Parkinson's Disease Models

While both types of models share several common features, such as robust neuroinflammation and neurodegeneration, there are specific differences. Based on the particular target(s) and mechanism(s)-of-action of a therapeutic agent, one model may possess advantages over the other.

PFF-injected animals demonstrate spreading of misfolded α-synuclein fibrils, which is thought to be a key pathologic process in neurodegenerative diseases, including Parkinson’s disease. The specific phenotype depends on the injection site (neuroanatomical pathways targeted) and disease duration. These animals can develop widespread pathology throughout the brain (including dopaminergic and non-dopaminergic neurons) with a well-defined spatiotemporal pattern in cortical and subcortical structures, thereby replicating multiple motor and non-motor aspects of human PD.

AAV-injected animals develop a strong phenotype associated with unilateral dopaminergic deficits. Behaviorally, these mice are similar to 6-hydroxydopamine (6-OHDA) lesioned animals, with the advantage that the pathology is driven by α-synuclein, rather than by a chemical toxin, thereby providing greater clinical relevance. These mice show selective degeneration of dopaminergic neurons in the substantia nigra pars compacta and concomitant loss of dopaminergic terminals in the striatum. Highly significant motor deficits can be readily measured in these mice (e.g. rotarod test) within a relatively short timeframe (2-3 months).

Transgenic mice overexpressing human α-synuclein have higher levels of α-synuclein expression in neurons compared to non-transgenic animals. As such, there is more “endogenous” α-synuclein “substrate” available for induced misfolding as part of the pathology spreading process. As a result, a greater level of α-synuclein aggregates can be observed in cell bodies and processes compared to that observed in wild-type mice. This greater burden of α-synuclein pathology leads to significant neuroinflammation (with activated microglia and reactive astrocytes) and neurodegeneration. As a consequence, distinct phenotypes with altered behavior, brain atrophy, changes in fluid biomarkers, etc., which can serve as robust readouts in preclinical efficacy studies, can be observed in these PFF-injected transgenic animals.

In PFF-induced models, which show extensive neurodegeneration in multiple brain regions, in-life measures, such as MRI-based brain atrophy and blood & CSF neurofilament light chain, can be used. An advantage of these measures is that they can serve as clinically translation biomarkers. Read more about these measures in Brain Atrophy Analysis in Mouse Models of Neurodegeneration and Neurofilament Light Chain in Parkinson's Disease Models.

In AAV-induced models, which demonstrate neurodegeneration of dopaminergic neurons localized to the substantia nigra and striatum, quantification of dopaminergic neuron nuclei, cell bodies, cell processes (axons, dendrites), and synaptic terminals can be readily achieved via immunohistochemistry or multiplex immunofluorescence. Examples can be seen in AAV A53T α-Synuclein Mouse Model of Parkinson's Disease and AAV α-Synuclein Models for Parkinson's Disease Drug Development.

Non-motor symptoms are key features of human Parkinson’s disease. Depending on the injection site of the PFFs in transgenic α-synuclein-overexpressing mice, non-motor symptoms (e.g. sleep alterations, reduced olfaction, behavioral & cognitive deficits) can be found. For example, by targeting the limbic system, highly significant, progressive changes in sleep-wake cycles can be observed and quantitatively measured.