The oDGal Mouse: A Novel, Physiologically Relevant Rodent Model of Sporadic Alzheimer's Disease.

Sporadic Alzheimer's disease (sAD) represents a serious and growing worldwide economic and healthcare burden. Almost 95% of current AD patients are associated with sAD as opposed to patients presenting with well-characterized genetic mutations that lead to AD predisposition, i.e., familial AD (fAD). Presently, the use of transgenic (Tg) animals overexpressing human versions of these causative fAD genes represents the dominant research model for AD therapeutic development. As significant differences in etiology exist between sAD and fAD, it is perhaps more appropriate to develop novel, more sAD-reminiscent experimental models that would expedite the discovery of effective therapies for the majority of AD patients. Here we present the oDGal mouse model, a novel model of sAD that displays a range of AD-like pathologies as well as multiple cognitive deficits reminiscent of AD symptomology. Hippocampal cognitive impairment and pathology were delayed with N-acetyl-cysteine (NaC) treatment, which strongly suggests that reactive oxygen species (ROS) are the drivers of downstream pathologies such as elevated amyloid beta and hyperphosphorylated tau. These features demonstrate a desired pathophenotype that distinguishes our model from current transgenic rodent AD models. A preclinical model that presents a phenotype of non-genetic AD-like pathologies and cognitive deficits would benefit the sAD field, particularly when translating therapeutics from the preclinical to the clinical phase.

D-Cycloserine Improves Difficult Discriminations in a Pattern Separation Task in Alzheimer's Disease Patients with Dementia.

Recent fMRI studies in human identified that pattern separation ability is associated with increased activity in the hippocampal dentate gyrus (DG), whereas no such DG changes are seen during pattern completion. Disruption to neurogenesis in the DG has been associated with Alzheimer's disease (AD). In a post-hoc analysis of two large unsuccessful AD clinical trials, we examined the effect of D-cycloserine (DCS) on a specific object pattern separation measure, a component of the picture recognition task from the Cognitive Drug Research (CDR) system. This task yields a measure of pattern separation and a measure of pattern completion. Study data were available for 756 AD patients with dementia, randomized to several doses of DCS. Data were available at week 2, 6, 14, and 26 for 732, 707, 653, and 559 patients, respectively. None of the DCS doses had a statistically significant benefit over placebo on pattern completion. However, the DCS 15 mg BID dose significantly increased accuracy over placebo on the pattern separation measure by 5.1%. Further, the magnitude of the benefit of DCS 15 mg BID over placebo was almost doubled relative to the whole study population in a subset of patients whose pattern separation scores were≥2 standard deviations poorer than the CDR norm of age-matched healthy individuals at baseline. These post-hoc analyses suggest a potential value of the pattern separation task for evaluating compounds promoting neurogenesis. Further, the use of a restrictive pattern separation eligibility criterion might facilitate signal detection.