Structural and functional alterations of cortical neurons in Alzheimer’s disease transgenic mice assessed by two-photon in vivo imaging

Liebscher, Sabine (2017): Structural and functional alterations of cortical neurons in Alzheimer’s disease transgenic mice assessed by two-photon in vivo imaging. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)

Abstract

Alzheimer’s disease (AD), the most common form of dementia, has been proposed to result from the degeneration of synapses, putatively caused by assemblies of the amyloid-β peptide (Aβ). The spatiotemporal dynamics of this synaptopathy, its potential reversibility as well as its consequences on the function of single neurons and neuronal circuits, however, are not fully understood to date. In order to address these questions, I assessed structural and functional alterations of neurons in the neocortex in a transgenic mouse model of Alzheimer’s disease, namely APP/PS1 (APPswe, PS1L166P) mice, using in vivo two-photon imaging. Chronic imaging of dendrites and axons over the course of four weeks revealed not only a reduction in dendritic spine density close to amyloid plaques (proteinaceous extracellular deposits typical of AD), but I also identified synaptic instability as a main aspect contributing to AD pathology. Importantly, while synapse loss was confined to the immediate plaque vicinity (up to 15µm from the histological plaque border), synaptic instability was evident in a much larger region surrounding plaques (50 µm) and affected both, pre- and postsynaptic compartments. As the prevailing hypothesis in AD holds that Aβ conveys these detrimental effects on synapses one therapeutic approach is based on the pharmacological inhibition of Aβ generation. I thus assessed the impact of a novel selective γ-secretase inhibitor (GSI), a compound that prevents the last cleavage step necessary for the release of Aβ from the longer transmembrane amyloid precursor protein (APP). Notably, the GSI used here primarily interferes with the processing of APP and still allows for processing of other γ-secretase substrates, and hence should largely reduce side effects seen with earlier generations of GSIs before. Daily treatment with the GSI reduced the deposition of Aβ as evidenced by the initial reduction in the number of new plaques and a sustained decrease in the growth of these newly deposited plaques. Importantly, it also ameliorated the plaque-associated synaptic instability, without displaying overt adverse effects on dendritic spines in WT mice. These data represent the first in vivo evidence that selective pharmacological inhibition of the γ-secretase mediated APP cleavage can have beneficial effects on synaptic pathology in AD. Given the widespread impact of Aβ assemblies on neuronal structures, I then asked to which extent these structural alterations affect the function of neurons. To address this question, I recorded neuronal response properties in the primary visual cortex of behaving APP/PS1 mice, employing in vivo two-photon calcium imaging using the genetically encoded calcium indicator GCaMP6m. In order to probe the impact of AD related pathology on specific aspects of information processing, which rely on multiple neuronal circuits, I characterized visually driven and motor-related activity, as well as signals based on mismatches between actual and expected visual input. My data reveal a massive reduction in responsiveness under almost all conditions tested, which is line with the profound impact on neuronal structure. Stimulus selectivity, like orientation or direction tuning, were not altered in APP/PS1 mice, indicating that the main effect is caused by a change in response gain. Along with the massive decrease in feedforward signals, I observed an increase in spontaneous, hence uncorrelated neuronal activity in AD transgenic mice. Both features jointly affected the coding accuracy of the network, and I propose that this combination may represent a common characteristic leading to impaired information processing in AD. Surprisingly, I found that responses elicited after a discordance of actual and expected visual flow during running, i.e. a visuomotor mismatch, were selectively spared in APP/PS1 mice, suggesting a particular resilience of this very signal. Together, both studies demonstrate that global widespread structural changes of neurons in the AD brain are accompanied by a severe impact on information processing, most prominently seen in a strong reduction of feedforward signals. My data, thus, provide a correlate of impaired cognition in AD at the level of single neurons and neural circuits.

Abstract

Abstract

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: Alzheimer's disease, APP/PS1 mice, two-photon imaging, dendritic spines, axonal boutons, amyloid plaques, gamma secretase inhibitor, calcium imaging, genetically encoded calcium indicator, sensorimotor integration, visual cortex, behaving mice, sensorimotor mismatch, interneurons
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Graduate School of Systemic Neurosciences (GSN)
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 31. Januar 2017
• 1. Bericht­erstatter:in: Hübener, Mark