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O2‐01‐06: The Gamma Secretase Inhibitor, BMS‐708163 Increases Alpha Secretase Abeta Peptide Cleavage Fragments and Decreases the Gamma Secretase Abeta Peptide 1‐34 Fragment in Cerebrospinal Fluid
Author(s) -
Portelius Erik,
Blennow Kaj,
Andreasson Ulf,
Zetterberg Henrik,
Soares Holly,
Simon Adam,
Slemmon Randy,
Albright Charlie,
Tong Gary,
Burns Leah,
Berisha Flora,
Rhyne Paul,
Coric Vlad,
Feldman Howard,
Berman Robert
Publication year - 2011
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.2011.05.838
Subject(s) - peptide , chemistry , cerebrospinal fluid , microbiology and biotechnology , amyloid precursor protein , cleavage (geology) , in vivo , biochemistry , alzheimer's disease , medicine , biology , paleontology , disease , fracture (geology)
to investigate the role of the innate immune system inAlzheimer’s disease (AD) bymeasuring complement factors in cerebrospinal fluid (CSF) of subjects with mild cognitive impairment (MCI), AD and other dementias (oDem).Methods: We selected healthy controls (n1⁄4 19, age1⁄4 63, MMSE1⁄4 29.1), subjects with MCI (n 1⁄4 56, age 1⁄4 70, MMSE 1⁄4 26.9), AD (n 1⁄4 45, age 1⁄4 72, MMSE 1⁄4 22.9) and oDem (n 1⁄4 31, age 1⁄4 69 MMSE 1⁄4 24.1) from the EDAR study (www.edarstudy.eu). We measured C3a, central to the classical, alternative and lectin complement pathways, C5a involved in the lytic complement pathway, and the soluble C5b-9 terminal complement complex (TCC). We also measured in CSF abeta 1-42, total tau, and serum amyloid P (SAP, an acute response protein which activates complement). We compared groups and correlated complement markers with other biomarkers, neuropsychological markers, andmarkers of functional impairment using non-parametric tests.Results: Complement data are shown in the table. C3a was decreased by 50-60% in subjects with MCI, AD, and oDem relative to controls (p < 0.003 all comparisons). C5a was increased 3-6 fold in AD relative to controls (p 1⁄4 0.077), MCI (p1⁄4 0.016), and oDem(p1⁄4 0.07). TCCdid not differ between the groups, although subjects with AD had higher concentrations than the other groups. In the combined sample of subjects with MCI, AD, and oDem, higher levels of C3a correlated with higher levels of TCC (r 1⁄4 0.51, p < 0.001), SAP (r 1⁄4 0.40, p< 0.001), and tau (r1⁄4 0.18, p1⁄4 0.048). Higher levels of C5a correlated with more impairment on memory, executive functioning, and the MMSE (r1⁄4 0.22-0.30, p 1⁄4 0.05-0.002). Higher levels of TCC correlated with higher SAP levels (r 1⁄4 0.41, p < 0.001) and more functional impairment (r 1⁄4 0.25, p 1⁄4 0.018).Conclusions: The innate immune system is actively involved in neurodegeneration and may provide diagnostic and prognostic information for AD. The large reduction of C3a in subjects with MCI, AD and oDem, suggests increased use of this factor, regardless of the cause of neurodegeneration. Alternatively, increased C3a levels may protect against neurodegeneration. The increase of C5a in AD suggests a disease specific activation of the lytic complement pathway. Since this measure correlated with clinical measures of severity, C5a activation may be a relatively late event in the disease process.