330 research outputs found
Should I Be Tested for Alzheimer\u27s Disease?
No full textNOTE FROM TED: While some viewers might find this talk helpful as a complementary approach, please do not look to this talk for medical advice. The role of lifestyle in disease remains an ongoing field of study. TEDx events are independently organized by volunteers. The guidelines we give TEDx organizers are described in more detail here: http://storage.ted.com/tedx/manuals/t... Alzheimer’s disease currently affects over 44 million worldwide and has no cure nor effective treatment. For most people over the age of 60, this disease represents their number one fear. But we don’t have to be afraid of Alzheimer’s. By better understanding our genetic risks, and defending ourselves against it with a variety of common sense, everyday activities, we can increase the odds of overcoming this devastating disease. Troy Rohn has been a professor in the Department of Biological Sciences for the past 20 years where he both teaches and has an active research program involving Alzheimer\u27s disease. For the past 10 years, his research program has focused on understanding how inheritance of the APOE4 gene enhances dementia risk at the molecular level. This talk was given at a TEDx event using the TED conference format but independently organized by a local community. Learn more at https://www.ted.com/ted
Remarks and observations on the plain of Troy, made during an excursion in June, 1799 /
No full textSignatures: pi⁴ A-G⁴.Errata: p. [2] at end; p. [1] and [3] at end blank.ESTC(RLIN)Mode of access: Internet.Library copy bound with: Description of the plain of Troy : with a map of that region, delineated from an actual survey : read in French before the Royal Society of Edinburgh, Feb. 21 and 28 and March 21 1791 / by the author, M. Chevalier. Edinburgh : Printed for T. Cadell, 1791. (90-B15413
Observations upon a treatise, entitled A description of the Plain of Troy, by Monsieur Le Chevalier /
No full textErrata: p. [1] at end.Signatures: [A]1 B-H⁴.Includes bibliographical references.ESTC(RLIN)Mode of access: Internet.Library copy bound with: Description of the plain of Troy : with a map of that region, delineated from an actual survey : read in French before the Royal Society of Edinburgh, Feb. 21 and 28 and March 21 1791 / by the author, M. Chevalier. Edinburgh : Printed for T. Cadell, 1791. (90-B15413
Some observations upon the Vindication of Homer, and of the ancient poets and historians, who have recorded the siege and fall of Troy, written by I.B.S. Morritt, esq. /
No full textFinal leaf blank, with errata slip attached.Signatures: A² B-N⁴ [M]1.ESTC(RLIN)Mode of access: Internet.Library copy bound with: Description of the plain of Troy : with a map of that region, delineated from an actual survey : read in French before the Royal Society of Edinburgh, Feb. 21 and 28 and March 21 1791 / by the author, M. Chevalier. Edinburgh : Printed for T. Cadell, 1791. (90-B15413
Highly efficient small interfering RNA delivery to primary mammalian neurons induces MicroRNA-like effects before mRNA degradation
No full textThe study of protein function in neurons has been hindered by the lack of highly efficient, nontoxic methods of inducing RNA interference in such cells. Here we show that application of synthetic small interfering RNA( siRNA) linked to the vector peptide Penetratin1 results in rapid, highly efficient uptake of siRNA by entire populations of cultured primary mammalian hippocampal and sympathetic neurons. This treatment leads to specific knock-down of targeted proteins within hours without the toxicity associated with transfection. In contrast to current methods, our technique permits study of protein function across entire populations with minimal disturbance of complex cellular networks. Using this technique, we found that protein knock-down ( evident after 6 hr) precedes any decrease in targeted message ( evident after 24 hr), suggesting an early, translational repression by perfectly targeted siRNAs.PT: J; CR: BARTEL DP, 2004, CELL, V116, P281 BERTRAND E, 2001, MOL CELL NEUROSCI, V18, P503 DEROSSI D, 1994, J BIOL CHEM, V269, P10444 DOENCH JG, 2003, GENE DEV, V17, P438 DOSTIE JE, 2003, RNA, V9, P180 ELBASHIR SM, 2001, EMBO J, V20, P6877 FINK CC, 2003, NEURON, V39, P283 FIRE A, 1998, NATURE, V391, P806 GAUDILLIERE B, 2002, J BIOL CHEM, V277, P46442 HANNON GJ, 2002, NATURE, V418, P244 HUTVAGNER G, 2002, SCIENCE, V297, P2056 JOHNSTON RJ, 2003, NATURE, V426, P845 JOLIOT A, 2004, NAT CELL BIOL, V6, P189 KHVOROVA A, 2003, CELL, V115, P209 KIM J, 2004, P NATL ACAD SCI USA, V101, P360 KRICHEVSKY AM, 2002, P NATL ACAD SCI USA, V99, P11926 KRICHEVSKY AM, 2003, RNA, V9, P1274 LAI EC, 2003, CURR BIOL, V13, R925 LLAVE C, 2002, SCIENCE, V297, P2053 MURATOVSKA A, 2004, FEBS LETT, V558, P63 OMI K, 2004, FEBS LETT, V558, P89 RABACCHI SA, 2004, NEUROBIOL AGING, V25, P1057 REYNOLDS A, 2004, NAT BIOTECHNOL, V22, P326 SAXENA S, 2003, J BIOL CHEM, V278, P44312 SCHERER LJ, 2003, NAT BIOTECHNOL, V21, P1457 SCHWARZ DS, 2003, CELL, V115, P199 THEODORE L, 1995, J NEUROSCI, V15, P7158 TOROCSIK B, 2002, J NEUROSCI, V22, P8971 TROY CM, 1994, P NATL ACAD SCI USA, V91, P6384 TROY CM, 1996, J NEUROSCI, V16, P253 TROY CM, 1996, P NATL ACAD SCI USA, V93, P5635 TROY CM, 2001, J NEUROSCI, V21, P5007 TROY CM, 2002, J BIOL CHEM, V277, P34295 VICKERS TA, 2003, J BIOL CHEM, V278, P7108 ZENG Y, 2003, P NATL ACAD SCI USA, V100, P9779; NR: 35; TC: 22; J9: J NEUROSCI; PG: 7; GA: 869ZASource type: Electronic(1
Proteolytic Cleavage of Apolipoprotein E4 as the Keystone for the Heightened Risk Associated with Alzheimer’s Disease
No full textAlzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by microscopic lesions consisting of beta-amyloid plaques and neurofibrillary tangles (NFTs). The majority of cases are defined as sporadic and are likely caused by a combination of both genetic and environmental factors. Of the genetic risk factors identified, the 34 kDa protein, apolipoprotein (apo) E4, is of significant importance as APOE4 carriers account for 65%–80% of all AD cases. Although apoE4 plays a normal role in lipoprotein transport, how it contributes to AD pathogenesis is currently unknown. One potential mechanism by which apoE4 contributes to disease risk is its propensity to undergo proteolytic cleavage generating N- and C-terminal fragments. The purpose of this review will be to examine the mechanisms by which apoE4 contributes to AD pathogenesis focusing on the potential loss or gain of function that may occur following cleavage of the full-length protein. In this context, a discussion of whether targeting apoE4 therapeutically is a rationale approach to treating this disease will be assessed
Intermittent Fasting Promotes Fat Loss with Lean Mass Retention, Increased Hypothalamic Norepinephrine Content, and Increased Neuropeptide Y Gene Expression in Diet-Induced Obese Male Mice
No full textClinical studies indicate alternate day, intermittent fasting (IMF) protocols result in meaningful weight loss in obese individuals. To further understand the mechanisms sustaining weight loss by IMF, we investigated the metabolic and neural alterations of IMF in obese mice. Male C57/BL6 mice were fed a high-fat diet (HFD; 45% fat) ad libitum for 8 weeks to promote an obese phenotype. Mice were divided into 4 groups and either maintained on ad libitum HFD (HFD), received alternate day access to HFD (IMF- HFD), switched to ad libitum low fat diet (LFD; 10% fat), or received IMF of LFD (IMF- LFD). After 4 weeks, IMF-HFD (~13%) and IMF-LFD (~18%) had significantly lower body weights than HFD. Body fat was also lower (~40-52%) in all diet interventions. Lean mass was increased in the IMF-LFD (~12-13%) compared with HFD and IMF-HFD groups. Oral glucose tolerance AUC was lower in the IMF-HFD (~50%), whereas insulin tolerance AUC was reduced in all diet interventions (~22-42%). HPLC measurements of hypothalamic tissue homogenates indicated higher (~55-60%) norepinephrine (NE) content in the anterior regions of the medial hypothalamus of IMF compared with ad libitum fed groups, whereas NE content was higher (~19-32%) in posterior regions in the IMF-LFD group only. Relative gene expression of Npy in the arcuate nucleus was increased (~65-75%) in IMF groups. Our novel findings indicate that intermittent fasting produces alterations in hypothalamic NE and NPY, suggesting an involvement in the counter regulatory processes of short-term weight loss are associated with an IMF dietary strategy.Peer reviewe
Gq Protein-Coupled Membrane-Initiated Estrogen Signaling Rapidly Excites Corticotropin-Releasing Hormone Neurons in the Hypothalamic Paraventricular Nucleus in Female Mice
No full textCRH neurons in the hypothalamic paraventricular nucleus (PVN) play a central role in regulating the hypothalamus-pituitary-adrenal (HPA) axis and are directly influenced by 17β-estradiol (E2). Although compelling evidence has suggested the existence of membrane-associated estrogen receptors (mERs) in hypothalamic and other central nervous system neurons, it remains unknown whether E2 impacts CRH neuronal excitability through this mechanism. The purpose of the current study is to examine the existence and function of mER signaling in PVN CRH neurons. Whole-cell recordings were made from CRH neurons identified by Alexa Fluor 594 labeling and post hoc immunostaining in ovariectomized female mice. E2 (100nM) rapidly suppressed the M-current (a voltage-dependent K(+) current) and potentiated glutamatergic excitatory postsynaptic currents. The putative Gq-coupled mER (Gq-mER) characterized in hypothalamic proopiomelanocortin neurons initiates a phospholipase C-protein kinase C-protein kinase A pathway; therefore, we examined the involvement of this pathway using selective inhibitors. Indeed, the ER antagonist ICI 182780 and inhibitors of Gq-phospholipase C-protein kinase C-protein kinase A blocked E2's actions, suggesting dependence on the Gq-mER. Furthermore, STX, a selective ligand for the Gq-mER, mimicked E2's actions. Finally, to examine the in vivo effect of Gq-mER activation, E2 or STX injection increased c-fos expression in CRH neurons in the PVN, suggesting CRH neuronal activation. This corresponded to an increase in plasma corticosterone. We conclude that the Gq-mER plays a critical role in the rapid regulation of CRH neuronal activity and the HPA axis. Our findings provide a potential underlying mechanism for E2's involvement in the pathophysiology of HPA-associated mood disorders.Peer reviewe
Caspase Cleavage of the Amyloid Precursor Protein is Prevented After Overexpression of Bcl-2 in a Triple Transgenic Mouse Model of Alzheimer’s Disease
No full textA recent study demonstrated the lack of beta-amyloid (Aβ) plaque formation and accumulation of the amyloid precursor protein (APP) in a triple transgenic mouse model of Alzheimer’s disease (3xTg-AD) following overexpression of the anti-apoptotic protein, Bcl-2 (Rohn et al., J. Neurosci. 28: 3051-9, 2008). The supposition from that study was the accumulation of APP resulted from a decrease in caspase-mediated processing of APP. To determine a direct role for the caspase-cleavage of APP in 3xTg-AD mice, we designed a site-directed caspasecleavage antibody to APP and demonstrated it is a specific marker for caspase-cleaved APP. Application of this antibody revealed neuronal staining in the hippocampus and subiculum of 3xTg-AD mice. These results were confirmed utilizing a similar site-directed antibody to caspase-cleaved APP (APPneo). The caspase cleavage of APP as well as the formation of extracellular Aβ plaques was prevented in 3xTg-AD animals overexpressing Bcl-2. These results provide further support that caspases play a proximal role in promoting the pathology associated with AD
Pigmentation Effects of ApoE4 Fragmentation In Transgenic Zebrafish
No full textAlzheimer’s disease (AD) is a progressive, fatal neurodegenerative disorder, and the most common cause of dementia. In addition to advancing age, there are known genetic risk factors associated with AD. Of the genetic risk factors identified, the 34 kDa protein apolipoprotein (Apo) E4 is significant, as ApoE4 carriers account for 65-80% of all AD cases. Recent data from the Rohn lab suggests that a 151 amino-terminal fragment of ApoE4 (nApoE41-151) can traffic to the nucleus, leading to toxicity and expression of inflammatory genes. We developed a stable zebrafish line through Tol2 transgenesis by creating a fusion construct that links the ApoE41–151 fragment with a self-cleaving 2A peptide and mCherry reporter. F2 homozygous mutants showed standard cardiac expression of the reporter and fragment, but about 10% of them also showed a significant loss of pigmentation, paralleling albinism. Quantitative image analysis demonstrated that pigmented area measurements in mutants were substantially lower than those in wild-type controls (p = 0.03) and approached the levels of true albino zebrafish (p = 0.039). We hypothesize that ApoE41–151 disrupts pigment cell development through interference with bone morphogenetic protein (BMP) signaling, which is vital for neural crest-derived melanophore differentiation. Zebrafish serve as a valuable research model to study systemic effects of Alzheimer’s-related genetic risk factors, and demonstrate that ApoE4 neurotoxicity can cause disrupted pigmentation
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