Differential amyloid-beta sensitivity across human and nonhuman primate neurons

The human brain has undergone a threefold increase in size as well as changes in cytoarchitecture and neurochemical organization since the split with the last common ancestor with chimpanzees and bonobos. These changes have likely promoted increased cognitive flexibility but may also have come at the cost of increased vulnerability to neurodegenerative diseases like Alzheimer's disease (AD). Alzheimer's disease is the most common form of age-dependent dementia, and previous research suggests that humans may be uniquely vulnerable to AD. Primate comparative induced pluripotent stem cell models offer a unique opportunity to study the cellular and molecular mechanisms underlying this vulnerability. Plaques composed of amyloid-beta (aβ) are a hallmark pathology of AD, and while the exact role of aβ in disease pathogenesis remains incompletely understood, it is clear that aβ can have a neurotoxic effect and plays a role in the characteristic loss of neurons and synapses. Here we investigate susceptibility to aβ-induced toxicity in induced pluripotent stem cell-derived neurons from humans-both with and without AD, the two Pan species-a chimpanzee and a bonobo, and a rhesus macaque. To measure toxicity, we looked at cell death, along with other metrics of neuronal health and connectivity (neuritic beading and synaptic puncta density, respectively). We also employed transcriptomic approaches (RNA sequencing) to investigate molecular mechanisms underlying observed species differences. Our findings show that macaque neurons are less sensitive to aβ than human and ape neurons, and RNA sequencing points to molecular mechanisms that may underlie potentially protective responses in both macaque and ape neurons relative to humans. This work highlights the importance of studying AD from a comparative lens and provides insights into variation in susceptibility to AD among primates.