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.

Spatial recognition test: A novel cognition task for assessing topographical memory in mice.

Dysfunction in topographical memory is a core feature of several neurological disorders. There is a large unmet medical need to address learning and memory deficits as a whole in central nervous system disease. There are considerable efforts to identify pro-cognitive compounds but current methods are either lengthy or labour intensive. Our test used a two chamber apparatus and is based on the preference of rodents to explore novel environments. It was used firstly to assess topographical memory in mice at different retention intervals (RI) and secondly to investigate the effect of three drugs reported to be beneficial for cognitive decline associated with Alzheimer's disease, namely: donepezil, memantine and levetiracetam. Animals show good memory performance at all RIs tested under four hours. At the four-hour RI, animals show a significantly poorer memory performance which can be rescued using donepezil, memantine and levetiracetam. Using this test we established and validated a spatial recognition paradigm to address topographical memory in mice by showing a decremental time-induced forgetting response and reversing this decrease in performance using pharmacological tools. The spatial recognition test differs from more commonly used visuospatial laboratory tests in both throughput capability and potentially neuroanatomical substrate. This test has the potential to be used to assess cognitive performance in transgenic animals, disease models and to screen putative cognitive enhancers or depressors.