New findings have revealed important differences between human and mouse models, which has important implications for disease research.
Led by UCLA, the study compared brain cells known as astrocytes in humans and mice, finding that mice astrocytes are more resilient to oxidative stress – a damaging imbalance behind many neurological disorders.
The findings have implications for understanding neurological disorders such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis – conditions whose underlying mechanisms include oxidative stress, lack of oxygen, and excessive inflammation.
A lack of oxygen triggers molecular repair mechanisms in mouse astrocytes but not in human astrocytes, and, in contrast, inflammation activates immune-response genes in human astrocytes but not mouse astrocytes.
Difference between humans and mice
Results from mouse studies are not always applicable to humans, with more than 90% of drug candidates showing that preclinical promise for neurological disorders fail when tested in humans. This is, in part, due to the lack of understanding regarding the differences in astrocytes and other brain cells between the two species.
Astrocytes are a critical element of the development and function of the brain and play a role in neurological disorders that is not yet fully understood. Injury or infection causes astrocytes to go from a resting to reactive state in which they can aid in repairing the brain but can also increase detrimental inflammation.
For this research, the team studied developing cells purified from mouse and human brain tissue, as well as cells grown in serum-free cultures from astrocytes selected using an antibody-based method. Using this strategy, the researchers were able to examine the astrocytes in a healthy state and in controlled conditions of oxidative stress, lack of oxygen, and excessive inflammation.
The authors suggest that, because mouse astrocytes stand up to oxidative stress better, laboratory models for neurodegeneration could be engineered to lessen that resistance, rendering them more human-like.
In addition, the mouse astrocyte’s facility for repair in response to lack of oxygen may suggest a new avenue of stroke research, and, the researchers point out, that neuroscientists can take a more informed approach to preclinical studies by accounting for differences in response to inflammation between mouse and human astrocytes, as well as metabolic differences.
