Dynamics of amyloid plaque formation in Alzheimer’s Disease

McCarter, Joanna F (2014): Dynamics of amyloid plaque formation in Alzheimer’s Disease. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)

Abstract

Alzheimer’s disease (AD) is a fast growing global problem. AD is a form of dementia characterised by the progressive loss of cognitive abilities. Pathologically, the disease is defined by two neuropathological hallmarks: neurofibrillary tangles and amyloid-β plaques. Plaques appear to be toxic to brain tissue and are surrounded by activated microglia and astrocytes, dystrophic neurites and neurons under oxidative stress. When plaques first develop, they are generally small, but in advanced AD, plaques can be much larger. How small plaques may develop into large plaques is still unclear. A number of studies have shown that small plaques grow uniformly over time to give rise to larger plaques. However, this study investigates an alternative hypothesis: that clusters of multiple small plaques merge over time to form large plaques. This hypothesis was inspired by a study that showed that plaques do not deposit in random locations within the brain parenchyma, but rather form in clusters and that these plaque clusters get bigger over time. The aim was to investigate the clustering of plaques in vivo, and follow these clusters over time to see whether they merge together to form a single, larger plaque. This study employed a 2-stage staining technique to follow individual plaques in APPPS1 transgenic mice over time. The fluorescent, amyloid-binding dye Methoxy-X04 was injected into the mice at Day 0 of the experiment. Methoxy-X04 crosses the blood brain barrier and binds stably to plaques for several months and thus labelled the original plaque population. Following 1 day, 1 month or 4 month incubation periods, acute in vivo plaque imaging was performed or the mice sacrificed for post mortem analysis. Antibodies against amyloid-β labelled the state of the plaques at these later time points. Hence this procedure enabled comparison of individual plaque status at different time points and the identification of new plaques that had developed over the incubation time. Detailed analysis of the new and pre-existing plaques revealed two key results. Firstly, that new plaques are more likely to form very close (< 40 µm) to a pre-existing plaque than at further distances. New plaques depositing very close to other plaques formed clusters of plaques in the tissue. Secondly, that clusters of close plaques can fuse over time to form a single large plaque. These two key results provide compelling evidence for a clustering hypothesis of large plaque formation and growth. Together, these data provide in vivo support for the clustering hypothesis by which clusters of small plaques merge together to form single plaques over time. This work expands our understanding of how plaques form and develop in AD and could inform the understanding of plaque clearance strategies to combat AD pathological changes in the brains of patients.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: Alzheimer's disease, neuroscience, amyloid, plaques
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
• Fakultäten: Graduate School of Systemic Neurosciences (GSN)
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: Februar 2014
• 1. Bericht­erstatter:in: Meyer-Luehmann, Melanie