A Translational 3D Map of Hippocampal Cell Types To Drive Investigations of Alzheimer's Disease

PROJECT SUMMARY/ABSTRACT
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that spreads across the brain from
its origin in the medial temporal lobe. The hippocampus is one of the earliest and most affected brain regions in
AD and hippocampal atrophy has been linked to the severity of the behavioral symptoms. Although numerous
theories have been put forth, the molecular underpinnings of hippocampal neurodegeneration remain unclear.
This lack of understanding has stymied AD drug development from translating animal research into human
treatment. I believe that a translational cellular atlas that bridges the gap between mouse and human AD
research is needed to determine which specific hippocampal cell types are affected by AD. My previous research
creating the mouse Hippocampus Gene Expression Atlas (HGEA) lays a strong foundation for this effort
(Bienkowski et al., Nature Neuroscience, 2018). The HGEA defines 20 distinct genetic subdivisions of the
hippocampus and subiculum based on mapped gene expression patterns, delineates each region’s input/output
pathways, and demonstrates how each region contributes to brain-wide networks. Overall, I found that
hippocampal gene expression patterns were highly related to specific anatomical connectivity patterns. Among
many new insights, I discovered that subiculum gene expression patterns revealed hidden lamina of pyramidal
neurons and demonstrated how this laminar architecture underlies a columnar organization similar to the
cerebral cortex. Altogether, the HGEA demonstrates the multiscale organization of the hippocampus from
individual genetic cell types to neuronal networks regulating animal behavior. I established a number of
resources and tools on the Mouse Connectome Project website so that other hippocampal scientists around the
world could use the HGEA to guide their own research experiments. The funding of this K01 Mentored Research
Scientist Career Development Award application will provide me with training and expertise I need in order to
develop a human version of the HGEA as a translational resource to understand AD neurodegeneration. Building
on the mouse HGEA, the proposed research uses a cutting-edge spatial transcriptomics approach in thick
optically-cleared tissue sections (STARmap) to reveal multiplexed gene expression patterns, build a human
HGEA that can be registered to MRI data, and investigate changes to HGEA-defined neuronal cell types caused
by hippocampal neurodegeneration within an AD mouse model (5XFAD mice) and humans with AD. To guide
this project and my career development, I have assembled a world-class team of supportive mentors (Drs. Arthur
Toga and Berislav Zlokovic) and collaborators (Dr. Carol Miller) to provide me with new training to investigate
Alzheimer’s disease in both transgenic mouse models and human post-mortem tissue. Ultimately, the funding of
this K01 proposal will complete my career development toward leading a translational neuroscience laboratory
studying the relationship of gene expression, connectivity, and behavior in neurological disease.

Grant Number: 5K01AG066847-05
NIH Institute/Center: NIH
Principal Investigator: Michael Bienkowski