Mouse Models Of Neurodegenerative Diseases Research Articles

Mouse models for neurodegenerative diseases and a theory of proteomics

Proteome analysis is usually performed by separating complex cellular protein extracts by two‐dimensional‐electrophoresis followed by protein identification using mass spectrometry. In this way proteins are compared from normal and diseased tissue in order to detect disease related protein changes. In a strict sense, however, this procedure cannot be called proteome analysis: the tools of proteomics are used just to detect some interesting proteins which are then investigated by protein chemistry as usual. Real proteome research would be studying the cellular proteome as a whole, its composition, organization and its kind of action. At present however, we have no idea how a proteome works as a whole; we have not even a theory about that. If we would know how the proteome of a cell type is arranged, we probably would alter our strategy to detect and analyze disease‐related proteins. I will present a theory of proteomics and show some results from our laboratory which support this theory. The results come from investigations of the mouse brain proteome and include mouse models for neurodegenerative diseases.

Transgenic mouse models of neurodegenerative disease: opportunities for therapeutic development.

Neurodegenerative diseases present an extraordinary challenge for medicine due to the grave nature of these illnesses, their prevalence, and their impact on individuals and caregivers. The most common of these age-associated chronic illnesses are Alzheimer's disease (AD) and Parkinson's disease (PD); other examples include the prion disorders, amyotrophic lateral sclerosis (ALS), and the trinucleotide (CAG) repeat diseases. All of these diseases are characterized by well-defined clinical syndromes with progressive courses that reflect the dysfunction and eventual loss of specific neuronal populations. Current therapies provide only symptomatic relief; none significantly alter the course of disease. We describe here how transgenic mice designed to model these diseases have substantially contributed to the identification and validation of many promising new therapies, and conversely how they have quickly and cost effectively eliminated several targets with unrealized expectations.

Genetically engineered mouse models of neurodegenerative diseases.

Recent research has significantly advanced our understanding of the molecular mechanisms of neurodegenerative diseases, including Alzheimer's disease (AD) and motor neuron disease. Here we emphasize the use of genetically engineered mouse models that are instrumental for understanding why AD is a neuronal disease, and for validating attractive therapeutic targets. In motor neuron diseases, Cu/Zn superoxide dismutase and survival motor neuron mouse models are useful in testing disease mechanisms and therapeutic strategies for amyotrophic lateral sclerosis (ALS) and spinal motor atrophy, respectively, but the mechanisms that account for selective motor neuron loss remain uncertain. We anticipate that, in the future, therapies based on understanding disease mechanisms will be identified and tested in mouse model systems.

Cell vehicles for gene transfer to the brain

Gene products of therapeutic value have been delivered directly to the brain by viral and physical transfer methods and indirectly using cell delivery vehicles. Neural precursor cells, produced by immortalization or expansion with growth factors (e.g. fibroblast growth factor (FGF2)), offer promise both as vehicles for gene delivery to the brain and for their inherent ability to differentiate into neurons and glia in vivo. Their ability to migrate widely throughout the brain after injection, and to integrate in a functional and non-disruptive manner are key advantages over non-neural cells. In mouse models of neurodegenerative disease, transplanted neural precursor cells performed dual functions; they acted as a gene delivery vehicle, supplying a deficient enzyme, and provided some neuroglial cell functions which had been lost. Genetically modified neural precursor transplants influenced the development of inherited neurological disease, establishing the feasibility of this novel approach as a treatment for neurodegenerative disorders.

Comparative in vivo and pathological analysis of the blood‐brain barrier in mouse telencephalic transplants

The post-transplantation status of the blood-brain barrier (BBB) is still a matter of debate. In an attempt to define BBB properties after neural transplantation in mice of a defined genetic background, we have used two exogenous markers (horseradish peroxidase and Evans blue), one endogenous marker (immunoglobulins), and in vivo contrast enhanced magnetic resonance imaging (MRI) and compared the results obtained with the different methods. With all four techniques employed, we found the BBB to be reconstituted in 67% of the grafts 3 weeks after grafting, and in more than 90% of all grafts 50 days after grafting. Horseradish peroxidase and contrast enhanced MRI were the most sensitive techniques, the latter offering the unique advantage of repetitive scanning of individual grafts. Our findings provide important information for transplantation studies in mouse models for neurodegenerative diseases.