TgCRND8 mice express a transgene encoding a double mutant (KM670/671NL plus V717F) form of human APP under control of the Syrian hamster prion (haPrP) promoter. These animals develop spatial reference memory impairments that can be discerned from 12 wks of age in Morris water maze tasks. It has been suggested that TgCRND8 plaque pathology begins after 9 wks and that cognitive impairments coincide with the onset of this plaque deposition (Hyde et al., 2005, Behav Brain Res 160:344–355). However, we typically find that the onset of plaque pathology begins only after the emergence of spatial deficits at 12 weeks and we have suspected that TgCRND8 mice might be impaired by other cognitive measures at even earlier ages. We examined object recognition memory in TgCRND8 and α–synuclein transgenic mice, in which expression of the mutant or wild type human proteins were under control of the haPrP promoter. Onset of progressive deficits in object recognition memory preceded plaques and spatial memory impairment in TgCRND8 mice by > 4 wks. Profound disruption of 3 h object recognition memory was observed before animals reached 8 wks of age. It seems unlikely that this phenotype arises because of a transgene insertional artifact, as other agreggating proteins, when expressed under this promoter, differentially affect the object recognition task. In particular, mice producing wild type, or missense mutant (A53T) human α–synuclein displayed intact 3 h object memory at 17 wks of age, while A30P mutant α–synuclein–Tg mice were impaired. In 1 yr old A53T and A30P mice, no 3 h object memory could be discerned, but performance in a subsequent 6 h trial remained intact. Both memory reactivation (Kelly et al., 2003, J Neurosci 12:5354–60) and lengthening of the testing delay (Hammond et al., 2004, Neurobiol Learn Mem 82:26–34) increase involvement of hippocampus relative to rhinal cortices in object recognition memory. Thus, these data support the notion that mutant human α–synuclein produces a relative sparing of hippocampus. The early impairment of object recognition memory in TgCRND8 mice suggests that rhinal cortices as well as hippocampus are early targets of pathology in this model.

When given orally to a transgenic mouse model of Alzheimer disease, cyclohexanehexol stereoisomers inhibit aggregation of amyloid β peptide (Aβ) into high-molecular-weight oligomers in the brain and ameliorate several Alzheimer disease–like phenotypes in these mice, including impaired cognition, altered synaptic physiology, cerebral Aβ pathology and accelerated mortality. These therapeutic effects, which occur regardless of whether the compounds are given before or well after the onset of the Alzheimer disease–like phenotype, support the idea that the accumulation of Aβ oligomers has a central role in the pathogenesis of Alzheimer disease.