Forsøksdyr: Cell-specific changes in metabolism and transmission as an initial cause of Alzheimer’s disease

Godkjenningsdato 30.01.2020

Godkjenningsperiode 15.02.2020-15.02.2023

Alzheimer’s disease (AD) is a progressive neurodegenerative disease, resulting in gross cognitive dysfunction that stems from initial synaptic loss, and eventually severe neuronal loss in the brain. Human studies convincingly point to the entorhinal cortex (EC) as a key inflicted structure in the initial stages of the disease. In brief, early pathology mainly confines to neurons in layer II of EC resulting in a staggering loss of neurons, which already by early stages surpass 50%, and by late stages reach more than 90%. The main hypothesis in this project is that the initial pathology in identified EC neurons triggers a series of interacting cascades of changes that eventually doom the network and subsequently downstream brain areas. Our previous research has provided strong indications that the main neurons involved in the initial phase of the disease are reelin expressing neurons in layer II of EC that originate one of the main inputs to the hippocampal formation, another component of the cognitive memory system which is strongly implicated in AD. One striking finding from us is that in transgenic animal models for the amyloid component of AD, intracellular accumulation in EC in early stages of the disease starts in the reelin-positive neurons. We have also provided evidence for this in human AD-subjects, although this evidence should still be considered preliminary. Our ongoing work is further pointing to a direct relationship between the levels of reelin and the levels of accumulated intracellular amyloid-â, suggesting a possible target (i.e. reelin) to intervene with at early stages. Thus, the animal experiments for which we request permission address the hypothesis that certain molecules expressed by EC layer II-neurons are among the features that make them vulnerable for AD. We aim to further explore a causal relationship between levels of reelin expression and intracellular amyloid-â, and we aim to also investigate the potential effects of this interaction on the cytoskeletal protein tau using several different transgenic models. We will lower the electrical activity of reelin positive neurons, lower the levels of reelin, and study the concomitant changes in intracellular abeta and tau accumulation. We will further examine possible changes in electrophysiological properties of local and long-range connections, and test this alongside tissue samples from which we are currently making cell cultures to explore disease mechanisms. The outcome of the proposed research will contribute to a causal description of the devastating series of events following an initial altered level and form of amyloid-â in identified EC layer II-neurons. These results may lead to the identification of early and specific biomarkers for specific and timely diagnosis as well as to the development of tailored treatment strategies.
430 rats and 440 mice.