Alzheimer Disease: Zhou J

Zhou J, Yu Q, Zou T. · Department of Medicine, Program in Neuroscience, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA. · BMC Neurosci. · Pubmed #19090983 links to  free full text

Abstract: Tau aggregation is one of the major features in Alzheimer's disease and in several other tauopathies, including frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), and progressive supranuclear palsy (PSP). More than 35 mutations in the tau gene have been identified from FTDP-17 patients. A group of these mutations alters splicing of exon 10, resulting in an increase in exon 10 inclusion into tau mRNA. Abnormal splicing with inclusion of exon 10 into tau mRNA has also been observed in PSP and AD patients. These results indicate that abnormal splicing of exon 10, leading to the production of tau with exon 10, is probably one of the mechanisms by which tau accumulates and aggregates in tauopathic brains. Therefore, modulation of exon 10 splicing in the tau gene could potentially be targeted to prevent tauopathies. To identify small molecules or compounds that could potentially be developed into drugs to treat tauopathies, we established a cell-based high-throughput screening assay. In this review, we will discuss how realistic, specific biological molecules can be found to regulate exon 10 splicing in the tau gene for potential treatment of tauopathies.

Kar A, Kuo D, He R, Zhou J, Wu JY. · Center for Molecular Neuroscience, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA. · Alzheimer Dis Assoc Disord. · Pubmed #16317255 links to  free full text

Abstract: A number of neurodegenerative diseases are characterized by the presence of abundant deposits containing Tau protein. Expression of the human tau gene is under complex regulation. Mutations in the tau gene have been identified in patients with frontotemporal lobe dementia. These mutations affect either biochemical/biophysical properties or the delicate balance of different splicing isoforms. In this review, we summarize recent advances in our understanding of genetics and molecular pathogenesis of tauopathies with the focus on frontotemporal lobe dementia. We review published studies on tau pre-mRNA splicing regulation. Understanding molecular mechanisms of tauopathies may help in developing effective therapies for neurodegenerative tauopathies and related disorders, including Alzheimer disease.

Zhou J, Fonseca MI, Pisalyaput K, Tenner AJ. · Department of Molecular Biology and Biochemistry, Institute for Brain Aging and Dementia, Center for Immunology, University of California, Irvine, California 92697-3900, USA. · J Neurochem. · Pubmed #18624920 No free full text.

Abstract: Alzheimer's disease (AD) is a neurodegenerative disease resulting in progressive cognitive decline. Amyloid plaque deposits consisting specifically of beta-amyloid peptides that have formed fibrils displaying beta-pleated sheet conformation are associated with activated microglia and astrocytes, are colocalized with C1q and other complement activation products, and appear at the time of cognitive decline in AD. Amyloid precursor protein (APP) transgenic mouse models of AD that lack the ability to activate the classical complement pathway display less neuropathology than do the APPQ+/+ mice, consistent with the hypothesis that complement activation and the resultant inflammation may play a role in the pathogenesis of AD. Further investigation of the presence of complement proteins C3 and C4 in the brain of these mice demonstrate that both C3 and C4 deposition increase with age in APPQ+/+ transgenic mice, as expected with the age-dependent increase in fibrillar beta-amyloid deposition. In addition, while C4 is predominantly localized on the plaques and/or associated with oligodendrocytes in APPQ+/+ mice, little C4 is detected in APPQ-/- brains consistent with a lack of classical complement pathway activation because of the absence of C1q in these mice. In contrast, plaque and cell associated C3 immunoreactivity is seen in both animal models and, surprisingly, is higher in APPQ-/- than in APPQ+/+ mice, providing evidence for alternative pathway activation. The unexpected increase in C3 levels in the APPQ-/- mice coincident with decreased neuropathology provides support for the hypothesis that complement can mediate protective events as well as detrimental events in this disease. Finally, induced expression of C3 in a subset of astrocytes suggests the existence of differential activation states of these cells.

Whitmer RA, Gunderson EP, Quesenberry CP, Zhou J, Yaffe K. · Kaiser Permanente Division of Research, Etiology and Prevention, 2000 Broadway, Oakland, CA 94612, USA. · Curr Alzheimer Res. · Pubmed #17430231 No free full text.

Abstract: Prior work has suggested that obesity and overweight as measured by body mass index (BMI) increases risk of dementia. It is unknown if there is a difference in the risk of developing Alzheimer disease (AD) versus vascular dementia (VaD) associated with high body weight. The goal of this study was to examine the association between midlife BMI and risk of both AD and VaD an average of 36 years later in a large (N= 10,136) and diverse cohort of members of a health care delivery system. Participants aged 40-45 participated in health exams between 1964 and 1968. AD and VaD diagnoses were obtained from Neurology visits between January 1, 1994 and June 15, 2006. Those with diagnoses of general dementia from primary care providers were excluded from the study. BMI was analyzed in WHO categories of underweight, overweight and obese, as well as in subdivisions of WHO categories. All models were fully adjusted for age, education, race, sex, marital status, smoking, hyperlipidemia, hypertension, diabetes, ischemic heart disease and stroke. Cox proportional hazard models showed that compared to those with a normal BMI (18.5-24.9), those obese (BMI > or = 30) at midlife had a 3.10 fold increase in risk of AD (fully adjusted model, Hazard Ratio=3.10, 95% CI 2.19-4.38), and a five fold increase in risk of VaD (fully adjusted model, HR=5.01, 95% CI 2.98-8.43) while those overweight ( BMI > or = 25 and <30) had a two fold increase in risk of AD and VaD (fully adjusted model, HR=2.09, 95% CI 1.69-2.60 for AD and HR=1.95, 95% CI 1.29-2.96 for VaD). These data suggest that midlife BMI is strongly predictive of both AD and VaD, independent of stroke, cardiovascular and diabetes co morbidities. Future studies need to unveil the mechanisms between adiposity and excess risk of AD and VaD.

Christie LA, Su JH, Tu CH, Dick MC, Zhou J, Cotman CW. · Institute for Brain Aging and Dementia, 1113 Gillespie Neuroscience Research Facility, University of California, Irvine, CA 92697, USA. · Neurobiol Dis. · Pubmed #17292615 links to  free full text

Abstract: Neuronal degeneration linked to apoptosis can be inhibited by a family of proteins known as inhibitors of apoptosis proteins (IAPs). We examined three members of the IAP family that are implicated in the regulation of neuronal death. We assessed NAIP, XIAP, and cIAP-2 protein levels in the entorhinal cortex of non-demented, cognitively impaired and Alzheimer's disease cases. Levels of paired helical filament-1 (PHF-1), a marker of neurofibrillary tangles, were assessed to determine their relationship to IAP levels. NAIP was decreased in AD cases compared to mildly impaired and unimpaired cases, and this decrease was associated with increased PHF-1 levels. Low NAIP levels were associated with higher Braak and Braak tangle stage and cognitive dysfunction. XIAP levels were higher in AD cases and cIAP-2 levels did not vary with clinical status. Our data suggest that decreased NAIP may place neurons at risk for the development of tangles and apoptosis.

Zhou J, Chen J, Feng Y. · Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. · J Huazhong Univ Sci Technolog Med Sci. · Pubmed #16961266 No free full text.

Abstract: The carboxyl-terminal amino acids 272-299-truncated apoE4 (delta272-299) is the main fragments of apoE4 hydrolysate in neurons. The effects of truncated-ApoE4 (delta272-299) overexpression on tau phosphorylation in cultured N2a cells were investigated. The truncated-apoE4 (delta272-299) cDNA was subcloned into pEGFP-c3 to form recombinant pEGFP-T-apoE4. pEGFP-c3, pEGFP-T-apoE4 and pEGFP-apoE4 were transfected into N2a cells respectively by lipofectamine 2000 method. After 24--48 h, tau phosphorylation was detected by Western blot assay and glycogen synthase kinase-3 (GSK-3) activity by using GSK-3 activity assay. The results showed that the overexpression of both full length-apoE4 and truncated apoE4 fragments in N2a cells induced a dramatic increase in phosphorylation of tau at Ser202 sites and the activation of GSK-3 as compared with untransfected cells, most significantly in the cells transfected with pEGFP-T-apoE4 (P < 0.05). It was concluded that in vitro overexpression of truncated-ApoE4 (delta272-299) can result in tau hyperphosphorylation in N2a cells by activating GSK-3, suggesting truncated-ApoE4 (delta272-299) might contribute the pathogenesis of Alzheimer disease.

Chen J, Zhou J, Feng Y, Wang J. · Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. · J Huazhong Univ Sci Technolog Med Sci. · Pubmed #16196280 No free full text.

Abstract: In this study, we studied the effect of glycogen synthase kinase-3 (GSK-3) overactivation on neurofilament phosphorylation in cultured cells. After N2a cells were treated with the specific inhibitor (wortmannin) of phosphoinositol-3 kinase (PI-3K) or treated with wortmannin and the specific inhibitor (LiCl) of glycogen synthase kinase-3 (GSK-3), GSK-3 activity and neurofilament phosphorylation were detected by using GSK-3 activity assay, Western blots and immunofluoresence. Our results showed that after treatment of N2a cells with wortmannin for 1 h, overactivation of GSK-3 caused a reduced staining with antibody SMI32 and an enhanced staining with antibody SMI31. When N2a cells were treated with wortmannin and LiCl, the activity of GSK-3 was reduced substantially. At the same time, the phosphorylation of neurofilament was also reduced. The study demonstrated that overactivation of GSK-3 induced hyperphosphorylation of neurofilament and suggested that in vitro overactivation of GSK-3 resulted in neurofilament hyperphosphorylation and this may be the underlying mechanism for Alzheimer's disease.

Fonseca MI, Zhou J, Botto M, Tenner AJ. · Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697, USA. · J Neurosci. · Pubmed #15269255 links to  free full text

Abstract: C1q, the recognition component of the classical complement activation pathway, is a multifunctional protein known to be expressed in brain of Alzheimer's disease (AD) patients. To experimentally address the role of C1q in AD, a mouse model lacking C1q (APPQ-/-) was generated by crossing Tg2576 animals (APP) with C1q-deficient mice. The pathology of APPQ-/- was compared with that of APP mice and B6SJL controls at 3-16 months of age by immunohistochemistry and Western blot analysis. At younger ages (3-6 months), when no plaque pathology was present, no significant differences were seen in any of the neuronal or glial markers tested. At older ages (9-16 months), the APP and APPQ-/- mice developed comparable total amyloid and fibrillar beta-amyloid in frontal cortex and hippocampus; however, the level of activated glia surrounding the plaques was significantly lower in the APPQ-/- mice at 12 and 16 months. In addition, although Tg2576 mice showed a progressive decrease in synaptophysin and MAP2 in the CA3 area of hippocampus compared with control B6SJL at 9, 12, and 16 months, the APPQ-/- mice had significantly less of a decrease in these markers at 12 and 16 months. In a second murine model for AD containing transgenes for both APP and mutant presenilin 1 (APP/PS1), a similar reduction of pathology was seen in the APPPS1Q-/- mice. These data suggest that at ages when the fibrillar plaque pathology is present, C1q exerts a detrimental effect on neuronal integrity, most likely through the activation of the classical complement cascade and the enhancement of inflammation.

Meng Y, Xu H, Wang R, Ji Z, Yu S, Zhou J, Sheng S. · Beijing Brain Aging Research Institute, Xuan Wu Hospital, Capital University of Medical Sciences, Beijing 100053, China. · Zhonghua Bing Li Xue Za Zhi. · Pubmed #12622899 No free full text.

Abstract: OBJECTIVES: To explore the mechanisms of neuronal loss and apoptosis in the brains of Alzheimer's disease (AD) patients, through studying the expression of proteins related to signal transduction pathways, which are important for neuron survival. METHODS: (1) Immunohistochemistry: Sections were double stained with Tunel and NSE antibodies. (2) The hippocampal tissue taken from 6 cases of AD and 6 cases of non-AD brains was homogenized. Protein estimation was done by Lowry method. Equal amounts of protein were taken from each specimen and immunoprecipitation was performed and analyzed by Western blot; color development was done by alkaline phosphatase method or luminol reagent. RESULTS: (1) Tunel positive neurons were found in both AD and non-AD brains, but the number in the former was more than the latter. (2) The AD hippocampal tissue showed diminished expression of Akt/PKB, CREB, P-CREB, increased expression of apoptosis-related protein apoptosis-inducing factor, and diminished expression of apoptosis-related protein bcl-2. The expression of bax did not change. CONCLUSIONS: Diminished expression of CREB, P-CREB, bcl-2 in AD hippocampus indicates that the neuron survival signal transduction pathway in AD brains is impaired. Neurons are in apoptotic or pro-apoptotic state. In addition, increased expression of apoptosis-inducing factor, diminished expression of bcl-2, which is an anti-apoptotic factor, promotes further neuron apoptosis.

Wang R, Zhou J, Tang XC. · State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Tai-yuan Road, Shanghai 200031, PR China. · Brain Res Mol Brain Res. · Pubmed #12414117 No free full text.

Abstract: The present studies investigated the effects of tacrine, a selective acetylcholinesterase (AChE) inhibitor and promising anti-dementia agent, on hydrogen peroxide (H(2)O(2))-induced apoptosis and the expression of apoptosis-related genes in rat pheochromocytoma line PC12 cells. Transient exposure of the cells to H(2)O(2) (100 microM) triggered typical apoptosis as evidenced by chromatin condensation, nuclei fragmentation and DNA laddering. RT-PCR studies showed upregulated p53 and bax mRNA levels with H(2)O(2) treatment. The results were further confirmed at protein levels by immunocytochemistry with specific antibodies. Preincubation with tacrine significantly attenuated H(2)O(2)-induced injury, prevented the cells from apoptosis and attenuated H(2)O(2)-induced overexpression of bax and p53. The present findings suggest that tacrine exert significant protection against H(2)O(2)-induced apoptosis possibly through inhibiting expression of pro-apoptosis genes.

Bi X, Gall CM, Zhou J, Lynch G. · Psychiatry and Human Behavior, 101 Theory, Suite 250, University of California at Irvine, 92697, USA. · Neuroscience. · Pubmed #12088742 No free full text.

Abstract: Many synapses contain two types of receptors - integrins and N-methyl-D-aspartate (NMDA) receptors - that have been implicated in peptide internalization. The present studies tested if either class is involved in the uptake of the 42-residue form of amyloid beta peptide (Abeta1-42), an event hypothesized to be of importance in the development of Alzheimer's disease. Cultured hippocampal slices were exposed to Abeta1-42 for 6 days in the presence or absence of soluble Gly-Arg-Gly-Asp-Ser-Pro, a peptide antagonist of Arg-Gly-Asp (RGD)-binding integrins, or the disintegrin echistatin. Abeta uptake, as assessed with immunocytochemistry, occurred in 42% of the slices incubated with Abeta peptide alone but in more than 80% of the slices co-treated with integrin antagonists. Uptake was also found in a broader range of hippocampal subfields in RGD-treated slices. Increased sequestration was accompanied by two characteristics of early stage Alzheimer's disease: elevated concentrations of cathepsin D immunoreactivity and activation of microglia. The selective NMDA receptor antagonist D-(-)-2-amino-5-phosphonovalerate completely blocked internalization of Abeta, up-regulation of cathepsin D, and activation of microglia. Our results identify two classes of receptors that cooperatively regulate the internalization of Abeta1-42 and support the hypothesis that characteristic pathologies of Alzheimer's disease occur once critical intraneuronal Abeta concentrations are reached.

Taylor DH, Schenkman M, Zhou J, Sloan FA. · Center for Health Policy, Duke University, Durham, North Carolina 27708, USA. · J Gerontol B Psychol Sci Soc Sci. · Pubmed #11522810 No free full text.

Abstract: OBJECTIVES: Our primary objectives were (a) to determine the relative impact of Alzheimer's disease and related dementias (ADRD), disability, and common comorbid health conditions on the cost of caring for community-dwelling elderly person and (b) to determine whether ADRD serves as an effect modifier for the effect of disability and common comorbidities on costs. METHODS: Participants were drawn from community respondents to the 1994 National Long Term Care Survey. The authors compared total cost of caring for persons without ADRD with that of those who had moderate and severe ADRD. Using regression analysis, the author identified the adjusted effect of ADRD, limitations in activities of daily living (ADLs), and common comorbidities on total costs. RESULTS: Persons with severe ADRD had higher median total costs ($10,234) than did persons with moderate ADRD ($4,318) and those without ADRD ($2,268, p <.001). However, disability measured by ADL limitations was a more important predictor of total cost than was ADRD status in both stratified and multivariate analyses. Comorbidities such as heart attack, stroke, and chronic obstructive pulmonary disease also increased costs. Severe ADRD was an effect modifier for ADL limitations, increasing the positive impact of disability on total costs among persons with severe ADRD, but not for comorbidities. DISCUSSION: Disability, severe ADRD, and comorbidity all had independent effects that increased total costs. Thus, any risk adjustment procedure should account for disability and comorbidity and not just ADRD status.

Bi X, Yong AP, Zhou J, Ribak CE, Lynch G. · Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697, USA. · Proc Natl Acad Sci U S A. · Pubmed #11438710 links to  free full text

Abstract: Cultured hippocampal slices prepared from apolipoprotein E-deficient mice were exposed to an inhibitor of cathepsins B and L and then processed for immunocytochemistry using antibodies against human paired helical filaments. Dense, AT8-immunopositive deposits were found in the subiculum, stratum oriens of hippocampal field CA1, and the hilus of the dentate gyrus. This distribution agrees with that described for tangles in Alzheimer's disease. The appearance of the labeled structures fell into categories that correspond to previously proposed stages in the progression of intraneuronal neurofibrillary tangles in human hippocampus. Electron microscopic analyses confirmed that microtubule disruption and twisted bundles of filaments were present in neurons in the affected areas. These results support the hypothesis that partial lysosomal dysfunction is a contributor to Alzheimer's disease and suggest a simple model for studying an important component of the disease.

Zhou J, Fu Y, Tang XC. · State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Tai-yuan Road, 200031, Shanghai, People's Republic of China. · Neurosci Lett. · Pubmed #11403956 No free full text.

Abstract: Huperzine A (HupA) and donepezil, two novel selective acetylcholinesterase inhibitors available for Alzheimer's disease, were tested for their ability to alleviate injury from oxygen-glucose deprivation (OGD) in the rat pheochromocytoma line PC12 cells. OGD for 30 min triggered death in more than 50% of cells, along with major changes in morphology and biochemistry including elevated levels of lipid peroxide, superoxide disamutase activity and lactate. Cells pretreated for 2 h with HupA or donepezil showed improved survival and reduced biochemical and morphologic signs of toxicity (statistically significant over the range from 10 microM down to 1.0 and 0.1 microM, respectively). Our results indicated that HupA and donepezil protected PC12 cells against OGD-induced toxicity, most likely by alleviating disturbances of oxidative and energy metabolism.

Bi X, Haque TS, Zhou J, Skillman AG, Lin B, Lee CE, Kuntz ID, Ellman JA, Lynch G. · Department of Anatomy and Neurobiology, University of California at Irvine, 92697-3800, USA. · J Neurochem. · Pubmed #10737603 No free full text.

Abstract: Lysosomal disturbances may be a contributing factor to Alzheimer's disease. We used novel compounds to test if suppression of the lysosomal protease cathepsin D blocks production of known precursors to neurofibrillary tangles. Partial lysosomal dysfunction was induced in cultured hippocampal slices with a selective inhibitor of cathepsins B and L. This led within 48 h to hyperphosphorylated tau protein fragments recognized by antibodies against human tangles. Potent nonpeptidic cathepsin D inhibitors developed using combinatorial chemistry and structure-based design blocked production of the fragments in a dose-dependent fashion. Threshold was in the submicromolar range, with higher concentrations producing complete suppression. The effects were selective and not accompanied by pathophysiology. Comparable results were obtained with three structurally distinct inhibitors. These results support the hypothesis that cathepsin D links lysosomal dysfunction to the etiology of Alzheimer's disease and suggest a new approach to treating the disease.

Bi X, Zhou J, Lynch G. · Human Behavior, University of California, Irvine, California, 92697-3800, USA. · Exp Neurol. · Pubmed #10415139 No free full text.

Abstract: Lysosomal protease inhibitors induce signs of human brain aging in rat hippocampal slices. The present studies tested if they (1) also cause neurofibrillary tangles and (2) reproduce regional patterns of pathology found in Alzheimer's disease (AD). Slices of hippocampus plus retrohippocampal cortex were prepared from rats at postnatal days 6-7 and maintained for 2-5 weeks. In agreement with earlier studies, 6- to 12-day infusions of selective (ZPAD) or generalized (chloroquine) inhibitors of lysosomal proteases generated meganeurites of the type found in aged human cortex. Surveys and quantitative analyses established that the meganeurites developed almost exclusively in AD vulnerable regions. Antibodies against the phosphorylated tau protein in neurofibrillary tangles labeled thick filaments running through neurons in the superficial layers of entorhinal cortex in 6-day ZPAD-treated slices. The general appearance of the stained structures resembled that of early stage tangles. More mature tangle-like profiles were found at a number of sites after longer incubations; these were threefold more frequent in the superficial (AD vulnerable) than in the deep layers of the entorhinal cortex. Immunoblots indicated that essentially all phosphorylated tau labeling in the slices involved approximately 29-kDa fragments of the native isoforms. These findings establish that lysosomal dysfunction triggers the parallel formation of meganeurites and tangles with the regional distribution of both effects reflecting that for AD vulnerability.

Wei X, Zhang Y, Zhou J. · Beijing Institute of Pharmacology and Toxicology, People's Republic of China. · Neurosci Lett. · Pubmed #10406024 No free full text.

Abstract: The levels of Alzheimer's disease (AD)-related genes, including beta-amyloid precursor protein(APP), presenilin-1 (PS-1), PS-2, apoE, tau, c-fos, neural cell adhesion molecular 180 (NCAM-180), TGF-beta 1, IL-1 alpha/beta, IL-6, TNF-alpha/beta, alpha-2-Macroglobulin (alpha 2M), class II major histocompatibility antigen la (MHCII la), bcl-2 alpha, glucocorticoid receptor-alpha (GR alpha) and mineralocorticoid receptor (MR) mRNAs were determined by reverse transcription polymerase chain reaction (RT-PCR) in the hippocampus and cerebral cortex of senescence accelerated mouse (SAM). The levels of TGF-beta 1, IL-1 alpha, TNF-beta, c-fos, NCAM-180, PS-1 and APP mRNAs were normally expressed in SAMP8 compared with age-matched other subline that is resistant (SAMR1). The levels of apoE, GR alpha and MR mRNAs in the hippocampus of SAMP8, especially GR alpha, were evidently lower than those in the hippocampus of SAMR1. While bcl-2 alpha, PS-2 and tau mRNA levels of SAMP8 were significantly higher than those of SAMR1. Inflammatory cytokines (IL-1 beta, IL-6, TNF-alpha), alpha 2M and MHCII la antigen mRNAs were not detected in the brain of SAM. The differences of gene expression in the cerebral cortex were less evident than in the hippocampus. The results indicated that some genes abnormally expressed in the AD brain were also found in the brain of SAMP8, which may contribute to its age-related deterioration of learning and memory. Our results also suggested that functional and pathological changes which occurred in the brain of SAMP8 possessed some different aspects in comparison with the AD in consideration of the differences in gene expression.