Premium
P1–079: Human gamma–secretase reconstituted in yeast via co–expression of presenilin, nicastrin, APH1A and PEN2 deviates from the prototype and implies the existence of auxiliary components
Author(s) -
Mastrangelo Peter,
Arslanova Dilya,
Mazzella Matthew J.,
Strome Robert,
Fraser Paul E.,
Boone Charlie,
Mathews Paul M.,
St George-Hyslop Peter,
Westaway David
Publication year - 2006
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.2006.05.454
Subject(s) - presenilin , nicastrin , mutant , mutagenesis , lac operon , yeast , saccharomyces cerevisiae , gamma secretase , reporter gene , function (biology) , biology , chemistry , microbiology and biotechnology , biochemistry , gene , gene expression , alzheimer's disease , medicine , disease , pathology
loid levels by ELISA. Results: Analysis of AChE activity in hippocampus of lesioned mice revealed significant decreases by 68% in wild-type (WT) and by 88% in transgenic mice. In the cortex, only transgenic lesioned mice showed significant reductions in AChE activity (39%). Transgenic mice, regardless of the lesion, showed important spatial memory impairments in the Morris water maze, while lesioned WT mice showed partial learning deficits. The novel object recognition test revealed in lesioned mice, both WT and transgenic, significant cognitive deficits. -amyloid (A )1-40 and A 1-42 levels were found to be increased with age in transgenic mice. These increases were significantly higher in cholinergically lesioned transgenic animals (soluble A 1-40 by 60%; fibrillar A 1-40 by 73%; soluble A 1-42 by 14-fold; fibrillar A 1-42 by 2.3-fold). Levels of A 1-40 (soluble and fibrillar) were correlated to retention time in the Morris water maze in transgenic mice, but this correlation was lost in the lesioned group. Conclusions: Cholinergic neurons of Tg2576 mice appear to be especially vulnerable to a cholinergic lesion. Basal forebrain cholinergic dysfunction favours the amyloidogenic route of APP processing in Tg2576 mice by increasing A species, which does not lead to further cognitive impairments.