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

TitleA cell autonomous regulator of neuronal excitability modulates tau in Alzheimer's disease vulnerable neurons.
Publication TypeJournal Article
Year of Publication2024
AuthorsRodriguez-Rodriguez P, Arroyo-Garcia LEnrique, Tsagkogianni C, Li L, Wang W, Végvári Á, Salas-Allende I, Plautz Z, Cedazo-Minguez A, Sinha SC, Troyanskaya O, Flajolet M, Yao V, Roussarie J-P
JournalBrain
Volume147
Issue7
Pagination2384-2399
Date Published2024 Jul 05
ISSN1460-2156
KeywordsAlzheimer Disease, Animals, Entorhinal Cortex, Humans, Mice, Mice, Transgenic, Neurons, Proto-Oncogene Mas, tau Proteins
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. 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 the 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 Alzheimer's disease. The existence of a cell-autonomous mechanism linking Alzheimer's disease 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 Alzheimer's disease.

DOI10.1093/brain/awae051
Alternate JournalBrain
PubMed ID38462574
PubMed Central IDPMC11224620
Grant List / / Fisher Center for Alzheimer's Disease Research /
RF1 AG047779 / AG / NIA NIH HHS / United States
799638 / / European Union's Horizon 2020 /
/ / Alzheimerfonden and Margaretha af Ugglas Stiftelse /
/ / Cure Alzheimer's Fund /
RF1 AG054564 / GF / NIH HHS / United States