A Journey into the Brain: In Vivo Imaging of Alzheimer’s Disease Mouse Models

MEYER-LUEHMANN (Ludwig-Maximilians-Universität Munich):

Alzheimer’s disease is the most common form of senile dementia worldwide. Its debilitating effects create enormous social and economic problems. With an ever-aging population, its incidence is expected to increase exponentially in the years to come, giving a particular urgency to research. There is a multitude of theories about the causes and potential risk factors of Alzheimer’s disease, yet none have been conclusively proven — or most crucially — have led to an efficacious therapy for patients.

Many neurodegenerative diseases, including Alzheimer’s disease, are characterised by pathological protein aggregation in the brain. In Alzheimer’s disease patients, the brain has a clear pathology composed of two types of protein aggregates: extracellular plaques and intracellular so-called neurofibrillary tangles. Both types of aggregate are associated with the death of neurons and shrinkage of brain volume. However, the biochemical mechanism giving rise to the formation of these plaques and tangles and the associated neuronal cell death remains unclear.

To study Alzheimer’s disease, a variety of mouse models have been generated that develop several lesions similar to those seen in patients. These models only mimic specific parts of the pathogenesis described above, making them of great experimental value in dissecting the individual contributions of each type of lesion observed to the progression of the disease. Taking advantage of multiphoton microscopy — a fascinating and relatively new technique — we are able to study the temporal relationship between extracellular plaque formation and changes in local neuronal structures. This technique allows for imaging of the brain of individual mice over a long time period at very high resolution. It is possible to visit the same sites in the brain multiple times and track any changes that occur over several months. No other technique allows such finely detailed pictures — resolved to less than one-thousandth of a millimetre — which allows for the reconstruction of the three-dimensional structures in the brains of living mice. In addition to our own studies of plaque dynamics, multiphoton microscopy has been used with great success by several other labs to study — for example, the cellular response to brain injury. In our work, we are able to observe neurons, plaques and blood vessels simultaneously in the living mouse in real time.

During my postdoctoral work in Professor Brad Hyman’s lab at Harvard Medical School in Boston, I studied the temporal relationship between plaque formation and neuronal changes. Imaging the brains of living mice on a daily basis uncovered that plaques appear relatively suddenly — literally from one day to the next. After a plaque appears, progressive changes lead to increasingly curved, misshapen neuronal processes over the following days and weeks within the immediate vicinity of the plaque. In addition we also found a subtle increase in the curvature of neurons even further away from plaques. Our results suggest that plaque-related changes are a direct consequence of plaque formation; subtle changes distant from plaques may imply long-range effects of plaques or may be a consequence of intermediate forms of the plaque-forming amyloid-beta proteins.

In order to provide an effective therapy, it is essential to understand the pathogenesis of the disease. Therefore, using mouse models of Alzheimer’s disease, we visualize plaque development and the morphological neuronal changes associated with it in vivo. Our studies on plaque formation and the associated effects in the living animal also demonstrate that multiphoton microscopy provides a powerful tool to investigate preclinical plaque protein-targeting therapeutic strategies. Future studies will have to address relevant questions, in particular whether the structural pathologies observed in Alzheimer’s disease are reversible and if so, whether treatments can be developed that will promote this.

Melanie Meyer-Luehmann
Ludwig-Maximilians-Universität Munich
www.atomiumculture.eu

 

Reference

Meyer-Luehmann M, Spires-Jones TL, Prada C, Garcia-Alloza M, de Calignon A, Rozkalne A, Koenigsknecht-Talboo J, Holtzman DM, Bacskai BJ, Hyman BT (2008). Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease.Nature 451:720 – 724.

 

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