Investigating the Contribution of Amyloid Precursor Protein (APP) to Pathology in a Mouse Model of Amyotrophic Lateral Sclerosis (ALS) PDF Download
Are you looking for read ebook online? Search for your book and save it on your Kindle device, PC, phones or tablets. Download Investigating the Contribution of Amyloid Precursor Protein (APP) to Pathology in a Mouse Model of Amyotrophic Lateral Sclerosis (ALS) PDF full book. Access full book title Investigating the Contribution of Amyloid Precursor Protein (APP) to Pathology in a Mouse Model of Amyotrophic Lateral Sclerosis (ALS) by J. Barney N. B. Bryson. Download full books in PDF and EPUB format.
Author: J. Barney N. B. Bryson Publisher: ISBN: Category : Amyloid beta-protein precursor Languages : en Pages : 426
Book Description
In Amyotrophic Lateral Sclerosis (ALS), neuromuscular junction (NMJ) dysfunction and degeneration of spinal motor neurons causes progressive loss of skeletal muscle function, culminating in paralysis and ultimately death. Upregulation of amyloid beta (A4) precursor protein (APP) in muscle fibres coincides with symptom onset in both sporadic ALS (sALS) patients and the SOD1G93A mouse model of familial ALS. -- The results of this Thesis provide further characterization of this reactive APP response in muscle tissue from SOD1G93A mice, which revealed a clear correlation between the reactive APP-response and hallmarks of disease progression. Moreover, the results presented in this Thesis demonstrate that genetic ablation of APP in SOD1G93A mice significantly improved multiple disease parameters, including: NMJ innervation; motor function; muscle contractile characteristics; motor unit and motor neuron survival. Therefore these results strongly suggest that endogenous APP actively contributes to ALS-like pathology in SOD1G93A mice. Additionally, the results presented here demonstrate that [beta]-Amyloid (AP) peptides occur at elevated levels in spinal cord tissue and form aggregates within motor neurons in (120d) SOD1G93A mice. -- Along with previous observations of the reactive APP response in muscle tissue and accumulation of Ap peptides in motor neurons in cases of sALS, the results presented in this Thesis therefore suggest that APP upregulation and/or its amyloidogenic processing could contribute to ALS pathology irrespective of the initial trigger. Thus, targetting [sic] APP production or processing may provide a novel therapeutic strategy for ALS.
Author: J. Barney N. B. Bryson Publisher: ISBN: Category : Amyloid beta-protein precursor Languages : en Pages : 426
Book Description
In Amyotrophic Lateral Sclerosis (ALS), neuromuscular junction (NMJ) dysfunction and degeneration of spinal motor neurons causes progressive loss of skeletal muscle function, culminating in paralysis and ultimately death. Upregulation of amyloid beta (A4) precursor protein (APP) in muscle fibres coincides with symptom onset in both sporadic ALS (sALS) patients and the SOD1G93A mouse model of familial ALS. -- The results of this Thesis provide further characterization of this reactive APP response in muscle tissue from SOD1G93A mice, which revealed a clear correlation between the reactive APP-response and hallmarks of disease progression. Moreover, the results presented in this Thesis demonstrate that genetic ablation of APP in SOD1G93A mice significantly improved multiple disease parameters, including: NMJ innervation; motor function; muscle contractile characteristics; motor unit and motor neuron survival. Therefore these results strongly suggest that endogenous APP actively contributes to ALS-like pathology in SOD1G93A mice. Additionally, the results presented here demonstrate that [beta]-Amyloid (AP) peptides occur at elevated levels in spinal cord tissue and form aggregates within motor neurons in (120d) SOD1G93A mice. -- Along with previous observations of the reactive APP response in muscle tissue and accumulation of Ap peptides in motor neurons in cases of sALS, the results presented in this Thesis therefore suggest that APP upregulation and/or its amyloidogenic processing could contribute to ALS pathology irrespective of the initial trigger. Thus, targetting [sic] APP production or processing may provide a novel therapeutic strategy for ALS.
Author: C.L. Masters Publisher: Springer Science & Business Media ISBN: 3662011352 Category : Science Languages : en Pages : 277
Book Description
This book summarizes the last ten years' research on Alzheimer's disease. Genetic mutations in the gene which codes for amyloid precursor protein (APP) have now been shown to cause Alzheimer's disease in some families. Other genetic loci are now being discovered which relate to Alzheimer's disease in some families. Understanding the normal structure and function of the APP gene product will eventually provide avenues for developing specific therapeutic strategies targeted at the amyloid deposition in the Alzheimer's disease brain. Drugs which can inhibit or dissolve the amyloid, affect the synthesis and proteolysis of APP, or which regulate the activity of the APP gene all hold the promise of eventually yielding an effective treatment for Alzheimer's disease.
Author: Claire Carmen Ku Publisher: ISBN: 9781267013552 Category : Languages : en Pages : 65
Book Description
The amyloid cascade hypothesis states that altered processing of amyloid precursor protein (APP) leads to increased production of amyloid-beta 42 (A[beta]42). A previous study has shown that mice over-expressing human A[beta]42 develop amyloid deposits with age, but whether this process is attenuated in APP deficient mice is unknown. We characterized amyloid-associated pathology in young (3-6 month) and old-age (12-15 month) BRI-A[beta]42 mice that overexpress A[beta]42 in the presence or absence of endogenous APP. 6E10 immunostaining and Thioflavin S staining revealed that old-age BRI-A[beta]42; APP mice developed significant levels of amyloid deposits in the hippocampus, but APP deficiency did not attenuate the levels of amyloid burden. Using an A[beta]42 sandwich ELISA, we found that BRI-A[beta]42; APP mice expressed soluble and insoluble A[beta]42 in the hemibrain. Soluble A[beta]42 levels were maintained throughout age, but old-age BRI-A[beta]42; APP mice produced 7 to 15 fold higher levels of insoluble A[beta]42 than the young-age group. Previous groups have demonstrated that A[beta] and APP can mediate neurotoxicity in vitro, but whether this interaction also contributes to synaptic damage in vivo is unknown. We tested whether APP is essential for A[beta]-induced synaptic damage in vivo by assessing the levels of two synaptic proteins in BRI-A[beta]42; APP mice : synaptophysin and PSD-95. Using western blotting, we found that there was no change in synaptic protein levels in BRI-A[beta]42; APP mice, so we did not find an APP-dependent effect on synaptic damage. Taken together, these results show that absence of APP does not mediate amyloid-associated pathology in BRI-A[beta]42; APP mice.
Author: Pik Kay Chan Publisher: ISBN: Category : Languages : en Pages : 120
Book Description
Abnormal intracellular protein inclusions are consistently observable in the motor neurons affected by amyotrophic lateral sclerosis (ALS), also commonly referred as Lou Gehrig's disease. This disease was named after the famous Hall of Fame baseball player, Lou Gehrig, who suddenly experienced loss of physical strength and was diagnosed with ALS. The most prevalent hypothesis regarding the mechanism of ALS points to a toxic gain of function resulting from protein misfolding and aggregation. In the SOD1-ALS transgenic mouse model, protein aggregates composed of primarily full length apo SOD1 are consistently found in the spinal cords of mice exhibiting ALS symptoms. Moreover, these aggregates possess a filamentous structure, suggesting the involvement of SOD1 amyloid fibril in ALS pathology. Research on understanding the formation mechanism of SOD1 fibrils spurred over the past few years. Scientists are now convinced that the demetallated form of SOD1 is the most susceptible to aggregation. In this dissertation, we sought to understand the molecular mechanism by which apo SOD1 rearranges to adopt the fibrillar structure, seek SOD1 amyloid inhibitors as potential therapeutic leads, and use small molecules to modulate and stabilize SOD1 oligomeric intermediates from the amyloid pathway that have never been characterized before. We found that the SOD1 amyloid core is composed of the N-terminal sequence 1-63. The N-terminal tryptic fragment 1-69 is consistently the most trypsin resistant in all the fibrils examined, including WT and six SOD1 mutants. WT fibril displays regular twist pattern along the lateral axis with an average helical pitch distance of 62 nm. While some mutants (L38V, G93A, and G93S) have similar twist pattern as WT, a single point mutation resides within the fibril core can alter the overall amyloid morphology. This is most evident in mutants such as G37R and G41D. We successfully discovered several SOD1 amyloid inhibitors. Studies from a selection of SOD1 amyloid inhibitors (non-SOD1 synthetic peptides and small molecules) suggest that although peptides exhibiting a beta-strand conformation, such as DpV16 and DpV19, effectively inhibit SOD1 amyloid formation, peptides lacking beta-strand secondary structure, such as AzV31 and colivelin-tat are also effective. Out of all the inhibitors tested, only small molecules such as EGCG (a green tea derived flavonoid) and CLR01 (a molecular tweezer) formed stable oligomers with SOD1. SOD1 oligomers were never observed with peptide inhibitors. DpV16 was able to inhibit the initiation of fibrillation by reduced apo SOD1 but had no effect on the elongation phase, suggesting that it might prevent the formation of amyloid-competent nuclei. For the first time, we characterized SOD1 oligomers isolated from the in-vitro fibrillation assay. These CLR01-stabilized oligomers have an estimated molecular mass of 87,000 and exhibit a significant amount of beta-sheet content.
Author: Publisher: ScholarlyEditions ISBN: 148169183X Category : Medical Languages : en Pages : 194
Book Description
Proteins—Advances in Research and Application: 2013 Edition is a ScholarlyBrief™ that delivers timely, authoritative, comprehensive, and specialized information about ZZZAdditional Research in a concise format. The editors have built Proteins—Advances in Research and Application: 2013 Edition on the vast information databases of ScholarlyNews.™ You can expect the information about ZZZAdditional Research in this book to be deeper than what you can access anywhere else, as well as consistently reliable, authoritative, informed, and relevant. The content of Proteins—Advances in Research and Application: 2013 Edition has been produced by the world’s leading scientists, engineers, analysts, research institutions, and companies. All of the content is from peer-reviewed sources, and all of it is written, assembled, and edited by the editors at ScholarlyEditions™ and available exclusively from us. You now have a source you can cite with authority, confidence, and credibility. More information is available at http://www.ScholarlyEditions.com/.
Author: Chelsea Cavanagh Publisher: ISBN: Category : Languages : en Pages :
Book Description
"Since the advanced stages of Alzheimer's disease (AD) have proven to be difficult to treat, investigating ways to prevent AD has become a priority for the research community. Although neuroinflammation is commonly associated with amyloid plaque deposits and neurodegeneration that are characteristic of advanced stages, emerging evidence suggests that inflammatory mediators may play a role in the early development of AD pathology. Importantly, inflammatory mediators such as the pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), have important effects modulating synaptic function. Therefore, TgCRND8 mice, which overexpress a mutated form of the human amyloid precursor protein, were investigated at a prodromal stage to study whether TNF-alpha may be contributing to alterations in synaptic function and precipitating alterations in cognitive performance.Western blot and ELISA experiments indicated a significant increase in hippocampal TNF-alpha expression in 1-month-old TgCRND8 mice before plaque deposition that correlated with levels of the Beta-C-terminal fragment, the precursor to amyloid-beta. Cluster of differentiation 11b labeling indicated changes in microglial morphology toward an activated state, suggesting that these cells may be a putative source of the observed TNF-alpha increase during this prodromal stage of AD-like pathology. While TNF-alpha is recognized for its role in the immune system, this cytokine has neuromodulatory actions as well and modulates the insertion of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in synapses to increase glutamatergic transmission under conditions of low activity. Therefore, the pre-plaque increase in TNF-alpha may affect transmission at glutamate synapses and precipitate synaptic pathologies. To test the hypothesis that TNF-alpha is contributing to hyperexcitability of glutamate synapses and alterations in cognitive function, hippocampal synaptic and cognitive function were compared between TgCRND8 mice and control littermates at the 1-month time point and the effects of a soluble dominant-negative TNF-alpha inhibitor, XPro1595, were examined. Pre-plaque TgCRND8 mice exhibited increased basal synaptic function and long-term potentiation that were reversed by XPro1595 treatment. In vivo XPro1595 treatment also reversed the enhanced performance of 1-month-old TgCRND8 mice in a hippocampus-dependent inhibitory avoidance task. Although synaptic deficits are commonly found in animal models of amyloidosis, it is unclear how amyloid pathology may impair synaptic function. In some amyloid mouse models of AD, however, synaptic deficits are preceded by hyperexcitability of glutamate synapses. To study whether the early TNF-alpha-associated enhancement of glutamatergic transmission was responsible for the development of later synaptic deficits 1-month-old TgCRND8 mice were treated for 4 weeks with XPro1595. This targeted treatment prevented deficits in basal glutamatergic transmission otherwise apparent at age 6 months. These findings suggest that the increase in TNF-alpha before amyloid plaque formation could be an early process leading to the hyperexcitability of glutamate synapses, which leads to alterations in cognitive function. In this mouse model at least, reversing the hyperexcitability of glutamate synapses via TNF-alpha blockade before the onset of amyloid plaque formation prevented later synaptic deficits. " --
Author: E. Edet-Amana Publisher: ISBN: Category : Languages : en Pages :
Book Description
Recent evidence has shown that non-neuronal cells within the CNS play a role in motoneuron degeneration in ALS. However, while it is accepted that various muscles are differentially affected within the disease, it is still unclear whether muscle has a causal role in ALS. In this Thesis, using a mouse model of ALS (mutant SOD1 transgenic mice), I examined muscle and NMJ pathology in two different muscle types, at various stages of disease progression. Using morphological and functional markers of innervation, I found that mSOD1- mediated pathology was present in fast-twitch muscles of mSOD1 mice prior to motoneuron degeneration. This occurred at a time when slow-twitch muscles remain innervated. This difference in the vulnerability of fast-twitch and slow-twitch muscles to disease was reflected in a differential heat shock response (HSR), with the slow-twitch soleus muscle displaying higher heat shock protein (hsp) levels over a longer duration of disease than the fast-twitch TA muscle. Equally, examination of the NOS response revealed a significant difference in nNOS expression between the fast-twitch TA and slow-twitch soleus muscles. Furthermore, fast-twitch muscles from mSOD1 mice also demonstrated greater vulnerability to cell stress such as glucose deprivation and caffeine stress in vitro. This Thesis also examined the effect of treatment with Arimoclomol, a pharmacological co-inducer of the HSR, on muscle and NMJ pathology. I found that treatment with was sufficient to decrease muscle pathology, augment the HSR and reduce mSOD1-meditated changes in nNOS expression. These findings support previous suggestions that targeting the periphery, in conjunction with the CNS, is an effective therapeutic strategy against ALS. Furthermore, that Arimoclomol's previously reported beneficial effects are due, at least in part, to its effect in the periphery.
Author: J. Barney N. B. Bryson
Author: J. Barney N. B. Bryson
Author: Polina Rabinovich Toidman
Author: C.L. Masters
Author: Debra Kay Kumasaka![Amyloid Precursor Protein Deficiency Does Not Attenuate Amyloid-associated Pathology in BRI-A[beta]42 Mice PDF](https://books.google.com/books/content/images/frontcover/cSNqAQAACAAJ?fife=w80-h100)
Author: Claire Carmen Ku
Author: Pik Kay Chan
Author: 
Author: Chelsea Cavanagh![Exploring the Role of Alzheimer's Amyloid-[beta] Precursor Protein APP and Its Relative APLP2 in Xenopus Intermediate Pituitary PDF](https://books.google.com/books/content/images/frontcover/L8bGtgAACAAJ?fife=w80-h100)
Author: Rob Wilhelmus Johanna Collin
Author: E. Edet-Amana