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Controlled Expression of a Cystatin C‐Peptide as Therapy for Alzheimer's Disease
Author(s) -
Shaw Phyllis A.,
Luo Jian
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.643.2
Subject(s) - cystatin c , in vivo , cystatin , peptide , chemistry , cysteine , amyloid precursor protein , p3 peptide , amyloid (mycology) , senile plaques , biochemistry , alzheimer's disease , medicine , biology , disease , enzyme , inorganic chemistry , microbiology and biotechnology , renal function
Alzheimer's disease (AD) is an incurable, degenerative neurological disorder leading to memory loss, impaired cognitive abilities and changes in behavior and personality. Hallmarks of AD are neurofibrillary intracellular tangles and extracellular senile plaques, resulting from improperly processed amyloid precursor protein (APP) and aggregated amyloid β (Aβ) peptides. A major therapeutic effort in AD centers on prevention of Aβ aggregates/fibrils. The cysteine proteinase inhibitor, cystatin C (CysC), plays a prominent role in amyloidogenesis. The intact CysC molecule exerts both protective anti‐Aβ effect through its C‐terminal portion (amino acid 101–117) by preventing fibril formation and, a detrimental effect, in its role as a cathepsin inhibitor, preventing Aβ degradation. We showed that a similar cysteine proteinase inhibitor, cystatin S (CysS), is highly regulated in vivo by steroid hormones and the autonomic nervous system, and its 1.9kb promoter is active in vivo in the brain during postnatal development. We made a construct of the CysS promoter and the secreted CysC, 101–117 Aβ binding‐peptide, and are testing the best routes of construct delivery into TgCRND8 AD mice, determining the optimal concentration necessary for Aβ binding in neuroblastoma cells stably expressing APP695 and Aβ, and testing the expression of Aβ binding‐peptide in vivo in TgCRND8 mice.