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

Human studies convincingly point to the entorhinal cortex (EC) as a key inflicted structure in the initial stages of Alzheimer's disease (AD). Early pathology is mainly confined to neurons in layer II of EC eventually resulting in a staggering loss of up to 90 % of neurons in late stages. The main hypothesis in this project is that the initial pathology in identified entorhinal 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 the entorhinal cortex that originate one of the main inputs to the hippocampal formation, another component of our cognitive memory system, strongly implicated in AD. One striking finding is that in transgenic animal models for the amyloid-β (Aβ) component of AD, intracellular expression in early stages of the disease starts in the reelin-positive entorhinal neurons. The animal experiments for which we request permission address the hypothesis that neurons in layer II of EC have a number of features that make them vulnerable for AD. We aim to explore a causal relationship between levels of Reelin expression and intracellular Aβ (iAβ) levels, and how such a possible relationship might affect cell-autonomous autophagic factors and cell death. Further, we will introduce human tau into these neurons to study the other main pathological event in AD, namely tau-induced neurofibrillary tangles. These experiments will make use of different transgenic models. We will lower the electrical activity of reelin positive neurons, and lower or increase the levels of reelin expression and study the concomitant changes in iAβ expression, changes in electrophysiological properties of local and long-range connections. We will also use cell-cultures derived from tissue directly from the relevant regions of brain to study disease mechanisms. The outcome of the proposed research will contribute to a causal description of the devastating series of events following an initial altered Aβ expression in identified neurons. These results may potentially lead to the identification of early and specific biomarkers for specific and timely diagnosis, as well as to the development of tailored treatment strategies.