Understanding differential roles of stress and enrichment in pathogenesis of Alzheimer's Disease in a novel rat tau model

Abstract

Alzheimer’s Disease (AD) is the leading cause of dementia. A major hallmark of AD is the presence of neurofibrillary tangles (NFTs) formed from abnormally phosphorylated tau. Abnormal tau appears early in life in the locus coeruleus (LC), progressing through pre-tangle stages, before forming NFTs, creating an intervention window. Here, we use a novel pre-tangle rat model to examine the roles of stress and enrichment on pre-tangle AD development. Animals underwent stress or enrichment paradigms, either as neonates or adults, LC viral infusion surgeries at 2-3 months old (htauE14 or control), and a series of behavioural tests. htauE14, or pre-tangle, rats showed increased anxiety in an elevated plus maze (EPM), but late enrichment reversed this effect. htauE14 rats were impaired in spatial and olfactory discrimination tests, with males performing better than females in the Y-maze and olfactometer testing. Both early and late enrichment improved pre-tangle rat performance in spontaneous location recall. In olfactory discrimination training, late stress improved control rat performance but hindered htauE14 rats. Early stress, however, improved htauE14 olfactory discrimination. These results indicate increased anxiety and decreased spatial and olfactory acuity as early symptoms associated with pre-tangle pathology but confirm that environmental enrichment may provide rescuing effects.