SORL1 and its involvement in Alzheimer's disease pathogenesis and pathophysiology - Project 3

PROJECT 3 SUMMARY/ABSTRACT As discussed in detail in the Overall Program component, the PPG’s overarching goal is to investigate the pathogenesis and pathophysiology of different SORL1 AD-associated variants. Complementing and synergizing with other PPG components, this Project will rely on SORL1 mouse models to investigate the ‘anatomical biology’ of pathogenic SORL1 variants. Namely, we propose to exploit our state-of-the-art mouse MRI laboratory first to identify when and which brain regions are differentially affected by a specific pathogenic SORL1 variant, and then to attempt to provide a biological explanation for this differential regional vulnerability. Project 3 is informed by an overarching hypothesis, but at the same time the aims and experimental design are such they are not overly committed to hypothesis, incorporating the possibility of meaningful hypothesis-free results. The hypothesis is guided by three fundamental observations. The first is that MRI studies have confirmed previous postmortem observations establishing that the entorhinal cortex is a cortical brain region differentially vulnerable to AD. The second observation emerges from completed MRI studies in SORL1 haploinsufficient mice, modelling AD’s highly pathogenic protein-truncation variants, that show that the entorhinal cortex is vulnerable to SORL1’s loss of retromer-dependent function (as reviewed in the Preliminary Data section). Finally, as elaborated below, recent studies have suggested that the entorhinal’s distinct network properties provide a biological reason for why this region relies on retromer-dependent endosomal recycling. The Project’s general approach is to investigate AD-associated variants from SORL1’s different biochemical domains and use both structural and functional mouse MRI to test the hypothesis that all variants target one or more areas of the brain, which may include the entorhinal cortex. The MRI studies are designed to map the whole brain, and a whole brain analysis will allow for an unbiased search for brain regions that are affected by the variants. Whether the entorhinal cortex or other brain regions, once an affected region is identified we propose to investigate both neurons and glia in the particular region and to perform behavior studies and proteomic screens of that region. This general design therefore assures that we will either confirm or expand our understanding of the ‘anatomical biology’ of SORL1 pathogenic variants.