Transgenic rat models for deciphering neurodegenerative disease

Identification: Lopez, Peter


Transgenic rat models for deciphering neurodegenerative disease
T. Peter Lopez1, Kurt Giles1,2, Carlo Condello1,2, Zuzana Krejciova1, Noah Johnson1 Abby Oehler1, Julian Castaneda1, George A. Carlson1,2 and Stanley B. Prusiner1,2
1Institute for Neurodegenerative Diseases, 2Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158
Similar to PrP prion diseases, Alzheimer's disease, the tauopathies, Parkinson's disease, and multiple system atrophy (MSA) are thought to be caused by the misfolding of Abeta, tau, and alpha-synuclein proteins. Like PrP, these proteins become prions by undergoing a conformational change followed by self-propagation. Mouse models of neurodegenerative disease (ND) have been useful but are limited by the animal's small size, which precludes high-resolution imaging such as positron emission tomography (PET) and serial collection of cerebrospinal fluid (CSF). The brain of the laboratory rat is much larger than that of the mouse, making rats an attractive alternative to model for ND. Given the scarcity of rat models for ND, we developed tools to produce transgenic (Tg) rats that overexpress ND proteins. Wild-type rats infected with rat passaged PrP prions have 6-month incubation times; however, in our Tg rat model overexpressing PrP, prion disease onset was reduced to <4 months. We next developed Tg rat models for familial tauopathy and synucleinopathy by overexpression of MAPT*P301S and SNCA*A53T transgenes, respectively. Tg(MAPT*P301S) rats spontaneously developed phosphorylated tau (P-Tau) and neurofibrillary tangles in the frontal cortex and limbic system at 9 months of age followed by progressive neurological decline. This pathological window coincided with a 10-fold increase of a ND biomarker, neurofilament light chain, in the CSF. Importantly, P-Tau neuronal inclusions colocalized with an unlabeled tau PET tracer, PBB3. To model synucleinopathy, we inoculated Tg(SNCA*A53T) rats, which do not exhibit spontaneous disease, with human MSA samples. These rats developed phosphorylated alpha-synuclein (P-Syn) lesions in neurons and gliosis. Strikingly, we detected P-Syn aggregates in oligodendrocytes resembling glial cytoplasmic inclusions, a key feature of MSA not demonstrated in mice. Collectively, the Tg rat models described here offer new tools to identify disease mechanisms more biologically relevant to the human condition and potential therapeutics to treat them.


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