Molecular characterization of selectively vulnerable neurons in Alzheimer's disease.
Kun LengEmmy LiRana A EserAntonia PiergiesRene SitMichelle TanNorma F NeffSong Hua LiRoberta Diehl RodriguezClaudia Kimie SuemotoRenata Elaine Paraizo LeiteAlexander J EhrenbergCarlos A PasqualucciWilliam W SeeleySalvatore SpinaHelmut HeinsenLea Tenenholz GrinbergMartin Edward KampmannPublished in: Nature neuroscience (2021)
Alzheimer's disease (AD) is characterized by the selective vulnerability of specific neuronal populations, the molecular signatures of which are largely unknown. To identify and characterize selectively vulnerable neuronal populations, we used single-nucleus RNA sequencing to profile the caudal entorhinal cortex and the superior frontal gyrus-brain regions where neurofibrillary inclusions and neuronal loss occur early and late in AD, respectively-from postmortem brains spanning the progression of AD-type tau neurofibrillary pathology. We identified RORB as a marker of selectively vulnerable excitatory neurons in the entorhinal cortex and subsequently validated their depletion and selective susceptibility to neurofibrillary inclusions during disease progression using quantitative neuropathological methods. We also discovered an astrocyte subpopulation, likely representing reactive astrocytes, characterized by decreased expression of genes involved in homeostatic functions. Our characterization of selectively vulnerable neurons in AD paves the way for future mechanistic studies of selective vulnerability and potential therapeutic strategies for enhancing neuronal resilience.
Keyphrases
- cerebral ischemia
- functional connectivity
- climate change
- spinal cord
- resting state
- cognitive decline
- poor prognosis
- subarachnoid hemorrhage
- single cell
- brain injury
- high resolution
- working memory
- gene expression
- single molecule
- dna methylation
- spinal cord injury
- mild cognitive impairment
- depressive symptoms
- social support
- long non coding rna
- multiple sclerosis