Alzheimer Disease: Zhou X

Pei JJ, Björkdahl C, Zhang H, Zhou X, Winblad B. · Karolinska Institutet, KI-Alzheimer Disease Research Center, Novum, Huddinge, Sweden. · J Alzheimers Dis. · Pubmed #18688088 No free full text.

Abstract: The 70-kDa S6 kinase (p70S6K) is a Ser/Thr (S/T)-directed kinase that plays a crucial role in cell growth, cell differentiation, and cell cycle control. This article presented evidence that supports both toxic and protective roles of p70S6K activity towards tau in Alzheimer's disease (AD) brains. The p70S6K can phosphorylate tau at S262, S214, and T212 sites. Phosphorylation at these sites might release tau from microtubules, resulting in microtubule disruption. Evidence also suggests that p70S6K regulates the translation of tau mRNA by phosphorylating the 40S ribosomal protein S6. The extracellular amyloid-beta deposition in AD brains could be a causative factor that activates p70S6K. We hypothesized that amyloid-beta deposition activates p70S6K whose anti-apoptotic property subsequently keeps neurons from entering into the apoptotic process. This process provides the opportunity for the newly synthesized tau to be phosphorylated by p70S6K and by other tau kinases. This hyperphosphorylated tau then aggregates and is progressively deposited in neurons.

Zhou X, Patel AR, Perez F, Jurivich DA. · Department of Medicine, Section of Geriatric Medicine, University of Illinois at Chicago, Jesse Brown VAMC, Chicago, IL, USA. · Transl Res. · Pubmed #19218096 No free full text.

Abstract: Neuroprotection mediated by the cellular heat shock response offers 1 clinical strategy to prevent, stabilize, and possibly reverse neurodegenerative processes. Although damaged proteins are thought to be the primary stimulus for the heat shock response, several studies indicate that pharmaceutical agents can either directly induce the heat shock transcription factor (Hsf1) or enhance its activation during different forms of cellular stress. Because Hsf1 is now known to combat the proteotoxicity of aging and has a central role in modulating amyloid aggregation, pharmacologic interventions to strengthen Hsf1 action may have important implications for preventing neurodegeneration linked to altered and damaged proteins such as observed in Alzheimer's disease. Given reports that some agents for the treatment of Alzheimer's disease have neuroprotective properties, this project investigated whether rivastigmine, which is an acetyl and butaryl cholinesterase inhibitor, mediates the neuroprotection of the neuronal-like cell line SH-SY5Y. The cells were exposed to various concentrations of rivastigmine to determine whether the drug protected cells from toxic injury and induced the 1st phase of the cellular heat shock response. In all, 100-micromol/L rivastigmine decreases cell death by 40% compared with untreated cells. This concentration enhances Hsf1 activation by strengthening both its multimerization and its phosphorylation, which leads to increased messenger RNA (mRNA) for hsp70. Therefore, one of the putative neuroprotective mechanisms of rivastigmine seems to be mediated through the heat shock response. These results also are observed in cultured macrophage-like cells, which suggests a future clinical tool for monitoring pharmacologically improved stress responses in peripheral blood mononuclear cells during treatment of Alzheimer disease.

Li F, Zhou X, Zhu J, Xia W, Ma J, Wong ST. · Department of Information Science, School of Mathematical Sciences, and LMAM, Peking University, Beijing, 100871, China. · Neuroinformatics. · Pubmed #18506641 No free full text.

Abstract: Calcium ions (Ca2+) play a fundamental role in a variety of physiological functions in many cell types by acting as a secondary messenger. Variation of intracellular Ca2+ concentration ([Ca2+]i) is often observed when the cell is stimulated. However, it is a challenging task to automatically quantify intracellular [Ca2+]i in a population of cells. In this study, we present a workflow including specific algorithms for the automated intracellular calcium signal analysis using high-content, time-lapse cellular images. The experimental validations indicate the effectiveness of the proposed workflow and algorithms. We applied the workflow to analyze the intracellular calcium signals induced by different concentrations of H2O2 in the cell lines transfected by presenilin-1 (PS-1) that is known to be closely related to the familial Alzheimer's disease (FAD). The analysis results imply an important role of mutant PS-1, but not normal human PS-1 and mutant human amyloid precursor protein (APP), in enhancing intracellular calcium signaling induced by H2O2.

Björkdahl C, Sjögren MJ, Zhou X, Concha H, Avila J, Winblad B, Pei JJ. · Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, KI-Alzheimer's Disease Research Center, Novum, Huddinge, Sweden. · J Neurosci Res. · Pubmed #18061943 No free full text.

Abstract: The heat-shock proteins (HSPs) Hsp27 and alphaB-crystallin are up-regulated in Alzheimer's disease (AD), but the extent of this and the consequences are still largely unknown. The HSPs are involved in protein degradation and protection against protein aggregation, and they interact with several cytoskeletal components such as microtubules (MT) and neurofilaments (NF). AD pathology includes aggregated proteins (tau, NF), decreased protein degradation, and cytoskeletal disruption. It is thus of interest to investigate more closely the possible roles of the HSPs in AD pathology. The expressions of Hsp27 and alphaB-crystallin in AD brain samples were significantly increased (by approximately 20% and approximately 30%, respectively) and correlated significantly with phosphorylated tau and NF proteins. To investigate the consequences of increased HSP levels on tau and NF regulation, N2a cells were transfected with Hsp27 or alphaB-crystallin constructs, and overexpression of the HSPs was confirmed in the cells. Increased tau phosphorylation at the Ser262 site in the N2a cells was regulated by Hsp27 overexpression (possibly through p70S6k), whereas the overexpression of alphaB-crystallin resulted in decreased levels of phosphorylated tau, NF, and GSK-3beta. It was also shown that overexpression of HSPs causes an increase in the percentage of cells present in the G(1) phase. The results presented suggest that a cellular defense against dysregulated proteins, in the form of Hsp27 and alphaB-crystallin, might contribute to the cell cycle reentry seen in AD cells. Furthermore, Hsp27 might also be involved in AD pathology by aggravating MT disruption by tau phosphorylation.

Luo Y, Zhou X, Yang X, Wang J. · Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. · Neuroreport. · Pubmed #18007203 No free full text.

Abstract: Epidemiological and clinical data suggest that homocysteine (Hcy) may increase the risk of Alzheimer's disease, but the underlying mechanisms are elusive. To investigate the effect of Hcy on phosphorylation of tau, we injected Hcy into the lateral cerebral ventricle of rats. We found that level of the hyperphosphorylated tau at PHF-1 (Ser396/404) and tau-1 (Ser198/199/202) epitopes was elevated prominently at 6, 9, and 12 h after the injection, and it was recovered to normal at 24 h. Simultaneously, the level of protein phosphatase-2A catalytic subunit (PP-2Ac) was reduced markedly as compared with control. These results imply that Hcy may induce hyperphosphorylation of tau with PP-2Ac involved mechanism.

Zhou X, Xu J, Zhao Y. · Department of Neurology, The Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, PR China. · Ann Acad Med Singapore. · Pubmed #17483854 links to  free full text

Abstract: INTRODUCTION: Distress of Alzheimer's disease (AD) contribute significantly to decreased quality of life, increased morbidity, higher levels of caregiver distress, and the decision to institutionalise a patient. However, the risk factors of distress in AD patients have not been thoroughly discussed. The aim of this study was to identify the risk factors of distress in AD patients. MATERIALS AND METHODS: A large randomised controlled clinical trial on AD was analysed in this study. Both linear regression and decision tree models were used to identify the factors of distress in AD patients. RESULTS: The following variables were recognised as risk factors for AD patient's distress: Care recipients often visit physicians or have medical examinations; Care recipients take medicines that affect the central nervous system or stomach; Care recipients seldom visit nurses; Caregivers have chronic disease or cancer; Caregiver experience distress, feel lonely, or have an unsatisfactory relationship with patients. In addition, caregiver's smoking and drinking were found to correlate negatively with AD patient's distress. CONCLUSIONS: Multiple factors influence the distress of Alzheimer's patients, including patient's examination and medication, patient-caregiver relationships, caregiver's psychological and physical status, and the use of nursing services. These factors should be targeted when designing prevention and intervention strategies.

Hu X, Shi Q, Zhou X, He W, Yi H, Yin X, Gearing M, Levey A, Yan R. · Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA. · EMBO J. · Pubmed #17476306 links to  free full text

Abstract: Dystrophic neurites are swollen dendrites or axons recognizable near amyloid plaques as a part of important pathological feature of Alzheimer's disease (AD). We report herein that reticulon 3 (RTN3) is accumulated in a distinct population of dystrophic neurites named as RTN3 immunoreactive dystrophic neurites (RIDNs). The occurrence of RIDNs is concomitant with the formation of high-molecular-weight RTN3 aggregates in brains of AD cases and mice expressing mutant APP. Ultrastructural analysis confirms accumulation of RTN3-containing aggregates in RIDNs. It appears that the protein level of RTN3 governs the formation of RIDNs because transgenic mice expressing RTN3 will develop RIDNs, initially in the hippocampal CA1 region, and later in other hippocampal and cortical regions. Importantly, we show that the presence of dystrophic neurites in Tg-RTN3 mice causes impairments in spatial learning and memory, as well as synaptic plasticity, implying that RIDNs potentially contribute to AD cognitive dysfunction. Together, we demonstrate that aggregation of RTN3 contributes to AD pathogenesis by inducing neuritic dystrophy. Inhibition of RTN3 aggregation is likely a therapeutic approach for reducing neuritic dystrophy.

Zhou X, Xu J, Zhao Y. · Department of Neurology, The Shanghai First People's Hospital of Shanghai Jiao Tong University, Shanghai, P.R China. · Australas Phys Eng Sci Med. · Pubmed #17260584 No free full text.

Abstract: Recent studies proved that psychological distress is an accelerator of Alzheimer disease (AD). However, the factors that affect the psychological distress of AD patients are still unknown. The aim of this study was to predict the incidence and identify the risk factors of psychological distress in AD patients. Artificial neural networks and Machine learning models were used to predict the incidence of psychological distress in AD patients. Linear regression and decision tree models were used to identify the factors of psychological distress in AD patients. Among all models for predicting the incidence of psychological distress in AD patients, the artificial neural networks with 8 hidden neurons achieved the highest predictive accuracy of 81.92%. In the five machine learning models, the ADTree algorithm made the highest Predictive Accuracy of 77.94%. As for risk factor analysis, the Linear Regression and Decision Tree models reported similar sets of variables that affect the psychological distress of AD patients. Three variables were reported by Linear Regression to be in negative correlation with psychological distress: the use of professional care service, caregiver consuming cigarette, and caregiver consuming alcohol. The incidence of psychological distress in AD patients can be predicted by artificial neural networks with an accuracy of 81.92%. There are four main risk factors for psychological distress of AD patients: "Caregiver experiencing psychological distress", "Caregiver suffering from chronic disease or cancer", "Care recipient's health status being serious or getting worse", and "Lack of professional care service". These findings are potentially helpful for the prediction, prevention and intervention of psychological distress in AD patients.

He W, Hu X, Shi Q, Zhou X, Lu Y, Fisher C, Yan R. · Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. · J Mol Biol. · Pubmed #16979658 No free full text.

Abstract: BACE1 is a membrane-bound aspartyl protease that specifically cleaves amyloid precursor protein (APP) at the beta-secretase site. Membrane bound reticulon (RTN) family proteins interact with BACE1 and negatively modulate BACE1 activity through preventing access of BACE1 to its cellular APP substrate. Here, we focused our study on RTN3 and further show that a C-terminal QID triplet conserved among mammalian RTN members is required for the binding of RTN to BACE1. Although RTN3 can form homo- or heterodimers in cells, BACE1 mainly binds to the RTN monomer and disruption of the QID triplet does not interfere with the dimerization. Correspondingly, the C-terminal region of BACE1 is required for the binding of BACE1 to RTNs. Furthermore, we show that the negative modulation of BACE1 by RTN3 relies on the binding of RTN3 to BACE1. The knowledge from this study may potentially guide discovery of small molecules that can mimic the effect of RTN3 on the inhibition of BACE1 activity.

Rickle A, Bogdanovic N, Volkmann I, Zhou X, Pei JJ, Winblad B, Cowburn RF. · Karolinska Institutet Sumitomo Pharmaceuticals Alzheimer Center (KASPAC), Department of Neurotec, Division of Experimental Geriatrics, Neurotec, Novum Plan 5, S141 57 Huddinge, Sweden. · Neurochem Int. · Pubmed #16239049 No free full text.

Abstract: Phosphatase and tensin homologue deleted from chromosome 10 (PTEN) is a dual (protein tyrosine and lipid) phosphatase one of the functions of which is to dephosphorylate phosphatidylinositol 3,4,5-trisphosphate to phosphatidylinositol-3,4-biphosphate thereby inhibiting phosphoinositide-dependent kinase activation of the cell survival kinase Akt. Akt activity is up regulated in Alzheimer's disease (AD) brain in parallel to the progression of neurofibrillary pathology. The present study determined whether altered expression of PTEN occurs in Alzheimer's disease brain. Western immunoblotting revealed no significant changes of PTEN protein levels in nuclear and membrane fractions of medial temporal cortex from a series of Alzheimer's disease and control cases. Similarly, no changes in PTEN protein levels, as determined by dot-blotting, were seen in temporal cortex homogenates from a separate series of Alzheimer's disease and control brains. A small but significant decrease in the levels of Ser(380) p-PTEN was seen in homogenates of Alzheimer's disease temporal cortex. Immunohistochemistry revealed PTEN immunoreactivity in a number of brain structures including neurons, capillaries and structures resembling oligodendrocytes and astrocytes. The majority of temporal cortex pyramidal neurons (93-100%) were PTEN immunopositive. The Alzheimer's disease cases had significantly lower numbers of total ( approximately 12% loss, P<0.02) and PTEN immunopositive ( approximately 15% loss, P<0.01) pyramidal neurons as compared to the control cases.

Hao J, Li K, Li K, Zhang D, Wang W, Yang Y, Yan B, Shan B, Zhou X. · Department of Radiology, Xuanwu Hospital, Capital University of Medical Sciences, No. 45 Changchun Street, Beijing 100053, PR China. · Neurosci Lett. · Pubmed #15970381 No free full text.

Abstract: Cognitive and neuroscience studies indicate that attentional operations are impaired in Alzheimer's disease (AD). Our goal was to define the anatomical areas of activation associated with visual attention processing and to define deficits or changes that may occur in AD patients compared with control group. Thirteen AD patients and 13 age- and education-matched normal controls were tested in two visual search tasks (one was a conjunction task, where feature binding is required. The other was a subset task, where group stimuli is needed without feature binding) using fMRI techniques. After stereotactical normalization, voxel-by-voxel t statistics was used to compare activated brain areas between patients and control subjects. Our findings suggest that both search tasks are controlled by partially overlapping cerebral networks, including parietal, frontal and occipital-temporal cortical regions and primary visual cortex. The AD patient group showed less activation in both parietal lobes and the left frontal regions, while increased activation was found in the right frontal lobes and the right occipito-temporal cortical regions with the conjunction task. In the subset task, decreased activation in AD patients was seen in the left parietal lobe and bilateral frontal lobes, while increased activation was seen in both medial temporal lobes. In addition, for the comparison between tasks, The difference is very small for AD patients. Control group showed a higher amplitude in the right prefrontal region, temporal cortical regions and parietal lobe. These results indicate that attention deficits in AD patients may be attributed to both binding problem and grouping inefficiency.

Zou L, Xiao J, Zhou X, Sun C, Xiong Y. · Department of Radiology, West China Hospital, Sichuan University, Chengdu 610041, China. · Sichuan Da Xue Xue Bao Yi Xue Ban. · Pubmed #14619592 No free full text.

Abstract: OBJECTIVE: To define the normal range of volumetric values of hippocampal formations (HPF), amygdala (AM) and anterior temporal lobes (ATL). METHODS: One hundred and two Chinese normal adults underwent MRI scan on oblique coronal section. Volumes of the anterior temporal lobes, hippocampal formations and amygdala were obtained on T1WI. The mean values and the range of 95% normal values were obtained by statistical data processing and analysis. RESULTS: The mean values of standardized volumes of anterior temporal lobes in the subjects aged 20 yr.-, 40 yr.- and > or = 60 yr. were: 59.07 +/- 2.02 cm3, 55.55 +/- 2.23 cm3, 52.88 +/- 2.07 cm3 (Right); 57.25 +/- 2.15 cm3, 53.23 +/- 1.72 cm3, 51.63 +/- 2.18 cm3 (Left); and of amygdala in those aged 20 yr.-, 40 yr.- and > or = 60 yr. were: 1.54 +/- 0.09 cm3, 1.38 +/- 0.08 cm3, 1.29 +/- 0.09 cm3 (R); 1.37 +/- 0.09 cm3, 1.29 +/- 0.08 cm3, 1.23 +/- 0.09 cm3(L). The 95% normal values of HPF in the subjects aged 20 yr.- ranged from 2.52 to 3.11 cm3(R), and from 2.40 to 2.98 cm3(L); in those aged > or = 60 yr. ranged from 2.33 to 2.65 cm3 (R) and from 1.98 to 2.64 cm3(L). There was no significant difference in the volumes of hippocampal formations between two groups under 60 yr.. And a decrease of the volumes of hippocampal formations could been seen in the > or = 60 yr. group. No significant difference in the volumes of hippocampal formations, amygdala and anterior temporal lobes was seen in the sex groups and handedness groups. CONCLUSION: The data on standardized volumes of HPF, AM, ATL in this study can serve as a foundation on which to provide normal index and useful guidelines for reference in early diagnosis and treatment of Alzheimer's disease and temporal lobe epilepsy.

Cui T, Zhou X, Jin W, Zheng F, Cao X. · Molecular Unit, Union Hospital, Tongji Medical University, Wuhan 430022, China. · Chin Med J (Engl). · Pubmed #11775232 links to  free full text

Abstract: OBJECTIVE: To evaluate the association of apolipoprotein E (apoE) and presenilin-1 (PS-1) gene polymorphism with late-onset Alzheimer's disease (AD). METHODS: A case-control study was undertaken to detect the polymorphism of apoE and PS-1 by polymerase chain reaction and digestion with the endonucleases of BspL I, Hha I and BamH I. RESULTS: The frequencies of apoE epsilon 3/4 genotype and epsilon 4 allele in late-onset AD (n = 42) were significantly higher than those of age-matched controls (P < 0.05). The frequencies of the apoE intron 1 enhancer (IE1) G/G genotype and G allele in late-onset AD were also significantly higher than those in controls (P < 0.05). The frequencies of the PS-1 1/1 genotype but not the 1 allele in AD were significantly higher than those in controls (P < 0.05). The apoE epsilon 4 allele was associated with a tripling of risk for late-onset AD compared with that with no epsilon 4 allele (odds ratio: 2.932). Homozygosity of the G allele in IE1 and 1/1 genotype in PS-1 was associated with a doubling of risk for late-onset AD, and odds ratios were 2.223 and 2.066, respectively. When the apoE epsilon 4 was controlled, the association between the IE1 G/G genotype AD was no longer statistically significant (P > 0.05). We sequenced the exon 4 of apoE in patients with late-onset AD, and found no other genetic polymorphism or mutation except for apoE epsilon 4 and IE1 G alleles associated with AD. CONCLUSION: apoE epsilon 4 gene appears to be the strongest gene risk factor for late-onset AD and its apparent association between the IE1 G/G genotype and late-onset AD is a consequence of the association between the epsilon 4 and IE1 G/G genotype. The PS-1/1 genotype is weakly associated with late-onset AD.