Premium
P4‐021: Picomolar aggregated, but not soluble, Aβ inhibits cathepsin b and l activities
Author(s) -
Singh Rakesh K.,
Singh Prabhakar,
Hu Liangyan,
Zhang Qiang,
Peng Wei,
Suo William Z.
Publication year - 2015
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.2015.06.1725
Subject(s) - cathepsin b , lysis , chemistry , cathepsin d , cathepsin , recombinant dna , enzyme , biochemistry , cathepsin l , protease , microbiology and biotechnology , biology , gene
diet-induced elevation of Hcy levels results in an exacerbation of all 3 major pathological features of the AD phenotype: cognitive deficits and Abeta and tau neuropathology in the 3xTgmouse model of AD. High Hcy levels induce an elevation of S-adenosylhomocysteine (SAH), which by inhibiting methyl-transferase reactions results in DNA hypomethylation. Since reduced methylation of 5lipoxygenase (5LO) DNA increases its protein and activity we investigated whether this pathway was involved in the Hcy-dependent development of the AD-like phenotype. Methods: 3xTg mice with diet-induced high Hcy were compared with mice having normal Hcy. Neuro-2 A neuroblastoma (N2A) cells stably expressing human APP Swedish mutation (N2A-APPswe) were incubated with and without Hcy. Results: Compared with controls, brains form mice with high Hcy had a significant increase in SAH, which was associated with a decrease in DNA methyltransferase 1 (DNMT1), and reduction in 5LO DNA methylation. In addition, the same mice had increased 5LO mRNA level, 5LO protein expression and activity. In vitro studies with N2A-APPswe cells confirmed these observations, and demonstrated the essential role that 5LO activation plays in Hcy-dependent effect on AD phenotype. Conclusions: High Hcy worsens AD neuropathology and cognitive deficit in the 3xTg mice via 5LO DNA hypomethylation and subsequent activation of this pathway. The understanding of the molecular interplay between Hcy and 5LO in relationship to AD pathogenesis could reveal clues for the treatment of individuals with this risk factor to prevent AD onset.