The best animal model we’ve had for PSP over the last 20 years has been a mouse genetically engineered to carry a mutated human tau gene. The mutation is typically one of two single-nucleotide substitutions, each found in a form of hereditary frontotemporal dementia. Such a model has been convenient and productive. But it would be preferable for a PSP model that a) is in a species with a brain whose circuitry is a bit closer our own, and b) to more closely mimic the pathology of human PSP. A vivid illustration of the inadequacy of the tau mouse has been the recent failure of two anti-tau antibodies to help human PSP after clear success in slowing progression of pathology in the tau mouse. Dogs, cats or monkeys present practical and ethical difficulties. Rats have been a candidate but attempts to create a tau rat have failed. Until now.
A team at the State University of New York at Buffalo led by Dr. Stewart D. Clark has just created a rat with something resembling PSP. The lead author was Dr. Gabriella King. The title of the article, in the European Journal of Neuroscience, says it all: Human wildtype tau expression in cholinergic pedunculopontine tegmental neurons is sufficient to produce PSP-like behavioural deficits and neuropathology.
The researchers took advantage of the fact that PSP involves a complex cluster of cell bodies in the brainstem called the pedunculopontine tegmentum (PPT; often called in the literature the pedunculopontine nucleus, or PPN). The PPT uses acetylcholine as its neurotransmitter and provides input to many other brain areas involved in PSP. A loss of acetylcholine-based connections is a major part of the pathology of PSP. Damage to the PPT alone causes severe gait and balance problems, and loss of its acetylcholine input to other areas causes many other symptoms. Attempts are ongoing to develop deep-brain stimulation to the PPT as treatment for the balance problems of PSP and Parkinson’s.
The researchers started with rats that were genetically engineered to readily incorporate any introduced gene into neurons that make acetylcholine. Then, they put the gene for normal human tau into a kind of virus that readily and safely enters brain cells – called an adeno-associated virus. It’s a commonly-used laboratory tool. They injected those viruses into five spots in each PPT and three in a part of each thalamus that projects to the PPT, for a total of 16 injections into each rat’s brain.
A month later, the result was gait and balance difficulties and a loss of reactivity to loud noises (which occurs to a degree in human PSP). Autopsy showed fewer acetylcholine-making neurons in the PPT, fewer dopamine-making neurons in the substantia nigra (presumably because of a loss of input from the PPT), and abnormal aggregates of tau protein in the brainstem resembling neurofibrillary tangles. None of these abnormalities occurred in control rats receiving injections of adeno-associated virus carrying the gene for a harmless protein into the same 16 spots.
Clearly, this model is not as convenient as the tau mouse, which can be bred in colonies without a need for 16 carefully placed brain injections. Another problem is that rats are more expensive to purchase and maintain than mice, mostly just because they’re larger. But for smaller-scale projects, this is a major advance. Let’s watch for commercialization of the model and for its utilization by other labs.