Days to Criterion as an Indicator of Toxicity Associated with Human Alzheimer Amyloid-beta Oligomers

作者：Gandy Sam^*; Simon Adam J; Steele John W; Lublin Alex L; Lah James J; Walker Lary C; Levey Allan I; Krafft Grant A; Levy Efrat; Checler Frederic; Glabe Charles; Bilker Warren B; Abel Ted; Schmeidler James; Ehrlich Michelle E

来源：Annals of Neurology, 2010, 68(2): 220-230.

DOI：10.1002/ana.22052

Objective: Recent evidence suggests that high molecular weight soluble oligomeric A beta (oA beta) assemblies (also known as A beta-derived diffusible ligands, or ADDLs) may represent a primary neurotoxic basis for cognitive failure in Alzheimer disease (AD). To date, most in vivo studies of oA beta/ADDLs have involved injection of assemblies purified from the cerebrospinal fluid of human subjects with AD or from the conditioned media of A beta-secreting cells into experimental animals. We sought to study the bioactivities of endogenously formed oA beta/ADDLs generated in situ from the physiological processing of human amyloid precursor protein (APP) and presenitin1 (PS1) transgenes.
Methods: We produced and histologically characterized single transgenic mice overexpressing APPE(693Q) or APP(E693Q) X PS1 Delta E9 bigenic mice. APP(E693Q) mice were studied in the Morris water maze (MWM) task at 6 and 12 months of age. Following the second MWM evaluation, mice were sacrificed, and brains were assayed for A beta total, A beta 40, A beta 42, and oA beta/ADDLs by enzyme-linked immunosorbent assay (ELISA) and were also histologically examined. Based on results from the oA beta/ADDL ELISA, we assigned individual APP(E693Q) mice to either an undetectable oA beta/ADDLs group or a readily detectable oA beta/ADDLs group. A days to criterion (DTC) analysis was used to determine delays in acquisition of the MWM task.
Results: Both single transgenic and bigenic mice developed intraneuronal accumulation of APP/A beta, although only APP(E693Q) X PS1 Delta 9 bigenic mice developed amyloid plaques. The APP(E693Q) mice did not develop amyloid plaques at any age studied, up to 30 months. APP(E693Q) mice were tested for spatial learning and memory, and only 12-month-old APP(E693Q) mice with readily detectable oA beta/ADDLs displayed a significant delay in acquisition of the MWM task when compared to nontransgenic littermates.
Interpretation: These data suggest that cerebral oA beta/ADDL assemblies generated in brain in situ from human APP transgenes may be associated with cognitive impairment. We propose that a DTC analysis may be a sensitive method for assessing the cognitive impact in mice of endogenously generated oligomeric human A beta assemblies. ANN NEUROL 2010;68:220-330

• 出版日期2010-8