Big steps forward for mouse models that mimic tauopathy in humans
Researchers have long searched for an explanation for why there is so much variety in how abnormal aggregates of the protein tau occur in the brains of people with Alzheimer's disease. Two recent NIA-supported studies led by Dr. Virginia M-Y Lee, at the University of Pennsylvania School of Medicine, have taken important steps forward in that quest by creating a new mouse model for Alzheimer's disease that more realistically mimics the different forms of tau — and the key interactions between amyloid-beta and tau — seen in the human version of the disease.
Scientists suspect that multiple factors are involved in shaping the diverse architectures of tau strains, such as a person's age when amyloid plaques and tau-associated tangles first appear, the brain region where the disease first takes root, the body's inflammatory response, and the influence of other health conditions. A growing body of evidence shows that different presentations of Alzheimer's are connected at the molecular level to different types of misfolded tau.
In the first study, Dr. Lee and her colleagues successfully injected enriched preparations of different types of tau from postmortem donated human brain tissue into transgenic mice with different amounts of amyloid plaques in their brains. They found that once seeded with the tau samples, the mouse brains with higher levels of amyloid plaques created an environment that promoted the fast development and spread of abnormal tau. They observed that misfolded tangles appeared in the seeded mice brains in distinct patterns like those in humans.
In the second study, Dr. Lee and her team were able to reproduce and see clearly in mice the forms of three major types of tau found in human Alzheimer's: tau aggregates in deteriorated axons or dendrites emanating from amyloid plaques; neurofibrillary tangles; and a type of abnormal dendrite structure known as neuropil threads.
Scientists caution that despite this initial success in seeding and modeling human disease structure in mice brains, they have not yet evaluated the mice for memory and cognitive symptoms seen in human Alzheimer's. Also, the investigators are refining the process for preparing and injecting uniform samples of enriched tau into mice brains. Future studies may refine these innovative mouse models as useful new tools to study Alzheimer's. If forthcoming projects can show that these tau pathologies pass to a new generation of mice, additional steps forward for Alzheimer's disease research mouse models that could more closely approximate human disease could be on the horizon.
Lee VM, et al. Amyloid-β plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med. 2017 Dec 4. doi: 10.1038/nm.4443. [Epub ahead of print]
Lee VM, et al. Pathological Tau Strains from Human Brains Recapitulate the Diversity of Tauopathies in Nontransgenic Mouse Brain. J Neurosci. 2017;37(47):11406-11423.