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Neurodegeneration

QuestionAnswer
Ehrnhoefer et al 2011 Review: HD begins with loss of medium spiny neurons in the striatum. AD begins with loss of large pyramidals in area CA1 (hippocampus). Protein misfolding in both diseases. AD and HD transfected cell models have enhanced NMDA currents (excitotoxicity?)
Kitazawa et al 2004 Review: AD inflammation involves activated microglia and reactive astrocytes. Amoeboid microglia may facilitate progression of tangles. Microglial cytokines thought to activate several proteins linked to tau phosphorylation.
Li et al 2003 IL1 shown to cause tau phosphorylation. Effects of activated microglia on cocultured neuronal cells, mimicked by IL-1, abrogated by IL-1 antagonist. Inhibition of p38-MAPK also removed effects. Western blot to measure phosphorylated tau.
Stewart et al 1997 Showed reduced incidence of Alzheimers in patients regularly taking NSAIDs. Prospective cohort study
Mackenzie & Munoz 1998 Non-demented NSAID users had a 3x reduction in activated microglia versus non-demented non-NSAID users. Although did say that despite reduced number of microglia the number of senile plaques was unaltered between the NSAID users and non-users
Morton & Edwardson 2001 Complexin II found to be decr in all brain regions of R6/2 HD model compared to wt littermate. Complexin found in neuronal inclusions. alphaSNAP depleted after 14 weeks, may compensate as complexin competes for SNARE binding, involved in vesicle release.
Morton et al 2009 Mice with repeats 200+ were found to be affected less early then some with shorter repeats. Super-long repeats increased the levels of extranuclear inclusions not normally seen until end stage huntingtons.
Wheeler et al 2003 Knocked out DNA repair enzyme Msh2, thought its mechanism would lend itself to CAG repeat expansion. Knockouts had decr CAG instability & slowed progress to disease milestone (nuclear huntingtin accumulation). No behaviour measured (better end point?)
Mullard 2012 (only author) Antibodies against amyloid often cause cerebral oedema, may be necessary. New plan is to target patients before symptoms appear. Some companies going with non-specific antibodie (AB42 monomers, oligomers & fibrils) as they dont know which target is best.
Nikolaev et al 2009 APP & death receptor 6 activate apoptosis through caspases. Cleaved N terminal of APP is a DR6 ligand. Cleavage by B secretase after deprivation of trophic factors, needs a further cleavage (which we know little about) to make it a better DR6 ligand.
Jonsson et al 2012 Polymorphism in APP (A673T) protects against Alzheimers and cognitive decline with age although greater number of carriers would aid characterisation (only had 41 with lrage variation in the group). Polymorhpism decr BACE cleavage of APP (western blot)
Kaplan et al 2007 Showed how expansion of CAG repeat might remain silent for years until passing the threshold of pathological length (proposed to be around 115 repeats). Homozygs would have a lower deviation of repeats, so same age of onset but all cells hit at once.
Brion et al 2010 Overexpression of tau creates tangles, synapse loss and neuronal death. X-breeding tangle mice with plaque mice increases tangle pathologies (cross-talk). Acute lithium reduced tau phosphorylation and stopped tangle formation, no change in motor deficits.
Arriagada et al 1992 Tangles but not plaques mirror the duration and severity of AD. 10 patients, 13 brain regions each, quite a bit of scatter, could do with more patients. Tangles correlated with both duration and severity of disease, plaques did not.
Rapoport et al 2002 Showed that tau knockout mice are more resistant to neurotoxicity following addition of fibrillar AB40 to the culture medium. Death increased to baseline by transfection of human tau into tau KO mice
Schellenberg & Montine 2012 Review: Mutant presenilin changes y-secretase product from AB40 to AB42. ApoE has roles in AB trafficking and synaptic function, ApoE2 is protective, E4 is a risk factor. ApoE may help clear AB. Inflammation proteins implicated by GWAS.
Wogulis et al 2005 Addition of monomer speeds development of neurotoxic AB fibrils. Fibrils were added to culture and allowed to bind, these were non-toxic until monomer was provided to expand the fibrils. Cells were not killed by fibrils unless monomer was present
Goodman et al 2011 HD patients record no sleep issues in questionnaires, but spend more time in stages 1 and 2, reduced stage 4 and REM sleep. 9 patients, early in disease. Shifted stages regularly. Difficult to exclude stress (lab environment, HD diagnosis)
Bezprozvanny et al 2004 Review: Dysfunctional calcium handling in HD cells, could be NMDAR and IP3R overactivity challenging less resistant mitochondria. IP3R is sensitised by long repeats, mitochondria taken from HD animals/humans open MPTP at lower ca concentrations
DiFiglia et al 1995 Huntingtin in the brain is usually cytoplasmic and associated with vesicles in the brains of humans and rats. Used antibody to HTT and membrane fractioning for comparison with known vesicle/membrane proteins. Western blot & immunohistochemistry
Sharp et al 1995 Huntingtin is expressed in virtually all tissues. Slight enrichment in cerebral cortex and cerebellum. Backs up cytoplasmic and vesicle localisation. Western blot and immunohistochemistry
Dragatsis et al 2000 Used delayed inactivation of huntingtin gene, showed cell death (progressive over a long period, as in disease). Indicates that loss of function contributes to disease phenotype. Conception KOs show embryonic lethality. CamKIIa linked to cre
Goedert et al 1988 Identification of human tau gene, which produces the paired helical filament seen in AD. Found using cDNA libraries from frontal cortex of AD patient, screened for a sequence derived from purification of tau protein.
Jung & Bonini 2007 Dysfunction of CREB binding protein alters repeat instability in Drosophila PolyQ disease model. Decr gene dose of CBP (-/+) incr instabiliy across generations, also altered response to DNA damage (role in DNA repair).
Kazantsev et al 1999 Pathological glutamine repeats sequester other glutamine repeats and also CBP. Insoluble, detergent-resistant complexes form between expanded and normal Glutamine repeats (CBP is one of the latter)
Leavitt et al 2006 Overexpressing normal huntingtin may be protective as it sequesters mutant HTT and also protects against excitotoxicity. YAC18 mice overexpress wt HTT and less neurons died after NMDA was applied, YAC72 (longer repeat) reduced neuronal survival.
McCampbell et al 2000 CBP is sequestered into HD neuronal inclusions (used Immhistchem). Western blot showed less soluble CBP. Overexpression of CBP is protective against polyglutamine induced cell death (may mean loss of function when sequestered by mutant HTT is important).
Nucifora et al 2001 CBP is redistributed from normal regions to inclusions (immhistchem). CBP glutamine repeats are reqd for mislocalisation due to mutant HTT. Overexpression of CBP (particularly CBP w/o polyQ repeat) protected against toxicity due to N terminal frag of HTT.
Preisinger et al 1999 First evidence of sequestration of normal polyQ repeats by abnormal PolyQ repeats when cotransfected, showed redistribution of the protein within cells. Led to CBP studies.
Ross & Poirier 2004 Most, if not all, neurodegenerative diseases show inclusions. Similarities of these diseases may indicate that we need to look for ways in which they differ, as the stereotypical response may well be protective.
Shelbourne et al 2007 Shows expansion of repeats without cell division, particularly in cells affected first in HD. DNA analysed from individual, laser-dissected, cells
Steffan et al 2000 P53 is found in huntingtons inclusions as is CBP, found by SDS PAGE following addition of tagged expanded HTT. Looked at downstream targets of p53 regulation and found genes normally repressed by p53 were upregulated such as MDR1 (p-glycoprotein)
Tini et al 2002 Links CBP to DNA repair by CBP binding to thymine DNA glycosylase. Explains the results of Jung 2007 which found decr dose of CBP increased instability across generations and also altered DNA repair mechanisms
Yang et al 2002 Created soluble polyQ repeats and tagged them with a nuclear localisation sequence. Nuclear polyQ sequences were more toxic than other sequences directed to the nucleus and the equivalent untargetted sequences (Used transfection to PC12 cells)
Cuesta et al 2012 Methamphetamine adds a 2nd component to circadian rhythm. In a mouse model of Huntingtons methamphetamine causes a total breakdown of routine (no 2nd component). Defect is present before other symptoms. Unable to show this component in humans, ethics.
Maywood et al 2010 Peripheral clocks are dysregulated in a R6/2 HD mice. Cry1 rhythm was lost in liver although other rhythms still intact. Food can still train sleep routines and this was used to restore liver cycling and normal behavioural cycles.
Morton et al 2005 R6/2 mice have dysregulated SCN clock genes as do human HD patients. This is accompanied by disrupted sleep cycles. Measured activity using an actiwatch. In situ hybridisation was used for mouse gene expression.
Pallier & Morton 2009 Drugs (short acting benzos) used to restore normal sleep/wake in R6/2 mice. Improved cognitive function (measured by two choice swim tank learning - swim to the correct end)
The Huntington’s Disease Collaborative Research Group 1993 Found HD gene using a large community with high incidence around Lake Maricaibo, Venezuela
Cramer et al 2012 Showed that Bexarotene (RXR agonist) induced removal of AB plaques and improved nesting behaviour/olfactory recognition. Thought to activate LXRs/PPARy (dimers with RXR) and induce ApoE clearance. 50% plaque reduction in 72 hrs.
Jin et al 2013 Rosiglitazone (PPARy agonist) is beneficial in cultures and mouse models of HD. Incr rotarod performance and incr BDNF (normally decr in HD mice. PPARy mRNA decr in striatum of HD mice. Think rosi was protective, rather than actively reversing disease
Li et al 2008 Found that mRNA CAACAG repeats are less toxic than CAGCAG in drosophila, both encode glutamine repeats although the effect was also seen when repeats were in 3' UTR, indicating mRNA toxicity. CAACAG possibly less prone to expansion in non-dividing cells?
Dragatsis et al 2009 Showed that super-long R6/2 repeats resulted in reduced mRNA and protein levels (~33% normal). Proposed due to altered DNA structure restricting access to the gene.
Sterniczuk et al 2010 Showed that a mouse model of AD (triple transgenic - Presenilin, APP and tau) showed loss of circadian rhythm similar to that seen in humans, general decrease in activity as well
Created by: Jonmassie