[PDF] Engineering Tools To Analyze Beta Amyloids Effect On Cellular Mechanisms Linked To The Neurodegeneration Observed In Alzheimers Disease eBook
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Alzheimer's disease (AD) is a progressive neurodegenerative disorder that primarily affects the elderly population above 65 years of age. The disease is characterized by cognitive impairment, neuronal degeneration and eventual cell death. Current treatments for AD only slow down the progression of the disease and minimize its symptoms.
There is now considerable genetic evidence that the type 4 allele of the apolipoprotein E gene is a major susceptibility factor associated with late-onset Alzheimer's disease, the common form of the disease defined as starting after sixty years of age. The role of apolipoprotein E in normal brain metabolism and in the pathogenesis of Alzheimer's disease are new and exciting avenues of research. This book, written by the most outstanding scientists in this new filed, is the first presentation of results concerning the implications of apolipoprotein E on the genetics, cell biology, neuropathology, biochemistry, and therapeutic management of Alzheimer's disease.
Alzheimer's disease (AD) is a neurodegenerative disorder featuring progressive cognitive and functional deficits. Pathologically, AD is characterized by tau and amyloid [beta]protein deposition in the brain. As the sixth leading cause of death in the U.S., the disease course usually last from 7 to 10 years on average before the consequential death. In 2019 there are estimated 5.8 million Americans living with AD affecting 16 million family members. At certain stage of the disease course, patients with inability of maintaining their daily functioning highly depend on caregivers, primarily family caregivers, that incur estimated 18.4 billion unpaid hours of cares, which is equivalent to 232 billion dollars. These huge economic burdens and inevitable emotional distress on the family and the society would also increase as the number of AD affected population could triple by 2050.Altered cellular composition is associated with AD progression and decline in cognition, such as neuronal loss and astrocytosis, which is a key feature in neurodegeneration but has often been overlooked in transcriptome research. To explore the cellular composition changes in AD, I developed a deconvolution pipeline for bulk RNA-Seq to account for cell type specific effects in brain tissues. I found that neuronal and astrocyte relative proportions differ between healthy and diseased brains and also among AD cases that carry specific genetic risk variants. Brain carriers of pathogenic mutations in APP, PSEN1, or PSEN2 presented lower neuron and higher astrocyte relative proportions compared to sporadic AD. Similarly, the APOE [epsilon]4 allele also showed decreased neuronal and increased astrocyte relative proportions compared to AD non-carriers. In contrast, carriers of variants in TREM2 risk showed a lower degree of neuronal loss compared to matched AD cases in multiple independent studies. These findings suggest that genetic risk factors associated with AD etiology have a specific effect on the cellular composition of AD brains. The digital deconvolution approach provides an enhanced understanding of the fundamental molecular mechanisms underlying neurodegeneration, enabling the analysis of large bulk RNA-sequencing studies for cell composition. It also suggests that correcting for the cellular structure when performing transcriptomic analysis will lead to novel insights of AD.With deconvolution methods to delineate cell population changes in disease condition, it would help interpret transcriptomics results and reveal transcriptional changes in a cell type specific manner. One application demonstrated in this dissertation work is to use cell type proportion as quantitative trait to identify genetic factors associated with cellular composition changes. I performed cell type QTL analysis and identified a common pathway associated with neuronal protection underlying aging brains in the presence or absence of neurodegenerative disease symptoms. A protective variant of TMEM106B, which was previously identified with a protective effect in FTD, was identified to be associated with neuronal proportion in aging brains, suggesting a common pathway underlying neuronal protection and cognitive reservation in elderly. This extended analysis yield from deconvolution results demonstrated one promising direction of using deconvolution followed by cell type QTL analysis in identifying new genes or pathways underlying neurodegenerative or aging brains.To understand the complexity of the brain under disease condition, network analysis as a large-scale system-level approach provides unbiased and data-driven view to identify gene-gene interactions altered by disease status. Using network analysis, I replicated and reconfirmed the co-expression pattern between MS4A gene cluster and TREM2 in sporadic AD, from which further evidence was inferred from Bayesian network analysis to show that MS4A4A might be a potential regulator of TREM2 that is validated by in-vitro experiments. In Autosomal Dominant AD (ADAD) cohort, disrupted and acquired genes were identified from PSEN1 mutation carriers. Among these genes, previously identified AD risk genes and pathways were revealed along with novel findings. These results demonstrated the great potential of applying network approach in identifying disease associated genes and the interactions among them.To conclude the dissertation work from methodological, empirical, and theoretical levels, deconvolution pipeline for bulk RNA-Seq, cell type QTL analysis, and network analysis approaches were applied to understand transcriptome changes underlying disease etiology. From which previous AD related findings were replicated that validated the methods, and novel genes and pathways were identified as potential new therapeutic targets. Based on prior knowledge and empirical evidence observed from this dissertation work, a model is proposed to explain how genetic factors are assembled as a highly interconnected interactome network to affect proteinopathy observed in neurodegenerative disorders, that cause cellular composition changes in the brain, which ultimately leads to cognitive and functional deficits observed in AD patients.
This book discusses the primary functions of microtubule-associated proteins (MAPs) such as MAP2 and tau in neuronal morphogenesis, as well as relationships between neuronal differentiation and the expression of neuronal intermediate filaments (nestin, alpha internexin, and neurofilament triplet proteins). It emphasizes the importance of several cytoskeletal proteins for neuronal differentiation and morphogenesis, organelle transport, and synaptic functions. The book considers the involvement of tau MAPs in the formation of paired helical filaments in Alzheimer's disease, and it examines the mechanisms of organelle transports and molecular motors such as kinesin, braindynein, and kinesin superfamily proteins. Cytoskeletal proteins involved in synaptic formation and transmitter release and new synaptic junctional-associated proteins are explored as well.
Alzheimer's disease (AD) is characterised by an accumulation of the [beta]-amyloid (A[beta]) in the brain. A[beta]-induced neuronal dysfunction in AD is probably mediated via a direct interaction with components of the neuronal cell membrane. Genetic and molecular evidence suggests that cholesterol and lipoprotein homeostasis influence AD pathogenesis, however the mechanism by which this occurs is unclear. The present study aimed to examine whether cholesterol or lipoprotein factors regulate the binding of A[beta] to neuronal cells. To examine A[beta]-cell binding, an N-terminal fluorescein (Fluo) conjugate of the 42-amino acid isoform of A[beta] (A[beta]1-42; FluoA[beta]1-42) was incubated with SH-SY5Y human neuroblastoma cells, and cell-¬associated fluorescence was measured by confocal microscopy and flow cytometry. FluoA[beta]1-42 bound to cells in an aggregation-dependent manner, and was internalised to late endocytic compartments. The cell binding and uptake of FluoA[beta]1-42 was not mediated by binding sites for either cholera toxin B subunit, or antibodies to the low-density lipoprotein-related protein 1 (LRPl). These data suggested that FluoA[beta]1-42 did not bind to GMl gangliosides or LRPI on the cell surface. However, FluoA[beta]1-42 did colocalise to the binding sites of the LRPI ligand, receptor-associated protein (RAP), on the plasma membrane. Moreover, co¬incubation with RAP enhanced the binding of A[beta] to cells, and A[beta] was immunoprecipitated by an anti-RAP antibody following the incubation of RAP with A[beta] in vitro. By SDS-PAGE, it was also observed that RAP inhibited the oligomerisation of A[beta], and formed an SDS-stable complex with A[beta]. An inhibition of A[beta] aggregation was also noted by atomic force microscopy. Since A[beta] aggregation alters its toxicity, the effect of RAP on A[beta]-induced neurotoxicity was tested. RAP inhibited both the A[beta]-induced increase in intracellular calcium of SH-SY5Y cells, and A[beta]-induced amnesia in chicks. Since the aggregation of A[beta] into SDS-stable low molecular weight oligomers has been closely linked to A[beta] neurotoxicity and AD, the effect of RAP on A[beta] oligomerisation was examined in more detail. RAP inhibited the formation of SDS-stable dimers of A[beta]. The binding and uptake of A[beta] and RAP-A[beta] by SH-SY5Y cells was inhibited by heparin. However, heparin did not inhibit the formation of the RAP-A[beta] complex, suggesting that the binding of A[beta] to cells involves its heparin-binding domains, whereas the binding of A[beta] to RAP does not. Together, these findings suggest that RAP alters A[beta] aggregation, cellular uptake of A[beta], and A[beta]-induced neuronal dysfunction. Therefore, the RAP-A[beta] interaction may be a viable target for the development of AD therapies.
Using the most well-studied behavioral analyses of animal subjects to promote a better understanding of the effects of disease and the effects of new therapeutic treatments on human cognition, Methods of Behavior Analysis in Neuroscience provides a reference manual for molecular and cellular research scientists in both academia and the pharmaceutic
Neuroscience Perspectives provides multidisciplinary reviews of topics in one of the most diverse and rapidly advancing fields in the life sciences.Whether you are a new recruit to neuroscience, or an established expert, look to this series for 'one-stop' sources of the historical, physiological, pharmacological, biochemical, molecular biological and therapeutic aspects of chosen research areas.The last decade has seen tremendous advances in our understanding of the pathobiology of Alzheimer's disease. These will lead to the first generation of drugs aimed at prevention rather than cure. This book covers some of the most important and exciting of these advances, with chapters written by many of the leading researchers in the field.With genetic studies as a backbone to this volume many chapters are devoted to the function and regulation of amyloid b-protein precursor (APP) and apolipoprotein E (ApoE). Other chapters describe cell biological approaches helping to piece together the link between the genetic alterations and the phenotype we call Alzheimer's disease.Although APP and its proteolytic cleavage product, amyloid b-protein, do not answer all the questions, detailed research into this system has undoubtedly increased our knowledge of the pathobiology of AD and has lead to the identification of other risk factors. Understanding the role of ApoE in the pathology of Alzheimer's disease promises to open a whole new field in AD research. * * Reviews the current knowledge of the pathogenesis of Alzheimer's Disease from a clinical perspective to a genetic and cell biological perspective* A comprehensive description of the role of amyloid B-protein precursor in Alzheimer's disease.* Up-to-date research data* Clear illustrations complement the text
Amyloid protein misfolding is a central pathological event in a spectrum of human age-related degenerative diseases including Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, tauopathies, and spongiform encephalopathy. These dementias are widespread and affect billions of people worldwide. Although the specific amyloid protein involved in each of these diseases is different, amyloid proteins misfold through a common, conserved pathway to form highly-ordered, beta-sheet-rich fibrillar aggregates. Oligomeric intermediates assembled during this process represent the primary toxic neurotoxic species in many of these diseases. In AD, despite extensive research dedicated to unravel the mechanisms underlying Amyloid beta oligomers' pathological role, the precise mechanisms remain unclear due to lack of detailed structural analysis. In this study, we investigated the causative link between the aberrant structures of protein oligomers and their toxic functions in disease pathogenesis. The data presented here reveal that soluble Amyloid beta oligomers have complex structural polymorphism as evident by the immunological differences between prefibrillar and fibrillar conformations (Chapters Two and Three). Soluble Amyloid beta fibrillar oligomers are rich in beta-sheets, on fibril-forming pathway and can eventually assemble into mature fibrils. In vitro, FOs propagate via an elongation, fragmentation, and replication mechanism that is similar to what is known for prion proteins. We also investigated the molecular mechanisms underlying FOs' pathological role in AD. The increased levels of FOs in AD patients, the tight correlation with the increased severity of dementia, and the structural similarity to fibrils present in amyloid plaques strongly suggest that FOs are highly pathological to AD. Through studies using rat hippocampal and cortical neurons, we found and confirmed that Amyloid beta-mediated neurotoxicity is highly conformation dependent (Chapter Four). In the in vitro cell culture model, FOs induce neuronal toxicity by preferentially binding to a selective-population of stressed neurons at non-synaptic sites through their exposed hydrophobic surface.
Alzheimer's disease (AD) is the most common age related neurodegenerative disorder pathologically linked with the accumulation of the extracellular senile plaques of [Beta]-Amyloid peptide (A[Beta]) and the intracellular neurofibrillary tangles of tau protein in AD's brains. The deposition of A[Beta] is regarded as the primary causative factor in AD, which involves both neuron cytotoxicity and tau protein hydrophosphorylation. Amyloid formation on the cell membrane involves multiple self-assembly processes in which A[Beta] peptides undergo complex conformational change, aggregation, and reorganization to form characteristic [Beta]-sheet rich fibrils. The kinetics of this self-assembly process and the inhibition of A[Beta] aggregation and toxicity remains an important but open question because of 1) the small size, fast transition, and heterogeneous intermediates of A[Beta] oligomers, 2) complicated surface environment of cell membrane, and 3) no effective pharmaceutical agent was produced to date to treat AD. In this dissertation, both computational and experimental approaches were conducted to (1) investigate the conformation, orientation, and aggregation of amyloid oligomers upon adsorption on artificial surfaces; (2) determine seeding effect of A[Beta] adsorption and kinetic on different artificial surfaces; (3) examine inhibition effect of tanshiones on A[Beta] aggregation and toxicity; (4) explore novel process for A[Beta] inhibitor design. Throughout this week, we for the first time determine the effect of surface chemistry on A[Beta] aggregation and adsorption (Chapter II); and reveal the role of size, conformation, and orientation of A[Beta] oligomer on A[Beta]-surface interaction (Chapter III and Chapter IV). As compared to A[Beta] aggregation in solution, all of the Self-Assembled Monolayers (SAMs) can greatly accelerate A[Beta] aggregation and promote the structural conversion from an unstructured conformation to a [Beta]-sheet-containing structure. Our results suggest that A[Beta] undergoes different aggregation pathways on different SAMs. All these experimental and simulation results represent the first important step towards a better fundamental understanding of amyloid aggregation and toxicity mechanisms at the molecular level. We also discover a type of novel inhibitors of tanshionones from herb extracts which possess multifunction of inhibiting A[Beta] aggregation, disaggregating A[Beta] fibers, and reducing A[Beta]-induced cell toxicity in vitro (Chapter V). Tanshinone-derived compounds constitute a new class of amyloid inhibitors with multiple advantages in amyloid inhibition, fibril disruption, and cell protection, as well as their well-known anti-inflammatory activity, which may hold great promise in treating amyloid diseases. In addition of investigating the naturally existed compounds, a novel technique for the design and identification of amyloidogenic hexapeptide-based A[Beta] inhibitor was developed (Chapter VI). We have suggested a novel hypothesis for the development of hexapeptide-based A[Beta] inhibitors and developed a high-throughput protocol for the design and screen of amyloidogenic hexapeptide sequences as A[Beta] aggregation and cytotoxicity inhibitors. The successful identification of A[Beta] inhibitors through this work highly confirmed that analyzing the self-recognition short peptide fragments is a promising strategy for developing peptide-based inhibitors of Alzheimer's disease. And the common concept of cross-amylid interaction could also potentially be used to the identification of inhibitors for other amyloid diseases. The self-recognition hexapeptide fragments designed in QSAR model, in together with the high throughput MD simulation model, can be widely used for amyloidosis mechanism study and amyloid inhibitor screen.
Author : Nancy Y. Ip Publisher : Springer Science & Business Media Page : 326 pages File Size : 42,44 MB Release : 2009-02-28 Category : Medical ISBN : 0387788875
Cyclin Dependent Kinase 5 provides a comprehensive and up-to-date collection of reviews on the discovery, signaling mechanisms and functions of Cdk5, as well as the potential implication of Cdk5 in the treatment of neurodegenerative diseases. Since the identification of this unique member of the Cdk family, Cdk5 has emerged as one of the most important signal transduction mediators in the development, maintenance and fine-tuning of neuronal functions and networking. Further studies have revealed that Cdk5 is also associated with the regulation of neuronal survival during both developmental stages and in neurodegenerative diseases. These observations indicate that precise control of Cdk5 is essential for the regulation of neuronal survival. The pivotal role Cdk5 appears to play in both the regulation of neuronal survival and synaptic functions thus raises the interesting possibility that Cdk5 inhibitors may serve as therapeutic treatment for a number of neurodegenerative diseases.