2. Academic Validation
  3. A cell autonomous regulator of neuronal excitability modulates tau in Alzheimer's disease vulnerable neurons

A cell autonomous regulator of neuronal excitability modulates tau in Alzheimer's disease vulnerable neurons

  • Brain. 2024 Mar 11:awae051. doi: 10.1093/brain/awae051.
Patricia Rodriguez-Rodriguez 1,  Luis Enrique Arroyo-Garcia 1,  Christina Tsagkogianni 1,  Lechuan Li 2,  Wei Wang 3,  Ákos Végvári 4,  Isabella Salas-Allende 5,  Zakary Plautz 5,  Angel Cedazo-Minguez 1,  Subhash C Sinha 6,  Olga Troyanskaya 7 8 9,  Marc Flajolet 5,  Vicky Yao 4,  Jean-Pierre Roussarie 10
Affiliations

Affiliations

  • 1 Department of Neurobiology Care Sciences and Society, Karolinska Institutet, 17 164, Solna, Sweden.
  • 2 Department of Computer Science, Rice University, Houston, TX 77004, USA.
  • 3 Bioinformatics Resource Center, The Rockefeller University. New York, NY 10065, USA.
  • 4 Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17 164, Solna, Sweden.
  • 5 Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University. New York, NY 10065, USA.
  • 6 Helen & Robert Appel Alzheimer's Disease Research Institute. Brain and Mind Research Institute, Weill Cornell Medicine. New York, NY 10065, USA.
  • 7 Department of Computer Science, Princeton University. Princeton, NJ 08540, USA.
  • 8 Lewis-Sigler Institute for Integrative Genomics, Princeton University. Princeton, NJ 08544, USA.
  • 9 Flatiron Institute, Simons Foundation. New York, NY 10010, USA.
  • 10 Boston University Chobanian & Avedisian School of Medicine. Boston, MA 02118, USA.
PMID: 38462574 DOI: 10.1093/brain/awae051
Abstract

Neurons from layer II of the entorhinal cortex (ECII) are the first to accumulate Tau Protein aggregates and degenerate during prodromal Alzheimer's disease (AD). Gaining insight into the molecular mechanisms underlying this vulnerability will help reveal genes and pathways at play during incipient stages of the disease. Here, we use a data-driven functional genomics approach to model ECII neurons in silico and identify the proto-oncogene DEK as a regulator of tau pathology. We show that epigenetic changes caused by Dek silencing alter activity-induced transcription, with major effects on neuronal excitability. This is accompanied by gradual accumulation of tau in the somatodendritic compartment of mouse ECII neurons in vivo, reactivity of surrounding microglia, and microglia-mediated neuron loss. These features are all characteristic of early AD. The existence of a cell-autonomous mechanism linking AD pathogenic mechanisms in the precise neuron type where the disease starts provides unique evidence that synaptic homeostasis dysregulation is of central importance in the onset of tau pathology in AD.

Keywords

Alzheimer; DEK; immediate early genes; selective vulnerability; tau pathology.

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