Molecular Neurodegeneration via MedWorm.com

WldS but not Nmnat1 protects dopaminergic neurites from MPP+ neurotoxicity

Molecular Neurodegeneration — Wed, 08 Feb 2012 05:00:00 +0100

Conclusions: Our data suggest that NAD+ and WldS act through separate and possibly parallel mechanisms to protect dopamine axons. As MPP+ is thought to impair mitochondrial function, these results suggest that WldS might be involved in preserving mitochondrial health or maintaining cellular metabolism. (Source: Molecular Neurodegeneration)

Spinal cord trauma and the molecular point of no return

Molecular Neurodegeneration — Wed, 08 Feb 2012 05:00:00 +0100

A mechanical trauma to the spinal cord can be followed by the development of irreversible and progressive neurodegeneration, as opposed to a temporary or partially reversible neurological damage. An increasing body of experimental and clinical evidence from humans and animal models indicates that spinal cord injury may set in motion the development of disabling and at times fatal neuromuscular disorders, whose occurrence is not normally associated with any major environmental event. This outcome appears to be dependent on the co-occurrence of a particular form of mechanical stress and of a genetically-determined vulnerability. This increased vulnerability to spinal cord injury may depend on a change of the nature and of the timing of activation of a number of neuroprotective and neurodestr...

Both common variations and rare non-synonymous substitutions and small insertion/deletions in CLU are associated with increased Alzheimer risk

Molecular Neurodegeneration — Mon, 16 Jan 2012 05:00:00 +0100

Conclusions: We identified a new genetic risk association of AD with rare coding CLU variations that is independent of the 5' common association signal identified in the GWA studies. At this stage the role of these coding variations and their likely effect on the beta-chain domain and CLU protein functioning remains unclear and requires further studies. (Source: Molecular Neurodegeneration)

Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway

Molecular Neurodegeneration — Mon, 09 Jan 2012 05:00:00 +0100

Conclusions: LRRK2 is important for the dynamic regulation of autophagy function in vivo. (Source: Molecular Neurodegeneration)

Adeno-Associated Virus-Mediated Brain Delivery of 5-Lipoxygenase modulates the AD-like phenotype of APP mice

Molecular Neurodegeneration — Thu, 05 Jan 2012 05:00:00 +0100

Conclusions: These data demonstrate that neuronal 5LO plays a functional role in the pathogenesis of AD-like amyloidotic phenotype by modulating the gamma-secretase pathway. They support the hypothesis that this enzyme is a novel therapeutic target for the treatment and prevention of AD. (Source: Molecular Neurodegeneration)

Transgenic neuronal overexpression reveals that stringently regulated p23 expression is critical for coordinated movement in mice

Molecular Neurodegeneration — Wed, 28 Dec 2011 05:00:00 +0100

Conclusions: These results demonstrate that proper level of p23 expression is critical for neuronal function, and perturbing p23 function by overexpression initiates a cascade of cellular reactions in brainstem that leads to severe motor deficits and other neurological problems, which culminate in premature death. The neurological phenotype observed in Hup23 mice highlights significant adverse effects associated with manipulating neuronal expression of p23, a previously described negative modulator of gamma-secretase activity and beta-amyloid production. Moreover, our report has broader relevance to molecular mechanisms in several neurodegenerative diseases as it highlights the inherent vulnerability of the early secretory pathway mechanisms that ensure proteostasis in neurons. (Source: Mo...

The Alzheimer's beta-secretase enzyme BACE1 is required for accurate axon guidance of olfactory sensory neurons and normal glomerulus formation in the olfactory bulb

Molecular Neurodegeneration — Wed, 28 Dec 2011 05:00:00 +0100

Conclusions: Our results demonstrate that BACE1 is required for the accurate targeting of OSN axons and the proper formation of glomeruli in the OB, suggesting a role for BACE1 in axon guidance. OSNs continually undergo regeneration and hence require ongoing axon guidance. Neurogenesis and the regeneration of neurons and axons occur in other adult populations of peripheral and central neurons that also require axon guidance throughout life. Therefore, BACE1 inhibitors under development for the treatment of AD may potentially cause axon targeting defects in these neuronal populations as well. (Source: Molecular Neurodegeneration)

Resorufin Analogs Preferentially Bind Cerebrovascular Amyloid: Potential Use as Imaging Ligands for Cerebral Amyloid Angiopathy

Molecular Neurodegeneration — Thu, 22 Dec 2011 05:00:00 +0100

Conclusions: To our knowledge, resorufin analogs are the fist class of amyloid dye that can discriminate between cerebrovascular and neuritic forms of amyloid. This unique binding selectivity suggests that this class of dye has great potential as a CAA-specific amyloid tracer that will permit non-invasive detection and quantification of CAA in live patients. (Source: Molecular Neurodegeneration)

Adult Hippocampal Neurogenesis and its Role in Alzheimer's Disease

Molecular Neurodegeneration — Thu, 22 Dec 2011 05:00:00 +0100

The hippocampus, a brain area critical for learning and memory, is especially vulnerable to damage at early stages of Alzheimer's disease (AD). Emerging evidence has indicated that altered neurogenesis in the adult hippocampus represents an early critical event in the course of AD. Although causal links have not been established, a variety of key molecules involved in AD pathogenesis have been shown to impact new neuron generation, either positively or negatively. From a functional point of view, hippocampal neurogenesis plays an important role in structural plasticity and network maintenance. Therefore, dysfunctional neurogenesis resulting from early subtle disease manifestations may in turn exacerbate neuronal vulnerability to AD and contribute to memory impairment, whereas enhanced neur...

Microglial p38alpha MAPK is critical for LPS-induced neuron degeneration through a mechanism involving TNFalpha

Molecular Neurodegeneration — Tue, 20 Dec 2011 05:00:00 +0100

Conclusions: The data suggest that selective targeting of p38alpha MAPK signaling should be explored as a potential therapeutic strategy for CNS disorders where overproduction of proinflammatory cytokines is implicated in disease progression. (Source: Molecular Neurodegeneration)

Analysis of striatal transcriptome in mice overexpressing human wild-type alpha-synuclein supports synaptic dysfunction and suggests mechanisms of neuroprotection for striatal neurons

Molecular Neurodegeneration — Tue, 13 Dec 2011 05:00:00 +0100

Conclusion: The results support a key role for SNCA in synaptic function and revealed an apoptotic signature in Thy1-aSyn mice, which together with specific alterations of neuroprotective genes suggest the activation of adaptive compensatory mechanisms that may protect striatal neurons in conditions of neuronal overexpression of SNCA. (Source: Molecular Neurodegeneration)

Aberrant Septin 11 is Associated with Sporadic Frontotemporal Lobar Degeneration

Molecular Neurodegeneration — Tue, 29 Nov 2011 05:00:00 +0100

Conclusions: The proteomic discovery of insoluble SEPT11 accumulation in FTLD-U, along with novel pathological associations, highlights a role for this cytoskeleton-associated protein in the pathogenesis of this complex disorder. (Source: Molecular Neurodegeneration)

Dantrolene is neuroprotective in Huntingtons disease transgenic mouse model

Molecular Neurodegeneration — Fri, 25 Nov 2011 05:00:00 +0100

Dantrolene, a RyanR inhibitor and calcium signalling stabilizer, is identified as a potential agent for the treatment of Huntingdons Disease, further implicating the disturbance of intracellular calcium signalling in the pathogenesis of polyglutamine expansion diseases. (Source: Molecular Neurodegeneration)

Transthyretin and the brain re-visited: Is neuronal synthesis of transthyretin protective in Alzheimer's disease?

Molecular Neurodegeneration — Wed, 23 Nov 2011 05:00:00 +0100

Since the mid-1990's a trickle of publications from scattered independent laboratories have presented data suggesting that the systemic amyloid precursor transthyretin (TTR) could interact with the amyloidogenic beta-amyloid (Abeta) peptide of Alzheimer's disease (AD). The notion that one amyloid precursor could actually inhibit amyloid fibril formation by another seemed quite far-fetched. Further it seemed clear that within the CNS, TTR was only produced in choroid plexus epithelial cells, not in neurons. The most enthusiastic of the authors proclaimed that TTR sequestered Abeta in vivo resulting in a lowered TTR level in the cerebrospinal fluid (CSF) of AD patients and that the relationship was salutary. More circumspect investigators merely showed in vitro interaction between the two mo...

Mitosis-specific phosphorylation of amyloid precursor protein at Threonine 668 leads to its altered processing and association with centrosomes

Molecular Neurodegeneration — Wed, 23 Nov 2011 05:00:00 +0100

Conclusions: The data presented here suggests that cell cycle-dependent phosphorylation of APP may affect its normal cellular function. For example, association of P-APP with the centrosome may affect spindle assembly and cell cycle progression, further contributing to the development of pathology in AD. The experiments with G1/S inhibitors suggest that cell cycle inhibition may impede the development of Alzheimer's pathology by suppressing modification of beta-APP, and thus may represent a novel approach to AD treatment. Finally, the cell cycle regulated phosphorylation and processing of APP into A-beta and the C-terminal fragment suggest that these proteins may have a normal function during mitosis. (Source: Molecular Neurodegeneration)

Superoxide dismutase 1 encoding mutations linked to ALS adopts a spectrum of misfolded states

Molecular Neurodegeneration — Thu, 17 Nov 2011 05:00:00 +0100

Conclusions: Our studies demonstrate how different methods of detecting misfolding and aggregation of mutant SOD1 reveal different forms of aberrantly folded protein. Immunological and biochemical methods can be used in combination to detect soluble and insoluble misfolded forms of mutant SOD1. Our findings support the view that mutant SOD1 can adopt multiple misfolded conformations with the potential that different structural variants mediate different aspects of fALS. (Source: Molecular Neurodegeneration)

Fractalkine/CX3CL1 protects striatal neurons from synergistic morphine and HIV-1 Tat-induced dendritic losses and death

Molecular Neurodegeneration — Thu, 17 Nov 2011 05:00:00 +0100

Conclusions: The results suggest that deficits in fractalkine-CX3CR1 signaling contribute to the synergistic neurotoxic effects of opioids and Tat. Importantly, exogenous fractalkine can selectively protect neurons from the injurious effects of chronic opioid-HIV-1 Tat co-exposure, and this suggests a potential therapeutic course for neuroAIDS. Although the cellular mechanisms underlying neuroprotection are not certain, findings that exogenous fractalkine reduces microglial motility and fails to protect neurons co-cultured with Cx3cr1(-/-) mixed glia suggest that fractalkine may act by interfering with toxic microglial-neuron interactions. (Source: Molecular Neurodegeneration)

Coordinated increase of [gamma]-secretase reaction products in the plasma of some female Japanese sporadic Alzheimer's disease patients : Quantitative analysis of p3-Alc[alpha] with a new ELISA system

Molecular Neurodegeneration — Tue, 08 Nov 2011 05:00:00 +0100

Conclusion: Reagents and procedures have been established that enable extraction of p3-Alc[alpha] from plasma and for quantification of plasma p3-Alc[alpha] levels by ELISA. Some populations of AD subjects apparently show increased levels of both p3-Alc[alpha] and A[beta]40. Quantification of p3-Alc[alpha] level may be useful as a readily accessible biomarker for a population of sporadic AD patients in which disease pathogenesis is associated with either dysfunction of [gamma]-secretase or with a disorder of the clearance of transmembrane domain-derived peptides. (Source: Molecular Neurodegeneration)

Generation and characterization of transgenic mice expressing mitochondrial targeted red fluorescent protein selectively in neurons: modeling mitochondriopathy in excitotoxicity and amyotrophic lateral sclerosis

Molecular Neurodegeneration — Wed, 02 Nov 2011 04:00:00 +0100

Conclusions: These novel transgenic mice will be a useful tool for better understanding the biology of mitochondria in mouse and cellular models of human neurological disorders as exemplified by the mitochondrial swelling and fission seen in excitotoxicity and mouse ALS. (Source: Molecular Neurodegeneration)

Increased 90-kDa ribosomal S6 kinase (Rsk) activity is protective against mutant huntingtin toxicity

Molecular Neurodegeneration — Mon, 31 Oct 2011 04:00:00 +0100

Conclusion: The increase of Rsk levels and activity would act as a compensatory mechanism with capacity to prevent mhtt-mediated cell death. We propose Rsk as a good target for neuroprotective therapies in HD. (Source: Molecular Neurodegeneration)

Dopamine and alpha-synuclein dysfunction in Smad3 null mice

Molecular Neurodegeneration — Thu, 13 Oct 2011 04:00:00 +0100

Conclusions: Smad3 deficiency promotes strong catabolism of DA in the striatum (ST), decrease trophic and astrocytic support to dopaminergic neurons and may induce alpha-synuclein aggregation, which may be related to early parkinsonism. These data underline a role for Smad3 in alpha-synuclein and DA homeostasis, and suggest that modulatory molecules of this signalling pathway should be evaluated as possible neuroprotective agents. (Source: Molecular Neurodegeneration)

Conditional BDNF release under pathological conditions improves Huntington's disease pathology by delaying neuronal dysfunction

Molecular Neurodegeneration — Mon, 10 Oct 2011 04:00:00 +0100

Conclusions: These results indicate that the conditional administration of BDNF under the GFAP promoter could become a therapeutic strategy for HD due to its positive effects on synaptic plasticity. (Source: Molecular Neurodegeneration)

Alzheimer-specific variants in the 3'UTR of Amyloid precursor protein affect microRNA function

Molecular Neurodegeneration — Fri, 07 Oct 2011 04:00:00 +0100

Conclusions: Taken together, our results provide proof-of-principle that APP 3'UTR polymorphisms could affect AD risk through modulation of APP expression regulation, and set the stage for further association studies in genetic and sporadic AD. (Source: Molecular Neurodegeneration)

Elevated CSF levels of TACE activity and soluble TNF receptors in subjects with mild cognitive impairment and patients with Alzheimer's disease

Molecular Neurodegeneration — Thu, 06 Oct 2011 04:00:00 +0100

In this study, we examined TACE in the CSF in 32 AD patients and 27 age-matched healthy controls (HCs). Interestingly, we found that TACE activity was significantly elevated in the CSF from AD patients compared with HCs. Furthermore, we also assayed the CSF levels of TACE cleaved soluble forms of TNFR1 and TNFR2 in the same patients. We found that AD patients had higher levels of both TACE cleaved soluble TNFR1 (sTNFR1) and TNFR2 (sTNFR2) in the CSF compared with aged- and gender-matched healthy controls. Levels of sTNFR1 correlated strongly with the levels of sTNFR2 (rs = 0.567-0.663, p < 0.01). The levels of both sTNFR1 and sTNFR2 significantly correlated with the TACE activity (rs = 0.491-0.557, p < 0.05). To examine if changes in TACE activity and in levels of cleaved soluble TNFRs are...

Selective inhibition of GluN2D-containing N-methyl-D-aspartate receptors prevents tissue plasminogen activator-promoted neurotoxicity both in vitro and in vivo

Molecular Neurodegeneration — Wed, 05 Oct 2011 04:00:00 +0100

Conclusions: In conclusion, tPA exerts noxious effects on neurons by acting on GluN2D-containing NMDAR and pharmacological antagonists of GluN2D-containing NMDAR could be used to prevent the ability of tPA to promote neurotoxicity. (Source: Molecular Neurodegeneration)

Phosphorylation of collapsin response mediator protein-2 disrupts neuronal maturation in a model of adult neurogenesis: Implications for neurodegenerative disorders

Molecular Neurodegeneration — Sat, 24 Sep 2011 04:00:00 +0100

Conclusions: These results reveal a functional mechanism involving microtubule destabilization through which abnormal CDK5 activation and CRMP2 hyperphosphorylation might contribute to defective neurogenesis in neurodegenerative disorders such as HIV encephalitis. (Source: Molecular Neurodegeneration)

Decreased expression of B cell related genes in leukocytes of women with Parkinson's disease

Molecular Neurodegeneration — Fri, 23 Sep 2011 04:00:00 +0100

Conclusions: Our results suggest that the down regulation of genes related to B cell activity reflect the involvement of these cells in PD in Ashkenazi individuals and represents a molecular aspect of gender-specificity in PD. (Source: Molecular Neurodegeneration)

Amyloid beta protein-induced zinc sequestration leads to synaptic loss via dysregulation of the ProSAP2/Shank3 scaffold

Molecular Neurodegeneration — Thu, 22 Sep 2011 04:00:00 +0100

Conclusions: We conclude that sequestration of Zn2+ ions by A significantly contributes to changes in ProSAP2/Shank3 platforms. These changes in turn lead to less consolidated (mature) synapses reflected by a decrease in Shank1 protein levels at the PSD and decreased synapse density in hippocampal neurons. (Source: Molecular Neurodegeneration)

TDP-43 knockdown impairs neurite outgrowth dependent on its target histone deacetylase 6

Molecular Neurodegeneration — Mon, 29 Aug 2011 23:00:00 +0100

Conclusions: TDP-43 deficiency leads to impairment of neurite growth in an HDAC6-dependent manner, thereby contributing to neurodegenerative events in TDP-43 diseases. (Source: Molecular Neurodegeneration)

Alzheimer's disease: synapses gone cold

Molecular Neurodegeneration — Thu, 25 Aug 2011 23:00:00 +0100

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by insidious cognitive decline and memory dysfunction. Synapse loss is the best pathological correlate of cognitive decline in AD and mounting evidence suggests that AD is primarily a disease of synaptic dysfunction. Soluble oligomeric forms of amyloid beta (Abeta), the peptide that aggregates to form senile plaques in the brain of AD patients, have been shown to be toxic to neuronal synapses both in vitro and in vivo. Abeta oligomers inhibit long-term potentiation (LTP) and facilitate long-term depression (LTD), electrophysiological correlates of memory formation. Furthermore, oligomeric Abeta has also been shown to induce synapse loss and cognitive impairment in animals. The molecular underpinnings of these...

Evaluation of the global association between cholesterol-associated polymorphisms and Alzheimer's disease suggests a role for rs3846662 and HMGCR splicing in disease risk

Molecular Neurodegeneration — Wed, 24 Aug 2011 23:00:00 +0100

Conclusions: Cholesterol-associated SNPs outside of APOE confer a global risk for AD. Rs3846662 and rs1532085 are associated with both AD risk and age-of-onset in our dataset. Rs3846662 is associated with HMGCR exon 13 inclusion. Since rs3846662 affects AD risk and age-of-onset as well as statin responsiveness, this SNP may confound clinical trials evaluating the protective effects of statins on AD. (Source: Molecular Neurodegeneration)

A glycine zipper motif mediates the formation of toxic beta-amyloid oligomers in vitro and in vivo.

Molecular Neurodegeneration — Mon, 22 Aug 2011 23:00:00 +0100

Conclusions: Our structure/function studies support the view that the glycine zipper motif present in the C-terminal portion of Abeta plays an important role in the formation of toxic Abeta oligomers. Compounds designed to specifically interfere with formation of the glycine zipper could have therapeutic potential. (Source: Molecular Neurodegeneration)

Mice lacking caspase-2 are protected from behavioral changes, but not pathology, in the YAC128 model of Huntington Disease.

Molecular Neurodegeneration — Thu, 18 Aug 2011 23:00:00 +0100

Conclusions: The rescue of behavioral phenotypes in the absence of pathological improvement suggests that different pathways may be operative in the dysfunction of neural circuitry in HD leading to behavioral changes compared to the processes leading to cell death and volume loss. Inhibition of caspase-2 activity may be associated with symptomatic improvement in HD. (Source: Molecular Neurodegeneration)

Downregulation of CREB expression in Alzheimer's brain and in Abeta-treated rat hippocampal neurons

Molecular Neurodegeneration — Thu, 18 Aug 2011 23:00:00 +0100

Conclusions: Our findings suggest that chronic downregulation of CREB-mediated transcription results in decrease of CREB content in the hippocampal neurons of AD brain which may contribute to exacerbation of disease progression. (Source: Molecular Neurodegeneration)

Renin angiotensin system and gender differences in dopaminergic degeneration

Molecular Neurodegeneration — Mon, 15 Aug 2011 23:00:00 +0100