Studies for Improving a Rat Model of Alzheimer's Disease: Icv Administration of Well-Characterized -Amyloid 1-42 Oligomers Induce Dysfunction in Spatial Memory

During the past 15 years, several genetically altered mouse models of human Alzheimer's disease (AD) have been developed. These costly models have greatly facilitated the evaluation of novel therapeutic approaches. Injecting synthetic -amyloid (A) 1-42 species into different parts of the brain of non-transgenic rodents frequently provided unreliable results, owing to a lack of a genuine characterization of the administered A aggregates. Previously, we have published a new rat AD-model in which protofibrillar-fibrillar A1-42 was administered into rat entorhinal cortex (Sipos 2007). In order to develop a more reliable model, we have injected well-characterized toxic soluble A1-42 species (oligomers, protofibrils and fibrils) intracerebroventricularly (icv) into rat brain. Studies of the distribution of fluorescent-labeled A1-42 in the brain showed that soluble A-species diffused into all parts of the rat brain. After seven days, the A-treated animals showed a significant decrease of spatial memory in Morris water maze test and impairment of synaptic plasticity (LTP) measured in acute hippocampal slices. The results of histological studies (decreased number of viable neurons, increased tau levels and decreased number of dendritic spines) also supported that icv administration of well-characterized toxic soluble A species into rat brain provides a reliable rat AD-model.