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

Amyloid beta (Aß) 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 Aß 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 Aß levels in the individuals examined (2-20+ years). The NMR Aß 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 Aß was less prone to aggregation than human Aß. Nevertheless, both NMR and human Aß were equally toxic to mouse hippocampal neurons, suggesting that Aß neurotoxicity and aggregation properties were not coupled. Understanding how NMRs acquire and tolerate high levels of Aß with no plaque formation could provide useful insights into AD, and may elucidate protective mechanisms that delay AD progression.