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P3‐408: Mechanism(s) of an apolipoprotein mimetic peptide in inhibitng amyloid plaque deposition‐ results from in vivo and in vitro studies
Author(s) -
Handattu Shaila P.,
Monroe Candyce E.,
Manchekar Medha P.,
Palgunachari Mayakonda,
Groen Thomas,
Kadish Inga,
Anantharamaiah Gattadahalli M.,
Garber David W.
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.1951
Subject(s) - peptide , microglia , neurotoxicity , apolipoprotein e , in vivo , apolipoprotein b , senile plaques , chemistry , amyloid (mycology) , lipoprotein , cerebrospinal fluid , p3 peptide , in vitro , inflammation , alzheimer's disease , amyloid precursor protein , biochemistry , cholesterol , pathology , immunology , biology , medicine , toxicity , disease , inorganic chemistry , microbiology and biotechnology , organic chemistry
Ab) in neurodegeneration. In addition, we found this modification also relevant for inflammatory chemokines such as monocyte-chemoattractant protein-1 (MCP-1, CCL-2). Here, the pGlu-residue originates from cyclization of N-terminal glutamine by QC in vivo and is responsible for biological activity such as immune cell invasion in overreacting peripheral immune response and recruitment of glial cells in neuroinflammation. However, modeling Alzheimer’s disease (AD)-like phenotypes in mice still does not mimic such features of AD including early neuronal loss and neuroinflammation. In these models this may indicate a lack of some pathogenic factors such as the high content of N-truncated and pGlu-modified forms of Ab found in the amyloid deposits of AD patients. Methods: We have developed novel transgenic mouse models specifically generating pGlu-Ab specifically studying the effects of neuronal pGlu-Ab, expressed either within the secretory pathway or in lysosomal/endosomal vesicles. We used different high-sensitivity ADand neurodegeneration staining methods as well as immunohistochemistry. For behavioral screening we applied a novel comprehensive behavioral phenotyping battery. Total Abeta load as well as pGlu-Ab were analyzed by ELISA. Results: In addition to showing significant pGlu-Ab levels, the new transgenic animals display age-dependent cell loss in a time frame of 4 month, gliosis and Ab deposits, all of these being hallmarks of AD. Also the neurodegenerative behavioral phenotype corresponds to the onset of pGlu-Ab expression. The CA1-neuronal layer is completely lost at month 5 of age. In additional pharmacological experiments we also could demonstrate a potential dual function of QC-inhibitors targeting Alzheimer’s disease, reducing both the amount of highly toxic and amyloidogenic pGlupeptides and ameliorating the neuroinflammation by suppression of biologically active MCP-1. Conclusions: The findings of neuronal expression of pGlu-Ab in vivo provide evidence for a direct pGlu-Ab toxicity and stimulation of immune response. Based on these data, we launched a broad QC-inhibitor development program which has approached the regulatory drug development phase.