Days-to-criterion as an indicator of toxicity associated with human Alzheimer amyloid-β oligomers

Objective Recent evidence suggests that high molecular weight soluble oligomeric Aβ (oAβ) assemblies (also known as Aβ-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 oAβ/ADDLs have involved injection of assemblies purified from the cerebrospinal fluid of human subjects with AD or from the conditioned media of Aβ-secreting cells into experimental animals. We sought to study the bioactivities of endogenously formed oAβ/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 APPE693Q or APPE693Q X PS1ΔE9 bigenic mice. APPE693Q 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 Aβtotal, Aβ40, Aβ42, and oAβ/ADDLs by enzyme-linked immunosorbent assay (ELISA) and were also histologically examined. Based on results from the oAβ/ADDL ELISA, we assigned individual APPE693Q mice to either an undetectable oAβ/ADDLs group or a readily detectable oAβ/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/Aβ, although only APPE693Q X PS1Δ9 bigenic mice developed amyloid plaques. The APPE693Q mice did not develop amyloid plaques at any age studied, up to 30 months. APPE693Q mice were tested for spatial learning and memory, and only 12-month-old APPE693Q mice with readily detectable oAβ/ADDLs displayed a significant delay in acquisition of the MWM task when compared to nontransgenic littermates. Interpretation These data suggest that cerebral oAβ/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 Aβ assemblies. ANN NEUROL 2010