Amyloid beta and the longest-lived rodent: the naked mole-rat as a model for natural protection from Alzheimer's disease

Amyloid beta (A beta) is implicated in Alzheimer's disease (AD) as an integral component of both neural toxicity and plaque formation. Brains of the longest-lived rodents, naked mole-rats (NMRs) approximately 32 years of age, had levels of A beta similar to those of the 3xTg-AD mouse model of AD. Interestingly, there was no evidence of extracellular plaques, nor was there an age-related increase in A beta levels in the individuals examined (2-20+ years). The NMR A beta peptide showed greater homology to the human sequence than to the mouse sequence, differing by only 1 amino acid from the former. This subtle difference led to interspecies differences in aggregation propensity but not neurotoxicity; NMR A beta was less prone to aggregation than human A beta. Nevertheless, both NMR and human A beta were equally toxic to mouse hippocampal neurons, suggesting that A beta neurotoxicity and aggregation properties were not coupled. Understanding how NMRs acquire and tolerate high levels of A beta with no plaque formation could provide useful insights into AD, and may elucidate protective mechanisms that delay AD progression. (C) 2013 Elsevier Inc. All rights reserved.