Chimpanzee and human ApoE isoforms differ in the stimulation of neurite differentiation consistent with structural predictions with relevance to brain development and aging

Background Among the anthropoids, humans uniquely have apolipoprotein E (ApoE) isoforms that modulate Alzheimer's disease (AD) risk and accelerate aspects of brain aging. While chimpanzee and human ApoE4 share R112 and R158, the oldest chimps do not show symptoms of advanced AD. Another key structural difference is T61 in chimps instead of R61 found in humans predicted to be structurally similar to ApoE3. Objective Besides their impact on later life brain health, ApoE isoforms influence the development of brain regions relevant to AD. We explored the functional impact of ApoE isoforms produced by astrocytes on neuronal morphology and considered structural predictions for their differences. Methods Astrocyte conditioned media (ACM) was collected from primary astrocytes cultured from mice with targeted replacement of mouse ApoE with human ApoE3, ApoE4, or chimp. Neuron morphology was then examined in neonatal rat hippocampal neurons cultured in ACM. In vitro data was complemented by structural analysis of ApoE isoforms. Results ApoE-chimp ACM stimulated 30% more neurites per neuron than human ApoE ACM. In contrast, ACM from ApoE-chimp more closely resembled human ApoE4 than ApoE3, yielding 40% shorter neurites and spines. Structural modeling confirmed that chimpanzee ApoE differs from both ApoE4 than ApoE3, consistent with the predicted evolutionary trajectory. Conclusions Chimpanzee ApoE is structurally and functionally closer to ApoE4 than ApoE3 but still differs for neuronal development and protein folding. These findings provide insight into species-specific ApoE evolution, with implications for AD susceptibility and neuronal development.