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 APP^E693Q or APP^E693Q X PS1ΔE9 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 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 APP^E693Q 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 APP^E693Q X PS1Δ9 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 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.