposition in leptomeninge. The cellular origin of angiopathic Aβ and the pathogenic course of CAA remain incompletely understood. Methods: The present study was aimed to explore the pathogenic course of CAA in the human cerebrum via examination of changes in β-secretase-1 (BACE1), the obligatory Aβ producing enzyme, relative to Aβ and other cellular markers, by neuroanatomical and biochemical characterizations with postmortem brain samples and primary cell cultures. Results: Immunoreactivity (IR) for BACE1 was essentially not visible at vasculature in cases without cerebral amyloidosis (control group, n = 15, age = 86.1 ± 10.3 year). In cases with brain amyloid pathology (n = 15, age = 78.7 ± 12.7 year), increased BACE1 IR was identified locally at capillaries, arterioles and along the pia, localizing to endothelia, perivascular dystrophic neurites and meningeal cells, and often coexisting with vascular iron deposition. Double immunofluorescence with densitometric analysis confirmed a site-specific BACE1 elevation at cerebral arterioles in the development of vascular Aβ deposition. Levels of BACE1 protein, activity and its immediate product (C99) were elevated in leptomeningeal lysates from cases with CAA relative to controls. The expression of BACE1 and other amyloidogenic proteins in the endothelial and meningeal cells was confirmed in primary cultures prepared from human leptomeningeal and arteriolar biopsies. Conclusion: These results suggest that BACE1 elevation in the endothelia and perivascular neurites may be involved in angiopathic Aβ deposition, while BACE1 elevation in meningeal cells might contribute Aβ to leptomeningeal amyloidosis.

Advances in Alzheimer's disease, 2014

Chronic neuroinflammation is thought to play an etiological role in Alzheimer's disease (AD),... more Chronic neuroinflammation is thought to play an etiological role in Alzheimer's disease (AD), which is characterized pathologically by amyloid and tau formation, as well as neuritic dystrophy and synaptic degeneration. The causal relationship between these pathological events is a topic of ongoing research and discussion. Recent data from transgenic AD models point to a tight spatiotemporal link between neuritic and amyloid pathology, with the obligatory enzyme for β-amyloid (Aβ) production, namely β-secretase-1 (BACE1), is overexpressed in axon terminals undergoing dystrophic change. However, the axonal pathology inherent with BACE1 elevation seen in transgenic AD mice may be secondary to increased soluble Aβ in these genetically modified animals. Here we explored the occurrence of the AD-like axonal and dendritic pathology in adult rat brain affected by LPS-induced chronic neuroinflammation. Unilateral intracerebral LPS injection induced prominent inflammatory response in glia...

Jasper's Basic Mechanisms of the Epilepsies, 2012

BMC neurology, Jan 14, 2014

BackgroundRecent studies have revealed an inverse epidemiological correlation between Alzheimer¿s... more BackgroundRecent studies have revealed an inverse epidemiological correlation between Alzheimer¿s disease (AD) and cancer¿¿¿patients with AD show a reduced risk of cancer, while cancer survivors are less likely to develop AD. These late discoveries in human subjects call for explorative studies to unlock the underlying biological mechanism, but also may shed new light on conceptual interrogation of the principal pathogenic players in AD etiology.DiscussionHere we hypothesize that this negative correlation reflects a rebalance of biosynthetic propensity between body systems under the two disease statuses. In normal condition the body cellular systems are maintained homeostatically under a balanced cell degenerative vs. surviving/regenerative propensities, determined by biosynthetic resources for anabolic processing. AD pathogenesis involves neurodegeneration but also aberrant regenerative, or reactive anabolic, burden, while cancer development is driving by uncontrolled proliferation...

Hippocampus, 1998

Corticotropin-releasing hormone (CRH) excites hippocampal neurons and induces death of selected C... more Corticotropin-releasing hormone (CRH) excites hippocampal neurons and induces death of selected CA3 pyramidal cells in immature rats. These actions of CRH require activation of specific receptors that are abundant in CA3 during early postnatal development. Given the dramatic effects of CRH on hippocampal neurons and the absence of CRH-containing afferents to this region, we hypothesized that a significant population of CRHergic neurons exists in developing rat hippocampus. This study defined and characterized hippocampal CRH-containing cells by using immunocytochemistry, ultrastructural examination, and colocalization with gammaaminobutyric acid (GABA)-synthesizing enzyme and calcium-binding proteins. Numerous, large CRH-immunoreactive (ir) neurons were demonstrated in CA3 strata pyramidale and oriens, fewer were observed in the corresponding layers of CA1, and smaller CRH-ir cells were found in stratum lacunosum-moleculare of Ammon's horn. In the dentate gyrus, CRH-ir somata resided in the granule cell layer and hilus. Ultrastructurally, CRH-ir neurons had aspiny dendrites and were postsynaptic to both asymmetric and symmetric synapses. CRH-ir axon terminals formed axosomatic and axodendritic symmetric synapses with pyramidal and granule cells. Other CRH-ir terminals synapsed on axon initial segments of principal neurons. Most CRH-ir neurons were coimmunolabeled for glutamate decarboxylase (GAD)-65 and GAD-67 and the majority also contained parvalbumin, but none were labeled for calbindin. These results confirm the identity of hippocampal CRH-ir cells as GABAergic interneurons. Further, a subpopulation of neurons immunoreactive for both CRH and parvalbumin and located within and adjacent to the principal cell layers consists of basket and chandelier cells. Thus, axon terminals of CRH-ir interneurons are strategically positioned to influence the excitability of the principal hippocampal neurons via release of both CRH and GABA.

Hippocampus, 2002

Granule cells with recurrent basal dendrites (RBDs) were previously reported in both control and ... more Granule cells with recurrent basal dendrites (RBDs) were previously reported in both control and epileptic rats. RBDs are dendrites that arise from the basal half of granule cell bodies and curve toward and extend into the molecular layer. They are increased in frequency in the pilocarpine model of epilepsy. The present study was undertaken to analyze the distribution and morphology of granule cells with RBDs and the synaptic connections of RBDs. Granule cells were labeled by retrograde transport of biocytin. Those with an RBD were found throughout the granule cell layer, but were most numerous at the hilar border. The morphology of these cells varied in the different depths of the granule cell layer; the angle of their cell body's long axis was mainly vertical at the hilar margin, and changed to virtually horizontal close to the molecular layer border. Quantitative data on the distribution of granule cells with RBDs and the angle of the cell body's long axis confirmed these descriptions. At the electron microscopic level, RBDs showed the typical features of dendrites and formed numerous axodendritic and axospinous synapses with labeled and unlabeled axon terminals. These results showed that RBDs of granule cells from epileptic rats are postsynaptic to axon terminals, including mossy fibers, and thus are involved in a similar synaptic circuitry as apical dendrites of granule cells from these animals.

PLoS ONE, 2012

Spectrins line the intracellular surface of plasmalemma and play a critical role in supporting cy... more Spectrins line the intracellular surface of plasmalemma and play a critical role in supporting cytoskeletal stability and flexibility. Spectrins can be proteolytically degraded by calpains and caspases, yielding breakdown products (SBDPs) of various molecular sizes, with SBDP120 being largely derived from caspase-3 cleavage. SBDPs are putative biomarkers for traumatic brain injury. The levels of SBDPs also elevate in the brain during aging and perhaps in Alzheimer's disease (AD), although the cellular basis for this change is currently unclear. Here we examined age-related SBDP120 alteration in forebrain neurons in rats and in the triple transgenic model of AD (36Tg-AD) relative to non-transgenic controls. SBDP120 immunoreactivity (IR) was found in cortical neuronal somata in aged rats, and was prominent in the proximal dendrites of the olfactory bulb mitral cells. Western blot and densitometric analyses in wild-type mice revealed an age-related elevation of intraneuronal SBDP120 in the forebrain which was more robust in their 36Tg-AD counterparts. The intraneuronal SBDP120 occurrence was not spatiotemporally correlated with transgenic amyloid precursor protein (APP) expression, bamyloid plaque development, or phosphorylated tau expression over various forebrain regions or lamina. No microscopically detectable in situ activated caspase-3 was found in the nuclei of SBDP120-containing neurons. The present study demonstrates the age-dependent intraneuronal presence of an aII-spectrin cleavage fragment in mammalian forebrain which is exacerbated in a transgenic model of AD. This novel neuronal alteration indicates that impairments in membrane protein metabolism, possibly due to neuronal calcium mishandling and/or enhancement of calcium sensitive proteolysis, occur during aging and in transgenic AD mice.

Neurobiology of Disease, 2004

The comorbidity between epilepsy and Alzheimer's disease (AD) is a topic of growing interest. Sen... more The comorbidity between epilepsy and Alzheimer's disease (AD) is a topic of growing interest. Senile plaques and tauopathy are found in epileptic human temporal lobe structures, and individuals with AD have an increased incidence of spontaneous seizures. However, why and how epilepsy is associated with enhanced AD-like pathology remains unknown. We have recently shown b-secretase-1 (BACE1) elevation associated with aberrant limbic axonal sprouting in epileptic CD1 mice. Here we sought to explore whether BACE1 upregulation affected the development of Alzheimer-type neuropathology in mice expressing mutant human APP, presenilin and tau proteins, the triple transgenic model of AD (36Tg-AD). 36Tg-AD mice were treated with pilocarpine or saline (i.p.) at 6-8 months of age. Immunoreactivity (IR) for BACE1, b-amyloid (Ab) and phosphorylated tau (p-tau) was subsequently examined at 9, 11 or 14 months of age. Recurrent convulsive seizures, as well as mossy fiber sprouting and neuronal death in the hippocampus and limbic cortex, were observed in all epileptic mice. Neuritic plaques composed of BACE1-labeled swollen/sprouting axons and extracellular AbIR were seen in the hippocampal formation, amygdala and piriform cortices of 9 month-old epileptic, but not control, 36Tg-AD mice. Densities of plaqueassociated BACE1 and AbIR were elevated in epileptic versus control mice at 11 and 14 months of age. p-Tau IR was increased in dentate granule cells and mossy fibers in epileptic mice relative to controls at all time points examined. Thus, pilocarpine-induced chronic epilepsy was associated with accelerated and enhanced neuritic plaque formation and altered intraneuronal p-tau expression in temporal lobe structures in 36Tg-AD mice, with these pathologies occurring in regions showing neuronal death and axonal dystrophy.

The Journal of Comparative Neurology, 2001

Active caspase-3 immunoreactivity was detected in the rat forebrain proliferative regions at birt... more Active caspase-3 immunoreactivity was detected in the rat forebrain proliferative regions at birth and remained high in these areas for about 2 weeks, during which period labeled cells were present centroperipherally across the olfactory bulb. By the end of the third postnatal week, only a small number of immunolabeled cells remained in these forebrain structures. Active caspase-3 immunolabeling was localized mostly to cell nuclei and co-localized partially with TuJ1 and NeuN immunoreactivity, but not with glial fibrially acidic protein, OX-42, ␥-aminobutyric acid, or terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL)-positive labeling. Active caspase-3 and 5-bromo-2Ј-deoxyuridine (BrdU) doublelabeled nuclei were seen in the proliferative regions after 2 hours and in the periglomerular region of the bulb after 7 days following BrdU injections. Examination of the cells with electron microscopy confirmed that the active caspase-3-containing nuclei in the proliferative regions often had infoldings and appeared to be undergoing division. Some of the cells with active caspase-3-labeled nuclei in the bulb had synapses on their somata or dendrites. Labeled dendritic spines and a few axon terminals were also observed in the olfactory bulb. Taken together, it appears that a wave of active caspase-3-positive cells are dividing in the proliferative zones and then migrating to the bulb as they differentiate into neurons. Therefore, active caspase-3 may play a role in cellular processes such as neuronal differentiation, migration, and plasticity, in addition to its role in cell death.

Frontiers in Neuroanatomy, 2009

Neuroplasticity is a complex process involving structural modulations at synaptic, neuronal and c... more Neuroplasticity is a complex process involving structural modulations at synaptic, neuronal and circuitry/pathway levels (Bruel-Jungerman et al., 2007). Of particular interest, formation of new neurons in the adult brain has been recently recognized as a key substrate for neuroplasticity and cognition (Lledo et al., 2006; Aimone et al., 2009). For instance, adult neurogenesis in the forebrain subventricular and subgranular zones (SVZ, SGZ) appears to be essential for olfaction and hippocampus-dependent learning and memory in rodents (

Experimental Neurology, 2012

The brain is capable of remarkable synaptic reorganization following stress and injury, often usi... more The brain is capable of remarkable synaptic reorganization following stress and injury, often using the same molecular machinery that governs neurodevelopment. This form of plasticity is crucial for restoring and maintaining network function. However, neurodegeneration and subsequent reorganization can also play a role in disease pathogenesis, as is seen in temporal lobe epilepsy and Alzheimer's disease. β-Secretase-1 (BACE1) is a protease known for cleaving β-amyloid precursor protein into β-amyloid (Aβ), a major constituent in amyloid plaques. Emerging evidence suggests that BACE1 is also involved with synaptic plasticity and nerve regeneration. Here we examined whether BACE1 immunoreactivity (IR) was altered in pilocarpine-induced epileptic CD1 mice in a manner consistent with the synaptic reorganization seen during epileptogenesis. BACE1-IR increased in the CA3 mossy fiber field and dentate inner molecular layer in pilocarpine-induced epileptic mice, relative to controls (saline-treated mice and mice 24-48 h after pilocarpine-status), and paralleled aberrant expression of neuropeptide Y. Regionally increased BACE1-IR also occurred in neuropil in hippocampal area CA1 and in subregions of the amygdala and temporal cortex in epileptic mice, colocalizing with increased IR for growth associated protein 43 (GAP43) and polysialylated-neural cell adhesion molecule (PSA-NCAM), but reduced IR for microtubule-associated protein 2 (MAP2). These findings suggest that BACE1 is involved in aberrant limbic axonal sprouting in a model of temporal lobe epilepsy, warranting further investigation into the role of BACE1 in physiological vs. pathological neuronal plasticity.

European Journal of Neuroscience, 2013

Deposition of β-amyloid (Aβ) peptides, cleavage products of β-amyloid precursor protein (APP) by ... more Deposition of β-amyloid (Aβ) peptides, cleavage products of β-amyloid precursor protein (APP) by β-secretase-1 (BACE1) and γ-secretase, is a neuropathological hallmark of Alzheimer's disease (AD). γ-Secretase inhibition is a therapeutical anti-Aβ approach, although less is clear about the change of the enzyme's activity in AD brain. Cerebrospinal fluid (CSF) Aβ peptides are considered to derive from brain parenchyma, thus may serve as biomarkers for assessing cerebral amyloidosis and anti-Aβ efficacy. The present study compared active γ-secretase binding sites with Aβ deposition in aged and AD human cerebrum, and explored a possibility of Aβ production and secretion by the choroid plexus (CP). Specific binding density of [ 3 H]-L-685,458, a radiolabeled high affinity γ-secretase inhibitor, in the temporal neocortex and hippocampal formation was similar for AD and control cases with comparable ages and postmortem delays. The CP in postmortem samples exhibited exceptionally high [ 3 H]-L-685,458 binding density, with the estimated maximal binding sites (Bmax) reduced in the AD relative to control groups. Surgically resected human CP exhibited APP, BACE1 and presenilin-1 immunoreactivity, and β-site APP cleavage enzymatic activity. In primary culture, human CP cells also expressed these amyloidogenic proteins but released Aβ40 and Aβ42 into the medium. These results suggest that γ-secretase activity appears not altered in the cerebrum in AD related to aged control, nor correlated with regional amyloid plaque pathology. The choroid plexus appears to represent a novel non-neuronal source in the brain that may contribute Aβ into cerebrospinal fluid, probably at reduced levels in AD.