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Amyloid Protein

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Lennart Mucke – One of the best experts on this subject based on the ideXlab platform.

  • high level neuronal expression of abeta 1 42 in wild type human Amyloid Protein precursor transgenic mice synaptotoxicity without plaque formation
    The Journal of Neuroscience, 2000
    Co-Authors: Lennart Mucke, Eliezer Masliah, Margaret Mallory, Edward Rockenstein, Gwen Tatsuno, Dora Kholodenko, Kelly Johnsonwood, Lisa Mcconlogue

    Abstract:

    Amyloid plaques are a neuropathological hallmark of Alzheimer’s disease (AD), but their relationship to neurodegeneration and dementia remains controversial. In contrast, there is a good correlation in AD between cognitive decline and loss of synaptophysin-immunoreactive (SYN-IR) presynaptic terminals in specific brain regions. We used expression-matched transgenic mouse lines to compare the effects of different human Amyloid Protein precursors (hAPP) and their products on plaque formation and SYN-IR presynaptic terminals. Four distinct minigenes were generated encoding wild-type hAPP or hAPP carrying mutations that alter the production of Amyloidogenic Aβ peptides. The platelet-derived growth factor β chain promoter was used to express these constructs in neurons. hAPP mutations associated with familial AD (FAD) increased cerebral Aβ1–42 levels, whereas an experimental mutation of the β-secretase cleavage site (671M→I) eliminated production of human Aβ. High levels of Aβ1–42 resulted in age-dependent formation of Amyloid plaques in FAD-mutant hAPP mice but not in expression-matched wild-type hAPP mice. Yet, significant decreases in the density of SYN-IR presynaptic terminals were found in both groups of mice. Across mice from different transgenic lines, the density of SYN-IR presynaptic terminals correlated inversely with Aβ levels but not with hAPP levels or plaque load. We conclude that Aβ is synaptotoxic even in the absence of plaques and that high levels of Aβ1–42are insufficient to induce plaque formation in mice expressing wild-type hAPP. Our results support the emerging view that plaque-independent Aβ toxicity plays an important role in the development of synaptic deficits in AD and related conditions.

  • high level neuronal expression of aβ1 42 in wild type human Amyloid Protein precursor transgenic mice synaptotoxicity without plaque formation
    The Journal of Neuroscience, 2000
    Co-Authors: Lennart Mucke, Eliezer Masliah, Margaret Mallory, Guiqiu Yu, Edward Rockenstein, Gwen Tatsuno, Kang Hu, Dora Kholodenko, Kelly Johnsonwood, Lisa Mcconlogue

    Abstract:

    Amyloid plaques are a neuropathological hallmark of Alzheimer’s disease (AD), but their relationship to neurodegeneration and dementia remains controversial. In contrast, there is a good correlation in AD between cognitive decline and loss of synaptophysin-immunoreactive (SYN-IR) presynaptic terminals in specific brain regions. We used expression-matched transgenic mouse lines to compare the effects of different human Amyloid Protein precursors (hAPP) and their products on plaque formation and SYN-IR presynaptic terminals. Four distinct minigenes were generated encoding wild-type hAPP or hAPP carrying mutations that alter the production of Amyloidogenic Aβ peptides. The platelet-derived growth factor β chain promoter was used to express these constructs in neurons. hAPP mutations associated with familial AD (FAD) increased cerebral Aβ1–42 levels, whereas an experimental mutation of the β-secretase cleavage site (671M→I) eliminated production of human Aβ. High levels of Aβ1–42 resulted in age-dependent formation of Amyloid plaques in FAD-mutant hAPP mice but not in expression-matched wild-type hAPP mice. Yet, significant decreases in the density of SYN-IR presynaptic terminals were found in both groups of mice. Across mice from different transgenic lines, the density of SYN-IR presynaptic terminals correlated inversely with Aβ levels but not with hAPP levels or plaque load. We conclude that Aβ is synaptotoxic even in the absence of plaques and that high levels of Aβ1–42are insufficient to induce plaque formation in mice expressing wild-type hAPP. Our results support the emerging view that plaque-independent Aβ toxicity plays an important role in the development of synaptic deficits in AD and related conditions.

  • Amyloid Protein precursor stimulates excitatory amino acid transport. Implications for roles in neuroprotection and pathogenesis
    The Journal of biological chemistry, 1998
    Co-Authors: Eliezer Masliah, Jacob Raber, M. Alford, Margaret Mallory, Mark P. Mattson, Daseng Yang, Derek Wong, Lennart Mucke

    Abstract:

    Excitatory neurotransmitters such as glutamate are required for the normal functioning of the central nervous system but can trigger excitotoxic neuronal injury if allowed to accumulate to abnormally high levels. Their extracellular levels are controlled primarily by transmitter uptake into astrocytes. Here, we demonstrate that the Amyloid Protein precursor may participate in the regulation of this important process. The Amyloid Protein precursor has been well conserved through evolution, and a number of studies indicate that it may function as an endogenous excitoprotectant. However, the mechanisms underlying this neuroprotective capacity remain largely unknown. At moderate levels of expression, human Amyloid Protein precursors increased glutamate/aspartate uptake in brains of transgenic mice, with the 751-amino acid isoform showing greater potency than the 695-amino acid isoform. Cerebral glutamate/aspartate transporter Protein levels were higher in transgenic mice than in non-transgenic controls, whereas transporter mRNA levels were unchanged. Amyloid Protein precursor-dependent stimulation of aspartate uptake by cultured primary astrocytes was associated with increases in Protein kinase A and C activity and could be blocked by inhibitors of these kinases. The stimulation of astroglial excitatory amino acid transport by Amyloid Protein precursors could protect the brain against excitotoxicity and may play an important role in neurotransmission.

Bhooma Shivakumar – One of the best experts on this subject based on the ideXlab platform.

  • Exposure to the Functional Bacterial Amyloid Protein Curli Enhances Alpha-Synuclein Aggregation in Aged Fischer 344 Rats and Caenorhabditis elegans
    Scientific Reports, 2016
    Co-Authors: Shu G. Chen, Vilius Stribinskis, Madhavi J. Rane, Donald R. Demuth, Evelyne Gozal, Andrew M. Roberts, Rekha Jagadapillai, Kyonghwan Choe, Bhooma Shivakumar, Richard Kerber

    Abstract:

    Misfolded alpha-synuclein (AS) and other neurodegenerative disorder Proteins display prion-like transmission of Protein aggregation. Factors responsible for the initiation of AS aggregation are unknown. To evaluate the role of Amyloid Proteins made by the microbiota we exposed aged rats and transgenic C . elegans to E . coli producing the extracellular bacterial Amyloid Protein curli. Rats exposed to curli-producing bacteria displayed increased neuronal AS deposition in both gut and brain and enhanced microgliosis and astrogliosis compared to rats exposed to either mutant bacteria unable to synthesize curli, or to vehicle alone. Animals exposed to curli producing bacteria also had more expression of TLR2, IL-6 and TNF in the brain than the other two groups. There were no differences among the rat groups in survival, body weight, inflammation in the mouth, retina, kidneys or gut epithelia, and circulating cytokine levels. AS-expressing C . elegans fed on curli-producing bacteria also had enhanced AS aggregation. These results suggest that bacterial Amyloid functions as a trigger to initiate AS aggregation through cross-seeding and also primes responses of the innate immune system.

  • exposure to the functional bacterial Amyloid Protein curli enhances alpha synuclein aggregation in aged fischer 344 rats and caenorhabditis elegans
    Scientific Reports, 2016
    Co-Authors: Shu G. Chen, Vilius Stribinskis, Madhavi J. Rane, Donald R. Demuth, Evelyne Gozal, Andrew M. Roberts, Rekha Jagadapillai, Kyonghwan Choe, Ruolan Liu, Bhooma Shivakumar

    Abstract:

    Misfolded alpha-synuclein (AS) and other neurodegenerative disorder Proteins display prion-like transmission of Protein aggregation. Factors responsible for the initiation of AS aggregation are unknown. To evaluate the role of Amyloid Proteins made by the microbiota we exposed aged rats and transgenic C. elegans to E. coli producing the extracellular bacterial Amyloid Protein curli. Rats exposed to curli-producing bacteria displayed increased neuronal AS deposition in both gut and brain and enhanced microgliosis and astrogliosis compared to rats exposed to either mutant bacteria unable to synthesize curli, or to vehicle alone. Animals exposed to curli producing bacteria also had more expression of TLR2, IL-6 and TNF in the brain than the other two groups. There were no differences among the rat groups in survival, body weight, inflammation in the mouth, retina, kidneys or gut epithelia, and circulating cytokine levels. AS-expressing C. elegans fed on curli-producing bacteria also had enhanced AS aggregation. These results suggest that bacterial Amyloid functions as a trigger to initiate AS aggregation through cross-seeding and also primes responses of the innate immune system.

David H. Small – One of the best experts on this subject based on the ideXlab platform.

  • high resolution scanning tunnelling microscopy of the β Amyloid Protein aβ1 40 of alzheimer s disease suggests a novel mechanism of oligomer assembly
    Journal of Structural Biology, 2006
    Co-Authors: Dusan Losic, Lisandra L Martin, Adam Mechler, Marieisabel Aguilar, David H. Small

    Abstract:

    Abstract The aggregation of the β-Amyloid Protein (Aβ) is an important step in the pathogenesis of Alzheimer’s disease. There is increasing evidence that lower molecular weight oligomeric forms of Aβ may be the most toxic species in vivo. However, little is known about the structure of Aβ oligomers. In this study, scanning tunnelling microscopy (STM) was used to examine the structure of Aβ monomers, dimers and oligomers. Aβ1–40 was visualised by STM on a surface of atomically flat gold. At low concentrations (0.5 μM) small globular structures were observed. High resolution STM of these structures revealed them to be monomers of Aβ. The monomers measured approximately 3–4 nm in diameter. Internal structure was seen in many of the monomers consistent with a conformation in which the polypeptide chain is folded into 3 or 4 domains. Oligomers were seen after ageing the Aβ solution for 24 h. The oligomers were also 3–4 nm in width and appeared to be formed by the end-to-end association of monomers with the polypeptide chain oriented at 90° to the axis of the oligomer. The results suggest that the oligomer formation can proceed through a mechanism involving the linear association of monomers.

  • Proteolytic processing of the AmyloidProtein precursor of Alzheimer’s disease
    , 2002
    Co-Authors: Janelle Nunan, David H. Small

    Abstract:

    The proteolytic processing of the Amyloid-� Protein precursor plays a key role in the development of Alzheimer’s disease. Cleavage of the Amyloid-� Protein precursor may occur via two pathways, both of which involve the action of proteases called secretases. One pathway, involving � – and � -secretase, liberates Amyloid-� Protein, a Protein associated with the neurodegeneration seen in Alzheimer’s disease. The alternative pathway, involving � -secretase, precludes Amyloid-� Protein formation. In this review, we describe the progress that has been made in identifying the secretases and their potential as therapeutic targets in the treatment or prevention of Alzheimer’s disease.

  • Gelatinase A possesses a β‐secretase‐like activity in cleaving the Amyloid Protein precursor of Alzheimer’s disease
    FEBS letters, 1995
    Co-Authors: Rex N. Lepage, Colin L. Masters, Konrad Beyreuther, Stephanie J. Fuller, Amanda J. Fosang, Gillian Murphy, Genevieve Evin, David H. Small

    Abstract:

    The ability of the 72 kDa gelatinase A to cleave the Amyloid Protein precursor (APP) was investigated. HeLa cells were transfected with an APP695 plasmid. The cells were incubated with gelatinase A, which cleaved the 110 kDa cell-surface APP, releasing a 100 kDa form of the Protein. A peptide homologous to the β-secretase site was cleaved by gelatinase A adjacent to a glutamate residue at position −3 (βA4 numbering system). A peptide homologous to the α-secretase site was not cleaved. The results demonstrate that 72 kDa gelatinase A is not an α-secretase, but that it may have a β-secretase activity.