Expression of Bcl‐2 in Adult Human Brain Regions with Special Reference to Neurodegenerative Disorders

Vyas, Sheela; Javoy‐Agid, F.; Herrero, María Teófila Vicente; Strada, Ornella; Boissière, Florence; Hibner, Urszula; Agid, Yves

doi:10.1046/j.1471-4159.1997.69010223.x

Cited by 67 publications

(20 citation statements)

References 40 publications

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“…Engidawork et al (2001) found increased Bcl-2 by ELISA in AD cerebellum, but the cortical increase did not reach statistical significance. Vyas et al (1997) saw no changes in expression of Bcl-2 in neurons of the nucleus basalis in AD. The conclusions from these studies would argue that there is an increase in Bcl-2 expression in AD, however, this is most strongly associated with reactive glial cells near plaques, and seems more associated with membrane than cytosolic fractions.…”

Section: Discussionmentioning

confidence: 81%

Up-regulation of Bcl-2 in APP transgenic mice is associated with neuroprotection

Karlnoski

Wilcock

Dickey

et al. 2007

Neurobiology of Disease

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Aβ-induced neurodegeneration is limited in APP and APP+PS1 transgenic mice. In middle-aged APP+PS1 transgenic mice, we found significantly increased Bcl-2 expression. The increase in Bcl-2 is restricted to amyloid-containing brain regions and is not found at young ages, suggesting that Aβ deposition is the stimulus for increased Bcl-2. Western blot results were confirmed with immunohistochemistry, and qRT-PCR. In addition, we found that APP transgenic mice were protected from neurotoxicity caused by an injection of bak BH3 fusion peptides, known to induce apoptosis by antagonizing bcl protein activity. Nissl and fluorojade stained slides showed that the active bak BH3 peptide caused substantial neuronal loss in the dentate gyrus and CA3 regions of nontransgenic, but not APP mice. The inactive mutant bak BH3 peptide did not cause degeneration in any mice. These data demonstrate that the increased Bcl-2 expression in brain regions containing Aβ deposits is associated with neuroprotection. KeywordsBax; APP+PS1 transgenic mice; Alzheimer's disease; neurotoxicity; Aβ; apoptosis The amyloid cascade hypothesis states that the dysregulation of amyloid precursor protein (APP) processing and Aβ production are the major causes for neuronal death and dysfunction leading to dementia in Alzheimer's disease (Hardy and Selkoe, 2002). Genetic and environmental factors, such as APP or PS-1 mutations, cause an accumulation of Aβ which forms diffuse and compact plaques. These plaques are thought to cause oxidative stress, activate microglia and astrocytes, causing cytokine release, inflammation and altered ionic homeostasis, culminating in cytotoxicity and neuronal death.The Aβ peptide can directly induce neuronal apoptosis in vitro (Pike et al., 1993); (Hensley et al., 1995); (Schubert and Chevion, 1995); (Wogulis et al., 2005). Intracellular Aβ may activate apoptosis by interacting with the endoplasmic reticulum and endosomes and by binding to alcohol dehydrogenase within the mitochondria (Dickson, 2004). Aβ also induces changes in nitric oxide production and mitochondrial activity facilitating apoptosis (Keil et al., 2004). InCorresponding author: Dave Morgan, Alzheimer Research Laboratory, University of South Florida 12901 Bruce B. Downs Blvd MDC Box 9 Tampa, FL 33612, Scientist.dave@gmail.com Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Aβ-induced neuronal toxicity is limited in the APP transgenic mouse models of AD. A modest reduction in hippocampal neurons was found in old APP23 mice, but the cortical neuron census was unaffected despite extensive amyloid deposition (Calhou...

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Section: Discussionmentioning

confidence: 81%

Up-regulation of Bcl-2 in APP transgenic mice is associated with neuroprotection

Karlnoski

Wilcock

Dickey

et al. 2007

Neurobiology of Disease

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“…This antibody (clone 124) has been previously characterized in human and nonhuman primates using Western blot techniques, and recognizes the 26 kD band characteristic of bcl-2 protein in several tissues, including the brain (Bernier and Parent, 1998;Pezzella et al, 1990;Vyas et al, 1997). Moreover, transfection studies in monkey (vero) cells engineered to overexpress either bcl-xl or bcl-2 protein, show that the clone 124 antibody specifically stains bcl-2, but not bcl-xl, expressing cells (Bernier and Parent, 1998).…”

Section: Immunocytochemistrymentioning

confidence: 99%

Bcl-2 immunoreactive neurons are differentially distributed in subregions of the amygdala and hippocampus of the adult macaque

Fudge

2004

Neuroscience

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The amygdala and hippocampus are key limbic structures of the temporal lobe, and are implicated in the pathology of mood disorders. Bcl-2, an intracellular protein, has recently been identified in the primate amygdala and hippocampus, and is now recognized as an intracellular target of mood stabilizing drugs. However, there are few data on the cellular phenotypes of bcl-2-expressing cells, or their distribution in specific subregions of the amygdala and hippocampus. We used a number of histochemical markers to define specific subregions of the primate amygdala and hippocampus, and examined phenotype-specific distributions of bcl-2 immunore-active cells within each subregion. Immature-appearing bcl-2 labeled neurons, which co-contain class III β-tubulin immuno-reactivity, are found in distinct subregions in each structure. In the amygdala, bcl-2 positive neurons with an immature morphology are densely distributed in the paralaminar nucleus and intercalated cell islands, the parvicellular basal nucleus, and the ventral periamygdaloid cortex and amygdalohippocampal area. In the hippocampus, immature-appearing bcl-2-labeled cells are confined to the polymorph layer (subgranular zone), and base of the granule cell layer in the dentate gyrus. Well-differentiated neurons also express bcl-2. In the amygdala, labeled cells with mature phenotypes are concentrated in the parvicellular basal nucleus, the accessory basal nucleus, and the periamygdaloid cortex. The medial nucleus and central extended amygdala also contain many well-differentiated bcl-2 positive cells. In the hippocampus, the dentate gyrus and Ammon's horn contain many bcl-2 immunoreactive nonpyramidal cells. These are preferentially distributed in the rostral hippocampus. CA3 and CA2 contain relatively higher concentrations of bcl-2-labeled cells than CA1 and the subiculum. Bcl-2 is thus important in intrinsic circuitry of the hippocampus, and in amygdaloid subregions modulated by the hippocampus. In addition, the extended amygdala, a key amygdaloid output, is richly endowed with bcl-2 positive cells. This distribution suggests a role for bcl-2 in circuits mediating emotional learning and memory which may be targets of mood stabilizing drugs.Keywords paralaminar nucleus; intercalated islands; dentate gyrus; class III β-tubulin; extended amygdala; mood disorderThe amygdala is involved in higher emotional processing (Ledoux, 1992;Meunier et al., 1999;Nishijo et al., 1988;Parkinson et al., 2001), and is modulated by the hippocampus which conveys sensory information associated with past emotional experiences (Mishkin, 1982; *Correspondence to: J. L. Fudge, Department of Psychiatry, University of Rochester Medical Center, Rochester, NY 14642, USA. Tel: +1-585-273-2028; fax: +1-585-756-5334. E-mail address: julie_fudge@urmc.rochester.edu (J. L. Fudge). NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2008 June 21. Published in final edited form as:Neuroscience. 2004 ; 127(2): 539-556. NIH-PA Author ManuscriptNIH-PA Aut...

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“…It is interesting that apoptotic neurons associated with neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases, have altered Bcl2 expression (Vyas et al, 1997;Mattson, 2000). Actually Bcl2, in addition to its antiapoptotic functions, has shown differentiative and neurotrophic properties.…”

Section: Downloaded Frommentioning

confidence: 99%

Increased Bcl2 Expression by Antisense Oligoribonucleotides Targeting the Adenine-Uridine-Rich Element Motif

Ghisolfi

Papucci²,

Bevilacqua³

et al. 2005

Mol Pharmacol

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RNA has become a promising target for pharmacological purposes. Most current strategies are directed toward down-regulating its functions. In this study, we provide evidence of the up-regulation of messenger RNA in a sequence-specific manner. The bcl2 (b)-ARE (adenine-uridine-rich element) in the 3Ј-untranslated region of the b-RNA that regulates the rate of RNA degradation has been targeted with three chemically modified oligoribonucleotides designed in the antisense orientation (asORNs). The three asORNs were studied by a cell-free degradation assay. All three slowed the rate of RNA decay in a dose-response fashion, they were specific to the b-ARE, and two of them were individually effective. asORNs were then transfected into the malignant cells in culture and b-RNA halflife was measured by real-time reverse transcriptase-polymerase chain reaction. We showed that by stabilizing b-RNA the three asORNs increased the expression of b-RNA and of the relevant protein in a dose-response fashion.

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Expression of Bcl‐2 in Adult Human Brain Regions with Special Reference to Neurodegenerative Disorders

Cited by 67 publications

References 40 publications

Up-regulation of Bcl-2 in APP transgenic mice is associated with neuroprotection

Up-regulation of Bcl-2 in APP transgenic mice is associated with neuroprotection

Bcl-2 immunoreactive neurons are differentially distributed in subregions of the amygdala and hippocampus of the adult macaque

Increased Bcl2 Expression by Antisense Oligoribonucleotides Targeting the Adenine-Uridine-Rich Element Motif

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