Papers by Claes Wahlestedt
Current Alzheimer Research, 2016
Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by ... more Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by welldefined neuropathological brain changes including amyloid plaques, neurofibrillary tangles and the presence of chronic neuroinflammation. Objective: The brain penetrant BET bromodomain inhibitor JQ1 has been shown to regulate inflammation responses in vitro and in vivo, but its therapeutic potential in AD is currently unknown. Method: Three-month-old 3xTg mice were injected once a day with JQ1 (50 mg/kg) or vehicle for 15 weeks. At the end of the treatment learning and memory was assessed using the modified Barnes maze and the Y maze behavioral tests. Tissue from the brain and other organs was collected for molecular evaluation of neuroinflammation tau pathology and amyloid β. Results: JQ1 treatment reduced splenomegaly and neuroinflammation in the brain of treated mice where we observed a reduction in the expression of the pro-inflammatory modulators Il-1b, Il-6, Tnfa, Ccl2, Nos2 and Ptgs2. Additionally, JQ1-treated mice showed a reduction of tau phosphorylation at Ser396 in the hippocampus and frontal cortex while total levels of tau remained unaffected. On the other hand, JQ1 did not ameliorate learning and memory deficits in 7-month-old 3xTg mice. Conclusion: Taken together, our data suggest that BET bromodomain inhibitors hold the promise to be used for the treatment of neurological disorders characterized by neuroinflammation.
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 11, 2015
Epigenetic processes that regulate histone acetylation play an essential role in behavioral and m... more Epigenetic processes that regulate histone acetylation play an essential role in behavioral and molecular responses to cocaine. To date, however, only a small fraction of the mechanisms involved in the addiction-associated acetylome have been investigated. Members of the bromodomain and extraterminal (BET) family of epigenetic "reader" proteins (BRD2, BRD3, BRD4, and BRDT) bind acetylated histones and serve as a scaffold for the recruitment of macromolecular complexes to modify chromatin accessibility and transcriptional activity. The role of BET proteins in cocaine-induced plasticity, however, remains elusive. Here, we used behavioral, pharmacological, and molecular techniques to examine the involvement of BET bromodomains in cocaine reward. Of the BET proteins, BRD4, but not BRD2 or BRD3, was significantly elevated in the nucleus accumbens (NAc) of mice and rats following repeated cocaine injections and self-administration. Systemic and intra-accumbal inhibition of BRD4 ...
Genome biology, 2006
Antisense transcription, yielding both coding and non-coding RNA, is a widespread phenomenon in m... more Antisense transcription, yielding both coding and non-coding RNA, is a widespread phenomenon in mammals. The mechanism by which natural antisense transcripts (NAT) may regulate gene expression are largely unknown. The aim of the present study was to explore the mechanism of reciprocal sense-antisense (S-AS) regulation by studying the effects of a coding and non-coding NAT on corresponding gene expression, and to investigate the possible involvement of endogenous RNA interference (RNAi) in S-AS interactions. We have examined the mechanism of S-AS RNA base pairing, using thymidylate synthase and hypoxia inducible factor-1alpha as primary examples of endogenous genes with coding and non-coding NAT partners, respectively. Here we provide direct evidence against S-AS RNA duplex formation in the cytoplasm of human cells and subsequent activation of RNAi. Collectively, our data demonstrate that NAT regulation of gene expression occurs through a pathway independent of Dicer associated RNAi....
International Journal of Alzheimer's Disease, 2011
Background. Alzheimer's disease (AD) is a devastating neurological disorder and the main caus... more Background. Alzheimer's disease (AD) is a devastating neurological disorder and the main cause of dementia in the elderly population worldwide. Adult neurogenesis appears to be upregulated very early in AD pathogenesis in response to some specific aggregates of beta-amyloid (Aβ) peptides, exhausting the neuronal stem cell pools in the brain. Previously, we characterized a conserved nonprotein-coding antisense transcript forβ-secretase-1 (BACE1), a critical enzyme in AD pathophysiology. We showed that the BACE1-antisense transcript (BACE1-AS) is markedly upregulated in brain samples from AD patients and promotes the stability of the (sense) BACE1 transcript. In the current paper, we examine the relationship between BACE1, BACE1-AS, adult neurogenesis markers, and amyloid plaque formation in amyloid precursor protein (APP) transgenic mice (Tg-19959) of various ages.Results. Consistent with previous publications in other APP overexpressing mouse models, we found adult neurogenesis ...
Nature Reviews Molecular Cell Biology, 2009
Nature Medicine, 2008
Recent efforts have revealed that numerous protein-coding messenger RNAs have natural antisense t... more Recent efforts have revealed that numerous protein-coding messenger RNAs have natural antisense transcript partners, most of which seem to be noncoding RNAs. Here we identify a conserved noncoding antisense transcript for b-secretase-1 (BACE1), a crucial enzyme in Alzheimer's disease pathophysiology. The BACE1-antisense transcript (BACE1-AS) regulates BACE1 mRNA and subsequently BACE1 protein expression in vitro and in vivo. Upon exposure to various cell stressors including amyloid-b 1-42 (Ab 1-42), expression of BACE1-AS becomes elevated, increasing BACE1 mRNA stability and generating additional Ab 1-42 through a post-transcriptional feed-forward mechanism. BACE1-AS concentrations were elevated in subjects with Alzheimer's disease and in amyloid precursor protein transgenic mice. These data show that BACE1 mRNA expression is under the control of a regulatory noncoding RNA that may drive Alzheimer's disease-associated pathophysiology. In summary, we report that a long noncoding RNA is directly implicated in the increased abundance of Ab 1-42 in Alzheimer's disease.
Nature Genetics, 2007
× 10-9 DSBs per bp are replicated, or about fourfold fewer than the estimate of about 0.8 × 10-8 ... more × 10-9 DSBs per bp are replicated, or about fourfold fewer than the estimate of about 0.8 × 10-8 DSBs per bp replicated in human somatic cells (or 50 DSBs per diploid human genome replication) from Vilenchik and Knudson (Proc. Natl. Acad. Sci. USA 100, 12871-12876; 2003). This would bring the number of DSBs per human genome replication down to approximately 13, if it were proportional to that in E. coli. Our error arose from calculating the human equivalent based on haploid, not diploid, human genome size. This error has been corrected in the HTML and PDF versions of the article.
Nature, 2010
Cocaine addiction is characterized by a gradual loss of control over drug use, but molecular mech... more Cocaine addiction is characterized by a gradual loss of control over drug use, but molecular mechanisms regulating vulnerability to this process remain unclear. Here we report that microRNA-212 (miR-212) is upregulated in the dorsal striatum of rats with a history of extended access to cocaine. Striatal miR-212 decreases responsiveness to the motivational properties of cocaine by dramatically amplifying the stimulatory effects of the drug on CREB signaling. This action occurs through miR-212-enhanced Raf-1 activity, resulting in adenylyl cyclase sensitization and increased expression of the essential CREB co-activator TORC (Transducer of Regulated CREB; also known as CRTC). Our findings suggest that striatal miR-212 signaling plays a key role in determining vulnerability to cocaine addiction, reveal novel molecular regulators that control the complex actions of cocaine in brain reward circuitries, and provide an entirely new direction for the development of anti-addiction therapeutics based on modulation of noncoding RNAs. Cocaine triggers a constellation of cellular and molecular alterations in brain reward systems, and cocaine addiction is commonly viewed as a disorder of neuroplasticity 1,2. Such long-lasting structural and functional modifications are thought to increase sensitivity to the motivational effects of cocaine and associated environmental stimuli, culminating in a loss of control over intake 3. However, recent findings support a more nuanced view in Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
European Journal of Pharmacology, 1990
We present a new proof of the extended arc-sine law related to Walsh's Brownian motion, known als... more We present a new proof of the extended arc-sine law related to Walsh's Brownian motion, known also as Brownian spider. The main argument mimics the scaling property used previously, in particular by D. Williams [12], in the 1-dimensional Brownian case, which can be generalized to the multivariate case. A discussion concerning the time spent positive by a skew Bessel process is also presented.
Alcohol and Alcoholism, 2004
Aims: To examine whether polymorphic variants of the HTR2C gene are associated with diagnosis of ... more Aims: To examine whether polymorphic variants of the HTR2C gene are associated with diagnosis of alcohol dependence. Methods: We compared allele frequencies of five HTR2C promoter polymorphisms in a Nordic population of alcohol dependent individuals (Males: n = 309; Females: n = 127) and ethnically matched controls (Males: n = 83; Females: n = 190) in whom alcohol dependence was established, or any diagnosis of substance disorder was excluded, respectively. Patients were further subtyped into Type I (late onset) and Type II (early onset) alcoholics. Results: None of the individual polymorphisms indicated significant association with alcohol dependence. A common promoter haplotype (GAGG) exhibited different distribution frequencies between males and females (Type I), however on Bonferroni's multiple-testing correction, this observation proved to be insignificant. Conclusions: Although we report a lack of association between alcohol dependence and five common promoter polymorphisms, and the constituted haplotypes, the analysis tends to indicate gender and sub-type differences. We suggest that a follow up study with larger sample numbers should be performed to improve the power to detect the genetic influences of HTR2C in alcohol dependence.
Journal of Alzheimer's Disease, 2010
Alzheimer&amp... more Alzheimer's disease (AD) is a devastating age-related neurodegenerative disorder characterized by progressive impairment of cognition and short-term memory loss. The deposition of amyloid-beta (Abeta) 1-42 into senile plaques is an established feature of AD neuropathology. Controversy still exists about the amyloid pathway as the initiating mechanism or a mere consequence of the events leading to AD. Nevertheless, Abeta toxicity has been probed in vitro and in vivo and increased production or decreased clearance of Abeta peptides are reported to play a major role in the development of AD. Treatment of neural stem cells with Abeta in vitro induces neuronal differentiation. Increased neurogenesis has been also described in AD patients as well as in amyloid-beta protein precursor (AbetaPP) transgenic mice. Adult neurogenesis is greatly enhanced in young AbetaPP transgenic mice, before other AD-liked pathologies, and reduced in older animals. This increased neurogenesis at young ages might be the first pathology related to AD, which is detectable long before other harmful manifestation of the disease. Therefore, understanding the mechanisms of Abeta-induced neurogenesis will reveal insights into the pathogenesis of AD and may prove useful as an early AD biomarker.
Buchhalter, JR & Dichter, MA in Neuromethods 23: Practical Cell Culture Techniques (eds Boulton, ... more Buchhalter, JR & Dichter, MA in Neuromethods 23: Practical Cell Culture Techniques (eds Boulton, A., Baker, G. & Walz, W.) 241−268 (Humana, Clifton, NJ, 1992). ... Franklin, SB, Elliott, K., Zhu, Y.-S., Wahlestedt, C. & ...
Molecular Brain Research, 1999
Comparing female and male brain structures reveals a variety of sex differences in many vertebrat... more Comparing female and male brain structures reveals a variety of sex differences in many vertebrates. These differences are manifested throughout the brain, in regions such as the hypothalamus, the preoptic area and the amygdala. Some are thought to be induced during the fetal period by the effect of steroid hormones produced in the gonads. It is well-established that fetal androgens, probably through the conversion to estrogen by the enzyme aromatase, masculinize the nervous system and set adult mounting behavior in rodents. However, less is known about molecular mechanisms involved in gender-specific development of the brain. We have taken a broad approach to Ž. isolate sex-specific genes from fetal brain. mRNAs from 18.5 days post-coitum dpc female and male mouse brain were screened with Ž. the classical and the recently developed signal peptide differential display SPDD and with representational difference analysis of cDNA Ž. cDNA-RDA. Two sex-specific cDNAs were isolated, F29 and M17, corresponding to the female-specific Xist gene and the male-specific Smcy gene, respectively.
The Journal of …, 1999
Recent molecular cloning studies by our laboratory and others have identified the existence of a ... more Recent molecular cloning studies by our laboratory and others have identified the existence of a novel rat galanin receptor subtype, GALR2. In the present study, we examined the regional and cellular distribution of GALR2 mRNA in the rat central nervous system (CNS) by in situ hybridization. For comparative purposes, adjacent sections were probed for GALR1 mRNA expression. Our findings indicate that dorsal root ganglia express by far the highest levels of GALR2 mRNA in the rat CNS. Hybridization signal is mainly concentrated over small and intermediate primary sensory neurons. In spinal cord, the large alpha motoneurons of the ventral horn are moderately labeled and several small, but less intensely labeled, cells are scattered throughout the gray matter. In brain sections, the highest levels of GALR2 mRNA are detected in granule cells of the dentate gyrus, in the mammillary nuclei, and in the cerebellar cortex. Moderate levels of GALR2 mRNA are observed in the olfactory bulb, olfactory tubercle, piriform and retrospinal cortices, hypothalamus (namely the preoptic area, arcuate nucleus, and dorsal hypothalamic area), substantia nigra pars compacta, and sensory trigeminal nucleus. Moderate to weak hybridization signal is also present in several other hypothalamic nuclei, specific layers of the neocortex, periaqueductal gray, and several nuclei within the pons and medulla, including locus coeruleus, lateral parabrachial, motor trigeminal, pontine reticular, hypoglossal, vestibular complex, ambiguus, and facial and lateral reticular nuclei. This novel pattern of GALR2 distribution within the rat CNS differs considerably from that of GALR1, suggesting that specific physiologic effects of galanin may be ascribed to the GALR2 galanin receptor subtype.
International review of cytology, 1986
ABSTRACT
The mouse adrenocortical Y-1 cell line expresses a high level of neuropeptide Y1 receptor (NPY-Y1... more The mouse adrenocortical Y-1 cell line expresses a high level of neuropeptide Y1 receptor (NPY-Y1). Moreover the receptor density can be up-regulated by dexarnethasone or down-regulated by cAMP. To determine whether such regulation occurs at the level of gene expression, Y1 receptor mRNA was measured using a reverse transcriptase-competitive PCR method. Dexamethasone treatment increased Yl mRNA in Y-1 cells, whereas the cAMP and ACTH decreased it. We also observed that the amount of Y1 receptor RNA was unaffected by phorbol 12-mylistate 13-acetate, a protein kinase C stimulator, but was abolished in a cell line expressing apolipoprotein E (apoE). The results indicated that NPY-Y 1 receptor mRNA in Y-1 cells is highly regulated by several intracellular messengers. The role of apoE in such regulation is of particular interest in view of evidence that the isoform of the molecule is highly correlated to the age of onset of Alzheimer's disease. The effect observed in the Y-1 cell line which expresses apoE may implicate a possible role of this protein in the process of neuronal death that occurred in the Alzheimer's disease.
The biology of …, 1993
The cardiovascular system is richly innervated by sympathetic nerves containing norepinephrine (N... more The cardiovascular system is richly innervated by sympathetic nerves containing norepinephrine (NE) and neuropeptide Y (NPY). Although NE is considered a major sympathetic neurotransmitter and a primary mediator of cardiovascular functions, the role of NPY is not yet well defined. Over the last several years, evidence has accumulated to indicate that NPY is a sympathetic cotransmitter mediating vasoconstriction independently of catecholamines, as well as being a modulator of autonomic cardiovascular responses (reviews: 1–4). NPY is also abundant in epinephrine-containing chromaffin cells of the adrenal medulla (5) and, under some conditions, may be secreted into the circulation as an adreno-medullary hormone (6). Finally, our (7) and other (8) recent data indicate the extraneuronal presence of NPY, e.g., in platelets, where it may subserve autocrine and paracrine functions in platelet—vascular interactions. Thus, there are at least three potential sources for circulating NPY: the sympathetic nerves, the adrenal medulla, and platelets. The first purpose of this chapter is to discuss the release of NPY from different sources into the cardiovascular system in humans and in other mammalian species, in physiological situations, such as stress, and in disease states, such as hypertension.
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Papers by Claes Wahlestedt