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P1–411: Characterization of a novel monoclonal antibody specific for a tau autoproteolytic cut site that differentiates between Alzheimer's disease and non‐Alzheimer's specimens
Author(s) -
Davidowitz Eliot,
Lopez Patricia,
Moe James
Publication year - 2013
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.2013.05.639
Subject(s) - tauopathy , neurodegeneration , chemistry , microtubule , tau protein , microbiology and biotechnology , biochemistry , neuroscience , biophysics , biology , alzheimer's disease , pathology , medicine , disease
Background: Tau pathology associates with several neurodegenerative diseases including Alzheimer’s disease (AD) collectively known as tauopathies. The role of inflammation in neurodegenerative diseases remains controversial yet provides opportunity for therapeutic intervention. Byproducts of certain activation profiles reduce disease pathology whereas others promote it. Inhibiting one pathway along the inflammatory milieu may promote an alternative cascade. Arginase 1 (Arg1) and nitric oxide synthases (NOS) increase during certain disease states and have been implicated in AD pathogenesis. Arg1 and NOS compete for L-arginine to produce either ornithine and polyamines or nitric oxide, respectively. Polyamines act as bivalent regulators of cellular function, promoting cell growth or cell death, depending on cell type and the microenvironment. Methods: We identified dysregulation of proteins associated with polyamine synthesis andmetabolism in rTg4510 tau transgenic mice compared to non-transgenic littermates. We postulate that increased Arg1 expression in the CNS impacts tau pathology. Four month-old rTg4510 tau transgenic mice receive an intracranial injection of recombinant adeno associated virus (rAAV) into the hippocampus of either rAAV-Arg1 or a control vector rAAV-GFP. Four months post injection brains were harvested for histology, immunohistochemistry, western blotting and ELISA. Results:We show that overexpression Arg1 for a duration of four months in the hippocampus of rTg4510 tau transgenic mice using rAAV-Arg1 reduced several phospho-tau epitopes (i.e. AT8, AT180, AT270, Ser262, Ser396) and tangle pathology indicated by Gallyas silver positive staining compared the control vector rAAVGFP (green fluorescent protein). Furthermore we found that Arg1 decreased several kinases associated with phospho-tau including phospho-GSK3 alpha 216/ beta 279 and CDK5 levels. Additionally, Arg1 overexpression decreased several cytokines and inflammatory markers including IL-1beta, TNF-alpha, IL-12, along with microglial activation measured by CD45 immunohistochemistry. Unbiased stereology showed no change in the number of neurons compared to the control vector however, Arg1 overexpression slightly but significantly mitigated hippocampal atrophy. Conclusions: These data suggests that Arg1 and the polyamine pathway may provide new and potential therapeutic targets for AD and tauopathies.