cyclin-d1 and Alzheimer-Disease

Herein, we assessed the effect of full native peptide of amyloid-beta (Aβ) (1-42) and its fragments (25-35 and 35-25) on tissue transglutaminase (TG2) and its isoforms (TG2-Long and TG2-Short) expression levels on olfactory ensheathing cells (OECs). Vimentin and glial fibrillary acid protein (GFAP) were also studied. The effect of the pre-treatment with indicaxanthin from Opuntia ficus-indica fruit on TG2 expression levels and its isoforms, cell viability, total reactive oxygen species (ROS), superoxide anion (O

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Betaxanthins; Cell Differentiation; Cyclin D1; Gene Expression Regulation, Enzymologic; Glial Fibrillary Acidic Protein; GTP-Binding Proteins; Humans; Mice; Nerve Regeneration; Nestin; Olfactory Bulb; Opuntia; Oxidative Stress; Protein Glutamine gamma Glutamyltransferase 2; Protein Isoforms; Pyridines; Reactive Oxygen Species; Transglutaminases; Vimentin

β-amyloid formation in the brain is one of the characteristics of Alzheimer's disease. Exposure to this peptide may result in reentry into the cell cycle leading to cell death. The phytoestrogen equol has similar biological effects as estrogen without the side effects. This study investigated the possible mechanism of the neuron cell-protecting effect of equol during treatment with Aβ. SH-SY5Y neuroblastoma cells were treated with either 1 μM S-equol or 10 nM 17β-estradiol for 24 h prior to 1 μM Aβ (25-35) exposure. After 24 h exposure to Aβ (25-35), a significant reduction in cell survival and a reentry into the cell cycle process accompanied by increased levels of cyclin D1 were observed. The expressions of estrogen receptor alpha (ERα) and its coactivator, steroid receptor coactivator-1 (SRC-1), were also significantly downregulated by Aβ (25-35) in parallel with activated extracellular signal-regulated kinase (ERK)1/2. However, pretreatment of cells with S-equol or 17β-estradiol reversed these effects. Treatment with the ER antagonist, ICI-182,780 (1 μM), completely blocked the effects of S-equol and 17β-estradiol on cell viability, ERα, and ERK1/2 after Aβ (25-35) exposure. These data suggest that S-equol possesses a neuroprotective potential as it effectively antagonizes Aβ (25-35)-induced cell cytotoxicity and prevents cell cycle reentry in SH-SY5Y cells. The mechanism underlying S-equol neuroprotection might involve ERα-mediated pathways.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cell Cycle; Cell Line, Tumor; Cell Survival; Cyclin D1; Equol; Estradiol; Estrogen Receptor alpha; Gene Expression; Humans; Neuroblastoma; Neurons; Neuroprotective Agents; Peptide Fragments; Phytoestrogens

Housefly (Musca domestica) Larvae powder (HL) is rich in antioxidants. As oxidative stress is considered as one of the main pathogenesis in Alzheimer's Disease (AD), this study was designed to explore the protective effects of HL as an antioxidant on APP/PS1 mice. 2-Month-old APP/PS1 mice were divided into a model control (MC) group, a Donepezil group and a HL group, and C57BL/6 mice were used as the normal control (NC) group. After 180 days of treatment, the memory ability was measured by Morris Water Maze (MWM). The presence of Aβ and the expression of Uncoupling Protein 4 (UCP4) and CyclinD1 were detected by immunohistochemistry. The expressions of Superoxide Dismutase 1 (SOD1), Catalase (CAT) and Mitogen-activated Protein Kinase (MAPK) signal pathways were measured by western blotting. Compared with untreated APP/PS1 mice, the memory abilities of the HL-treated mice were significantly improved. Furthermore, the HL treatment not only down-regulated the deposition of Aβ and the expression of CylinD1, but also increased both the mRNA and protein levels of SOD, CAT, and UCP4, and enhanced the phosphorylation of JNK and P38 MAPK activation. In conclusion, these results suggest that HL may have a protective effect against memory impairment and prevent oxidative stress-induced injury via the regulation of UCP4 and CyclinD1 and the modulation of JNK and P38 MAPK signaling in AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cyclin D1; Disease Models, Animal; Houseflies; Humans; Larva; MAP Kinase Kinase 4; Mice; Mice, Inbred C57BL; Mitochondrial Uncoupling Proteins; Neuroprotective Agents; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Signal Transduction

Objective To observe the effects of active ingredients of Qingxin Kaiqiao Recipe (QKR) , such as saponins, volatile oils, effective compositions of polysaccharides, on expressions of Bcl-2 associated X protein (Bax) , B-cell lymphoma-2 (Bcl-2) , cysteinyl aspartate specific proteinase-3 (Caspase-3) , and β-amyloid precursor protein (pAPP) in hippocampus of Ap1_40-induced Alzheimer's disease (AD) model rats. Methods Totally 112 male Sprague-Dawley (SD) rats were randomly divided into 7 groups, i.e., the normal control group, the sham-operation group, the model group, the Aricept group, the saponin group, the volatile oil group, the polysaccharide group, 16 in each group. The AD rat model was established by injecting Aβ₁₋₄₀ from bilateral hippocampus. Equal volume of double distilled water was administered to rats by gastrogavage in the normal control group, the sham-operation group, the model group from the 2nd day after modeling, once per day for 2 successive weeks (at 10:00 am). Aricept (Donepezil Hydrochloride Tablet, 1. 67 mg/kg per day) , saponin (9 mL/kg per day) , benzene (3. 33 mL/kg per day) , and polysaccharides (8. 33 mL/kg per day) was administered to rats by gastro- gavage to the Aricept group, the saponin group, the volatile oil group, the polysaccharides group, re- spectively, once per day for 2 successive weeks (at 10:00 am). By the end of gastrogavage spatial learning and memory capacities were detected using Morris water maze (MWZ). Apoptosis in hippocam- pal CAI region was detected using TUNEL staining. Expressions of Bax, Bcl-2, Caspase-3, and PAPP were measured via Real-time fluorescent quantitative PCR, Western blot, and immunohistochemistry, respectively. Results There was no statistical difference in pre-modeling escape latency and times of crossing platforms among groups at the same time point (P >0. 05). Besides, escape latency was gradu- ally shortened as time went by. Compared with the model group, escape latency was shortened, and times of crossing platforms was significantly increased in the Aricept group and the saponin group (P < 0. 05, P <0. 01). Compared with the model group, the amount of apoptotic cells in hippocampal CA1 re- gion was obviously reduced (P <0. 05, P <0. 01) , expressions levels of Bax, Caspase-3, and pAPP were down-regulated, Bcl-2/Bax ratio was obviously elevated in the saponin group, the volatile oil group, the polysaccharide group (P <0. 05, P <0. 01). Conclusion Three active ingredients (spaonins, ben

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Cyclin D1; Drugs, Chinese Herbal; Hippocampus; Lymphoma, B-Cell; Male; Rats; Rats, Sprague-Dawley; Spatial Learning

Neurons that reenter the cell cycle die rather than divide, a phenomenon that is associated with neurodegeneration in Alzheimer's disease (AD). Reexpression of cell-cycle related genes in differentiated neurons in AD might be rooted in aberrant mitogenic signaling. Because microglia and astroglia proliferate in the vicinity of amyloid plaques, it is likely that plaque components or factors secreted from plaque-activated glia induce neuronal mitogenic signaling. Advanced glycation end products (AGEs), protein-bound oxidation products of sugar, might be one of those mitogenic compounds. Cyclin D1 positive neurons are colocalized with AGEs or directly surrounded by extracellular AGE deposits in AD brain. However, a direct proof of DNA replication in these cells has been missing. Here, we report by using fluorescent in situ hybridization that consistent with the expression of cell cycle proteins, hyperploid neuronal cells are in colocalization with AGE staining in AD brains but not in nondemented controls. To complement human data, we used apolipoprotein E-deficient mice as model of neurodegeneration and showed that increased oxidative stress caused an intensified neuronal deposition of AGEs, being accompanied by an activation of the MAPK cascade via RAGE. This cascade, in turn, induced the expression of cyclin D1 and DNA replication. In addition, reduction of oxidative stress by application of α-lipoic acid decreased AGE accumulations, and this decrease was accompanied by a reduction in cell cycle reentry and a more euploid neuronal genome.

Topics: Alzheimer Disease; Animals; Astrocytes; Brain; Cell Cycle; Cells, Cultured; Cyclin D1; Disease Models, Animal; DNA Replication; Extracellular Signal-Regulated MAP Kinases; Gene Expression; Glycation End Products, Advanced; Humans; In Situ Hybridization, Fluorescence; Male; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Mitogen-Activated Protein Kinases; Nerve Degeneration; Neurons; Oxidative Stress; Signal Transduction; Thioctic Acid

Alzheimer's disease (AD) is characterized by accumulation and deposition of Aβ peptides in human brains. The present study aimed to determine the protective effect of HBO and EGB761 on Aβ25-35 peptides induced cognitive impairment and neuronal toxicity in rats. Characteristics of AD were induced in rats by the administration of Aβ25-35 in hippocampus. Rats were treated with HBO (2ATA 60min/day), EGB761 (20mg/kg/day), and the combination of HBO+EGB761 (20mg/kg/day+2ATA). The Morris water maze was used to detect the protective effects of HBO and EGB761 against cognitive impairment. The activities of SOD and GSH, the apoptosis-related genes and proteins and the apoptosis rate of hippocampus were detected. Compared to the model group, EGB761 and HBO treatments synergistically improved the escape latency. Furthermore, the activities of SOD and GSH in rat hippocampal tissue were found to have increased with a concomitant reduction in MDA levels, Bax expression, cytochrome c release, and the activity of caspase-9/3. Accordingly, a significant reduction was observed in the apoptosis rate following the treatment with EGB761 and HBO in this model of AD. Our findings suggest that HBO and EGB761 reduce cell toxicity and oxidative stress by blocking mitochondria-mediated apoptosis signaling in AD, and the combined treatment of HBO and Ginkgo further enhances these effects.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Animals; Apoptosis; bcl-2-Associated X Protein; Caspases; Cyclin D1; Disease Models, Animal; Gene Expression Regulation; Ginkgo biloba; Hippocampus; Hyperbaric Oxygenation; In Situ Nick-End Labeling; Male; Maze Learning; Motor Activity; Neurons; Neuroprotective Agents; Oxidative Stress; Peptide Fragments; Plant Extracts; Rats; Rats, Sprague-Dawley; Reaction Time; Reactive Oxygen Species; RNA, Messenger; Time Factors

Wnt/β-catenin signaling pathway plays an important role in the genesis and development of Alzheimer's disease. The study aims to investigate the effect of Curcumin on the expression of GSK-3β, β-catenin and CyclinD1 in vitro, which are tightly correlated with Wnt/β-catenin signaling pathway, and also to explore the mechanisms, which will provide a novel therapeutic intervention for treatment of Alzheimer's disease. Plasmid APPswe and BACE1-mychis were transiently co-transfected into SHSY5Y cells by Liposfectamin™2000. The cells were treated with Curcumin at 0, 1.25, 5.0, 20.0 μmol/L for 24 h, or with Curcumin at 5.0 μmol/L for 0, and 12, 24 and 48 h for time course assay. Cell lysates were collected for RT-PCR, Western blot assay and immunofluorescent staining were carried out for detecting the effect of Curcumin on the expression of GSK-3β, β-catenin and CyclinD1. RT-PCR and Western blot results showed that the expression of GSK-3β mRNA and protein significantly decreased in the transfected cells treated with Curcumin, and that the changes were in a dose and time-dependent manner (P<0.05); however, the protein expression of GSK-3β-Ser9 was increased (P<0.05). Meanwhile, the expressions of β-catenin and transcriptional factors CyclinD1 mRNA and protein increased and the changes were also in a dose and time-dependent manner (P<0.05). Immunofluorescent staining results not only confirmed the above changes, but also showed that β-catenin had translocated into the nucleus gradually with the increased dosage of Curcumin. Therefore, GSK-3β is a potential target for treatment of AD. Curcumin could activate the Wnt/β-catenin signaling pathway through inhibiting the expression of GSK-3β and inducing the expression of β-catenin and CyclinD1, which will provide a new theory for treatment of neurodegenerative diseases by Curcumin.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; beta Catenin; Blotting, Western; Cell Line, Tumor; Curcumin; Cyclin D1; Fluorescent Antibody Technique; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Microscopy, Confocal; Plasmids; Reverse Transcriptase Polymerase Chain Reaction; Transfection; Wnt Proteins

The cyclin-dependent kinase 5 activator p35 can be cleaved into p25. Formation of p25 has been suggested to contribute to neurodegeneration in Alzheimer's disease (AD). However, overexpression of low levels of p25 in mice enhances memory formation. Therefore, it has been suggested that p25 formation might be an event early in AD to compensate for impairments in synaptic plasticity. Ongoing p25 formation has been hypothesized to contribute to neurodegeneration at the later stages of AD.. Here, we tested the early compensation hypothesis by analyzing the levels of p25 and its precursor p35 in AD postmortem samples from different brain regions at different stages of tau pathology, using quantitative Western blots. Furthermore, we studied p35 and p25 during spatial memory formation. By employing quantitative mass spectrometry, we identified proteins downstream of p25, which were then studied in AD samples.. We found that p25 is generated during spatial memory formation. Furthermore, we demonstrate that overexpression of p25 in the physiological range increases the expression of two proteins implicated in spine formation, septin 7 and optic atrophy 1. We show that the expression of p35 and p25 is reduced as an early event in AD. Moreover, expression of the p25-regulated protein optic atrophy 1 was reduced in a time course similar to p25 expression.. Our findings suggest that p25 generation is a mechanism underlying hippocampal memory formation that is impaired in the early stages of AD. Our findings argue against the previously raised early compensation hypothesis and they propose that p25-mediated neurotoxicity does not occur in AD.

Topics: Alzheimer Disease; Animals; Brain; Cyclin D1; Disease Models, Animal; Down-Regulation; GTP Phosphohydrolases; Humans; Mass Spectrometry; Maze Learning; Memory; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Electron, Transmission; Mutation; Nerve Tissue Proteins; Phosphopyruvate Hydratase; Septins; Synapses; Synaptosomes; tau Proteins

Presenilin-1 (PS1) is a component of the beta-catenin degradation machinery, and PS1 mutations linked to familial Alzheimer's disease (FAD) represent a loss of this function, leading, in non-neuronal cells, to accumulation of cyclin D1, aberrant cell cycle activation and hyperproliferation. In post-mitotic neurons, cell cycle activation is thought to be abortive and initiate apoptosis, thus contributing to AD pathogenesis. Consequently, we tested here the hypothesis that, in the PS1 FAD brain, cyclin D1 accumulation may occur and lead to neuronal apoptosis secondary to an abortive entry into the cell cycle.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Apoptosis; beta Catenin; Brain; Cell Cycle; Cyclin D1; Enzyme Inhibitors; Female; Humans; Male; Mice; Middle Aged; Mutant Proteins; Mutation; Nerve Degeneration; Neurons; Presenilin-1; Quercetin

Reactivation of the cell cycle, including DNA replication, might play a major role in Alzheimer's disease. In this study, we report that the expressions of Swedish double mutation of amyloid precursor protein (Swe-APP) or of the APP intracellular domain (AICD) into nerve growth factor (NGF)-differentiated PC12 cells or rat primary cortical neurons increased mRNA and protein levels of cyclin D1 and cyclin B1. Treatment with lithium chloride (a glycogen synthase kinase-3beta inhibitor) down-regulated cyclin B1 induced by Swe-APP expression but up-regulated cyclin D1 expression induced by Swe-APP, suggesting that glycogen synthase kinase-3beta activity is involved in these expression changes of cyclins D1 and B1. Swe-APP, which is a prevailing cause of familial Alzheimer's disease, is well known to increase amyloid beta peptide production both in vitro and in vivo, but the underlying molecular means whereby it leads to the pathogenesis of AD remains unknown. The finding that cyclin D1 and B1 expressions were up-regulated by Swe-APP in in vitro cultured cells was substantiated in the brain tissues of Tg2576 mice, which harbor the Swe-APP mutation. These results suggest that some disturbances in cell cycle regulation may be involved in Swe-APP or AICD-induced neurodegeneration and that these contribute to the pathogenesis of AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Blotting, Western; Brain; Cell Cycle; Cyclin B; Cyclin B1; Cyclin D1; Enzyme Inhibitors; Humans; Immunohistochemistry; Immunoprecipitation; Mice; Mice, Transgenic; Mutation; Neurons; PC12 Cells; Rats; Reverse Transcriptase Polymerase Chain Reaction; Up-Regulation

We have shown previously that beta-catenin and cyclin D1 are up-regulated in cortical neurons from homozygous mice carrying the familial Alzheimer's disease (FAD) presenilin-1 M146V mutation in a knock-in model (PS1 KI(M146V) mice), leading to cell cycle-associated apoptosis. Here, we have aimed to determine (i) whether this phenotype is present in heterozygous PS1 KI(M146V) mice, which reflects more accurately the PS1 FAD condition in humans and (ii) whether Abeta(1-42), which is invariably present in the PS1 FAD brain and is thought to affect neuronal cell cycle kinetics, may contribute to the abnormal cell cycle/cell death phenotype seen in PS1 KI(M146V) mice. We demonstrate that cell cycle-linked apoptosis occurs in heterozygous PS1 KI(M146V) post-mitotic neurons. In addition, there is a significant Abeta-associated increase in cell cycle and cell death that is not further modified by the PS1 KI(M146V) mutation. Our results are consistent with a cell cycle-associated neurodegeneration model in the PS1 FAD brain in which the loss of PS1-dependent beta-catenin regulatory function is sufficient to commit susceptible neurons to an abortive cell cycle, and may act synergistically with the Abeta cytotoxic challenge present in the PS1 FAD brain to expand the neuronal population susceptible to cell cycle-driven apoptosis.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Animals; Apoptosis; beta Catenin; Bromodeoxyuridine; Cell Cycle; Cells, Cultured; Cerebral Cortex; Cyclin D1; Disease Models, Animal; Embryo, Mammalian; Hippocampus; Humans; Mice; Mice, Transgenic; Mutation; Neurons; Peptide Fragments; Presenilin-1; Up-Regulation

Thrombin, a multifunctional serine protease, is neurotoxic in vitro and in vivo. Thrombin has been shown to be increased in Alzheimer's disease (AD) and other neuropathological conditions and could be a mediator of pathological neuronal cell death in the brain. The mechanisms of thrombin-induced neuronal cell death are incompletely understood. The objective of this study is to explore mechanisms that contribute to thrombin-induced neuronal apoptosis focusing on the role of cell cycle regulators and the pro-apoptotic protein Bim (Bcl-2-interacting mediator of cell death) in this process. Our data show that thrombin treatment of primary cerebral cortical cultures results in dose-dependent apoptotic cell death. Exposure of neuronal cultures to thrombin leads to induction of cell cycle proteins cyclin D1 and cyclin E, at both mRNA and protein levels. In addition, thrombin treatment causes the appearance of cyclin-dependent kinase 4 (cdk4) and expression of the pro-apoptotic protein Bim. Inhibition of cdk4 prevents both induction of Bim expression and thrombin-induced neuronal apoptosis. These data demonstrate that thrombin-induced apoptosis proceeds via cell cycle activation involving cdk4 resulting in induction of Bim. Thus, cell cycle proteins could be therapeutic targets in diseases such as AD where thrombin has been implicated.

Topics: Alzheimer Disease; Animals; Apoptosis; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; Cell Cycle Proteins; Cells, Cultured; Cerebral Cortex; Cyclin D1; Cyclin-Dependent Kinase 4; Dose-Response Relationship, Drug; Membrane Proteins; Nerve Degeneration; Neurodegenerative Diseases; Neurons; Proto-Oncogene Proteins; Rats; RNA, Messenger; Thrombin

Cerebrospinal fluid prostaglandin E2 (PGE2) and tumor necrosis factor-alpha (TNF-alpha) levels are elevated in patients with Alzheimer's disease (AD), which suggests that they are involved in neurodegeneration. We previously reported that TNF-alpha derived from human macrophages, in response to beta-amyloid or amyloidogenic C-terminal peptide, is a main mediator of inflammatory neurotoxicity. In a continuation of this work, the present study investigated the direct effect of PGE2, one of the major prostaglandins produced in the brain, on cell viability in SH-SY5Y neuronal cells treated with TNF-alpha. PGE2 did not promote neurotoxicity, but rather had a strong protective effect against TNF-alpha by ameliorating TNF-alpha-induced apoptosis and also by rescuing the intracellular level of beta-catenin, a key transducer of the Wnt signaling pathway. PGE2-mediated stabilization of beta-catenin was accompanied by T-cell factor/lymphoid enhancer factor (Tcf/Lef)-mediated transcriptional activation, which was followed by an increase in the cyclinD1 level. Pharmacological studies provided further evidence supporting the notion that PGE2-mediated neuroprotection against TNF-alpha involves the stimulation of Tcf/Lef signaling through EP1-, EP2-, and EP4-mediated increases of beta-catenin in SH-SY5Y cells. In addition, this PGE2 effect appears to be dependent on the activation of protein kinase A, phosphatidylinositol 3-kinase, phospholipase C, and to a lesser extent protein kinase C. Thus, the molecular mechanism governing the inhibitory effect of PGE2 against TNF-alpha may involve the activation and cross talk of multiple signal transduction and play an important role in regulating the survival of neurons during the neurotoxic inflammatory response associated with neurodegenerative diseases including AD.

Topics: Alzheimer Disease; Apoptosis; beta Catenin; Cell Line, Tumor; Cell Survival; Cyclin D1; Cytoskeletal Proteins; Dinoprostone; DNA-Binding Proteins; Humans; Inflammation Mediators; Lymphoid Enhancer-Binding Factor 1; Neuroblastoma; Neurons; Neuroprotective Agents; Neurotoxins; Protein Kinases; Receptors, Prostaglandin E; Signal Transduction; Trans-Activators; Transcription Factors; Transcriptional Activation; Tumor Necrosis Factor-alpha; Type C Phospholipases

Regular use of non-steroidal anti-inflammatory drugs (NSAIDs) seems to reduce the progression of several diseases, including colon cancer, lung cancer, breast cancer and Alzheimer disease (AD). Several studies have shown that NSAIDs can modulate cell cycle progression, especially in the G0/G1 phase. The main target of most NSAIDs is the enzyme cyclo-oxygenase (COX), which occurs in 2 isoforms, COX-1 and COX-2. In AD and non-demented control brain, COX-2 is expressed in neuronal cells. In this study the expression of COX-2, cyclin D1, and cyclin E was investigated at the immunohistochemical level in AD and non-demented control temporal cortex. COX-2, cyclin D1, and cyclin E expression was detected in pyramidal neurons in both AD and control patients. The number of COX-2-immunoreactive neurons positively correlated with the number of cyclin E- and cyclin D1-immunoreactive neurons. Moreover, immunostaining of sequential tissue sections and double immunofluorescence labeling revealed co-expression of COX-2 and cyclin D1 and E in neuronal cells. In addition, an inverse correlation was observed between the neuronal expression of COX-2 and cyclin E and the Braak score for amyloid beta deposits. Our findings suggest a relationship between the neuronal expression of COX-2 and cell cycle markers, which may be involved early in AD pathology.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cyclin D1; Cyclin E; Cyclooxygenase 2; Female; Humans; Isoenzymes; Male; Membrane Proteins; Middle Aged; Neurons; Prostaglandin-Endoperoxide Synthases; Pyramidal Cells; Reference Values; Temporal Lobe; Tissue Distribution

In Alzheimer's disease, the peptidyl prolyl cis/trans isomerase Pin1 binds to phospho-Thr231 on Tau proteins and, hence, is found within degenerating neurons, where it is associated to the large amounts of abnormally phosphorylated Tau proteins. Conversely, Pin1 may restore the tubulin polymerization function of these hyperphosphorylated Tau. In the present work, we investigated, both at the cellular and molecular levels, the role of Pin1 in Alzheimer's disease through the study of its interactions with phosphorylated Tau proteins. We also showed that in neuronal cells, Pin1 upregulates the expression of cyclin D1. This, in turn, could facilitate the transition from quiescence to the G1 phase (re-entry in cell cycle) in a neuron and, subsequently, neuronal dedifferentiation and apoptosis. The involvement of Pin1 in the G0/G1 transition in neurons points to its function as a good target for the development of new therapeutic strategies in neurodegenerative disorders.

Topics: Alzheimer Disease; Cell Line; Cyclin D1; Humans; Magnetic Resonance Spectroscopy; Models, Molecular; Naphthoquinones; Neuroblastoma; Neurons; NIMA-Interacting Peptidylprolyl Isomerase; Peptidylprolyl Isomerase; Phosphopyruvate Hydratase; Phosphorylation; Protein Binding; Protein Structure, Tertiary; Spectrometry, Fluorescence; tau Proteins

Mutations in the presenilin 1 (PS1) gene have been associated to familial Alzheimer disease although the exact pathogenic mechanism is unclear. We report that stable overexpression of wild type PS1 led to a decrease in cyclin-dependent kinase 4 (CDK 4) activity and retinoblastoma tumor suppressor protein (pRb) phosphorylation that correlated with decreased levels of beta-catenin and cyclin D1. PS1 mutant D385A also precipitated a similar effect suggesting that gamma-secretase cleavage is not essential for PS1-mediated CDK 4 inhibition. We postulate that PS1 overexpression may balance the hyperphosphorylation of pRb associated with death of post mitotic neurons after injury.

Topics: Alzheimer Disease; Animals; beta Catenin; Cell Culture Techniques; CHO Cells; Cricetinae; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinases; Cytoskeletal Proteins; Immunoblotting; Membrane Proteins; Neurodegenerative Diseases; Phosphorylation; Presenilin-1; Protein Kinases; Proto-Oncogene Proteins; Retinoblastoma Protein; Trans-Activators; Transfection; Up-Regulation

In addition to its documented role in the proteolytic processing of Notch-1 and the beta-amyloid precursor protein, presenilin 1 (PS1) associates with beta-catenin. In this study, we show that this interaction plays a critical role in regulating beta-catenin/T Cell Factor/Lymphoid Enhancer Factor-1 (LEF) signaling. PS1 deficiency results in accumulation of cytosolic beta-catenin, leading to a beta-catenin/LEF-dependent increase in cyclin D1 transcription and accelerated entry into the S phase of the cell cycle. Conversely, PS1 specifically represses LEF-dependent transcription in a dose-dependent manner. The hyperproliferative response can be reversed by reintroducing PS1 expression or overexpressing axin, but not a PS1 mutant that does not bind beta-catenin (PS1Deltacat) or by two different familial Alzheimer's disease mutants. In contrast, PS1Deltacat restores Notch-1 proteolytic cleavage and Abeta generation in PS1-deficient cells, indicating that PS1 function in modulating beta-catenin levels can be separated from its roles in facilitating gamma-secretase cleavage of beta-amyloid precursor protein and in Notch-1 signaling. Finally, we show an altered response to Wnt signaling and impaired ubiquitination of beta-catenin in the absence of PS1, a phenotype that may account for the increased stability in PS1-deficient cells. Thus, PS1 adds to the molecules that are known to regulate the rapid turnover of beta-catenin.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Axin Protein; beta Catenin; Cyclin D1; Cytoskeletal Proteins; Cytosol; DNA-Binding Proteins; Endopeptidases; Fibroblasts; Gene Expression Regulation; Lymphoid Enhancer-Binding Factor 1; Membrane Proteins; Mice; Mutation; Presenilin-1; Protein Processing, Post-Translational; Proteins; Receptor, Notch1; Receptors, Cell Surface; Repressor Proteins; S Phase; Signal Transduction; Trans-Activators; Transcription Factors; Ubiquitins; Wnt Proteins; Wnt3 Protein

Topics: Alzheimer Disease; Animals; beta Catenin; Cyclin D1; Cytoskeletal Proteins; DNA-Binding Proteins; Lymphoid Enhancer-Binding Factor 1; Membrane Proteins; Mice; Presenilin-1; Signal Transduction; Skin Neoplasms; Trans-Activators; Transcription Factors

Recent findings from our and other laboratories indicate that cell cycle-related phenomena may play a key role in the formation of Alzheimer-type pathology and neuronal cell death in both Alzheimer's and cerebro-vascular diseases. In this study we examine the expression patterns of cyclins A, B1, D1 and E in neuronal nuclei in the hippocampus in autopsied healthy elderly individuals, Alzheimer's disease patients and subjects suffering from cerebrovascular disease with and without co-existing Alzheimer's disease. Nuclear cyclin B1 and cyclin E expression was detected in hippocampal neurones in each subject category. However, cyclin B1 expression was significantly elevated in the CA1 of patients suffering from cerebro-vascular disease alone, while cyclin E expression was significantly higher in the CA4 subfield in patients suffering from mixed Alzheimer's and cerebro-vascular diseases compared to subjects in other categories. We hypothesize that cell cycle re-entry may occur in healthy elderly people leading to age-related cell death and mild Alzheimer-type pathology in the hippocampus. However, in pathological conditions, the cell cycle arrest may lead either to the development of severe Alzheimer-related pathology or to excess apoptotic cell death as in vascular dementia.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Autopsy; Cell Cycle; Cell Nucleus; Cerebrovascular Disorders; Cyclin A; Cyclin B; Cyclin B1; Cyclin D1; Cyclin E; Cyclins; Dementia, Vascular; Hippocampus; Humans; Neurons; Reference Values