Intracellular Amyloid-β in the Normal Rat Brain and Human Subjects

Amyloid-beta (A{beta}) is a normal product of neuronal activity, and the two most common variants are 40 or 42 residues long. Of these, the 42 residue-version (A{beta}42) is normally less abundant but more prone to self-aggregate, and is thought to cause Alzheimers disease (AD). Much knowledge about AD-pathogenesis comes from the study of rodents made to model aspects of the disease by expressing AD-relevant human transgenes, like human amyloid precursor protein (APP) containing mutations that drive up A{beta} production or increase the A{beta}42/40 ratio and thereby causes AD. Yet, when it comes to the normal expression of A{beta}42 in rodent brains, surprisingly little is known. Here we characterize the expression of A{beta}42 throughout the brain of normal, outbred Wistar rats, including animals from 3-18 months of age. We find that intracellular A{beta}42 (iA{beta}42) is present in neurons located throughout the brain at all ages of normal Wistar rats, but that the levels vary greatly between brain regions. In cortex, we observe the highest levels of iA{beta}42 in neurons that are part of layer II of the entorhinal cortex (EC), along with neurons in the hippocampus, closely followed by neurons in the somatosensory cortex. Among subcortical structures, we observe the highest levels iA{beta}42 in the locus coeruleus. In order to explore whether the striking presence of iA{beta}42 in rat EC also holds true in human subject free of neurological disease, we examined EC of six such cases ranging from ages 20-88 years. In all six cases, we find that iA{beta}42 is present in EC layer II-neurons. Our findings support two conclusions about iA{beta}42. First, iA{beta}42 is present in neurons of wild-type Wistar rats and is restricted to the same structures where iA{beta} accumulates, and A{beta}-plaques form, in a much used AD model based on Wistar rats (the McGill-R-Thy1-APP rat model). The difference between wild-type Wistar rats and these AD model rats, with respect to A{beta}42, is therefore a quantitative one rather that a qualitative one. This indicates that the McGill rat model in fact models the underlying wild-type neuronal population-specific vulnerability to A{beta}42-accumulation. Second, because the McGill rat model closely mimics the human AD-associated spatiotemporal sequence of amyloid plaque deposition, this model may offer a useful representation of the pre-plaque neuronal accumulation of iA{beta}42. Our findings in human cases are in line with prior findings, and substantiate the notion that neurons in layer II of EC are vulnerable to accumulation of iA{beta}42.