A new transgenic rat that more closely models the human pathology of Alzheimer’s disease than the commonly used mouse model has been developed.
Since the 1990s, mice overexpressing amyloid-β peptide (Aβ) have been the primary experimental models for Alzheimer’s disease. Drug research has relied on these mouse models for pre-clinical tests. But so far, no drugs have been developed that are effective at treating Alzheimer’s.
“We reasoned that because rats are about 5 million years closer to humans on the evolutionary tree, they might better model the human pathological syndrome,” said Terrence Town, professor of physiology and biophysics at the University of Southern California’s Keck School of Medicine and author of a new paper published this week in the Journal of Neuroscience describing the new rat Alzheimer’s model (1).
To begin with, Town and colleagues looked at the Fischer 344 rat strain because it had known similarities with humans in regards to brain aging. The team then engineered that rat strain to express mutant versions of two genes that cause familial early-onset Alzheimer’s disease in humans, namely amyloid precursor protein (APP) and presenilin 1.
As a result, the animals exhibited disease markers matching those of human patients, including amyloid plaques, neurofibrillary tangles, and cortical neuron cell death.
“We expected to see more plaque pathology maybe than mice get, and some evidence of neuronal disease, but we didn’t expect to see neurofibrillary tangle pathology or loss of neurons in the cortex. Those were both pretty shocking,” said Town.
The difference may lie in the tau protein, which forms the neurofibrillary tangles. Of six isoforms that occur in humans, mice share only three—but rats share all six.
Town believes this similarity explains why the rat model is significantly better than the mouse. “By driving the amyloid pathway using two mutant human transgenes, which are each independently causative of early onset familial Alzheimer’s disease in humans, we’re elevating the amyloid pathology and… pushing a cascade that includes the neurofibrillary tangle pathology and the consequent loss of neurons,” said Town.
The new rat model also supports the theory that Aβ peptides deposits cause Alzheimer’s disease. Because mice that over-produce Aβ didn’t exhibit all of the pathologies of Alzheimer’s disease, some critics questioned whether Aβ really was the culprit. “Now we’ve shown if you change the species [to rats], the Aβ pathway can drive the other pathologies,” said Town.
Town’s group is now testing some of its own Alzheimer’s drug candidates using the rat model and plans to make the drugs available to others. “Hopefully we can fast track those drugs from animal models into the clinical and in the end find some drugs that will work,” he said.
- Cohen RM et al. A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric Aβ and frank neuronal loss. Journal of Neuroscience, April 10, 2013 DOI: 10.1523/JNEUROSCI.3672-12.2013