CaltechAUTHORS
Published April 19, 2023 | Version public
Journal Article Metadata-only

Lateral mammillary body neurons in mouse brain are disproportionately vulnerable in Alzheimer's disease

Creators

  • 1. ROR icon Massachusetts Institute of Technology
  • 2. ROR icon Broad Institute
  • 3. ROR icon Rush University Medical Center

Abstract

The neural circuits governing the induction and progression of neurodegeneration and memory impairment in Alzheimer's disease (AD) are incompletely understood. The mammillary body (MB), a subcortical node of the medial limbic circuit, is one of the first brain regions to exhibit amyloid deposition in the 5xFAD mouse model of AD. Amyloid burden in the MB correlates with pathological diagnosis of AD in human postmortem brain tissue. Whether and how MB neuronal circuitry contributes to neurodegeneration and memory deficits in AD are unknown. Using 5xFAD mice and postmortem MB samples from individuals with varying degrees of AD pathology, we identified two neuronal cell types in the MB harboring distinct electrophysiological properties and long-range projections: lateral neurons and medial neurons. lateral MB neurons harbored aberrant hyperactivity and exhibited early neurodegeneration in 5xFAD mice compared with lateral MB neurons in wild-type littermates. Inducing hyperactivity in lateral MB neurons in wild-type mice impaired performance on memory tasks, whereas attenuating aberrant hyperactivity in lateral MB neurons ameliorated memory deficits in 5xFAD mice. Our findings suggest that neurodegeneration may be a result of genetically distinct, projection-specific cellular dysfunction and that dysregulated lateral MB neurons may be causally linked to memory deficits in AD.

Additional Information

© 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. This is an article distributed under the terms of the Science Journals Default License. We thank the study participants and staff of the Rush Alzheimer's Disease Center. We thank all members of the Tsai laboratory for technical assistance and helpful comments. This research was supported in part by the JBP Foundation; Ludwig Family Foundation; and National Institutes of Health (NIH) grants RF1AG054321, RF1AG062377, RF1AG054012, U01NS110453, R01AG062335, and R01AG058002 (to L.-H.T.); P30AG10161, R01AG15819, and R01AG1717 (to D.A.B.); and RF1AG054012, U01NS110453, R01AG062335, and R01AG058002 (to M.K.). Author contributions: W.-C.H. and L.-H.T. conceived the study. W.-C.H., M.H.M., and Z.P. designed the study and collected the data. L.L. performed and analyzed the brain slice electrophysiological experiments. W.-C.H. performed the mouse experiments with help from M.C., Z.P., X.J., H.M., M.H.M., and F.A. W.-C.H. analyzed the mouse scRNA-seq data with help from H.M., X.J., and F.G. W.-C.H. and J.D.-V. analyzed the human snRNA-seq data with help from X.J., A.P.N., and H.M. D.A.B. provided the human postmortem brain tissue samples with clinical and pathologic data and critically reviewed the manuscript. M.K. and L.-H.T. supervised the study. W.-C.H., M.H.M., Z.P., and L.-H.T. wrote the paper with critical input from all the authors. Data and materials availability: All data associated with this study are present in the paper or the Supplementary Materials. Mouse MB sequencing data can be found in GEO with accession code GSE224647. Human MB sequencing data can be found in Synapse at www.synapse.org/#!Synapse:syn50670858 using the SynID syn50670858. Code used to prepare the processed counts from the raw reads and differential gene expression analysis can be accessed at Zenodo with accession number 7787348. Competing interests: D.A.B. serves on the scientific advisory boards of AbbVie, Takeda, Origent Inc., and Vigorous Minds. M.K. serves on the scientific advisory board of the NSF-Simons Center for Multiscale Cell Fate Research (CMCF). L.-H.T. serves on the scientific advisory boards of Cognito Therapeutics, Souvien Therapeutics, Cell Signaling Technology, 4M Therapeutics, Metro Bio LLC, and Jupiter Neurosciences Inc. All other authors declare that they have no competing interests.

Additional details

Identifiers

Eprint ID
121661
Resolver ID
CaltechAUTHORS:20230601-110492100.5

Funding

JBP Foundation
Ludwig Family Foundation
NIH
RF1AG054321
NIH
RF1AG062377
NIH
RF1AG054012
NIH
U01NS110453
NIH
R01AG062335
NIH
R01AG058002
NIH
P30AG10161
NIH
R01AG15819
NIH
R01AG1717
NIH
RF1AG054012
NIH
U01NS110453
NIH
R01AG062335
NIH
R01AG058002

Dates

Created
2023-06-12
Created from EPrint's datestamp field
Updated
2023-06-12
Created from EPrint's last_modified field