Probing the correlation of neuronal loss, neurofibrillary tangles, and cell death markers across the Alzheimer's disease Braak stages: a quantitative study in humans

Panos Theofilas, Alexander J. Ehrenberg, Austin Nguy, Julia M. Thackrey, Sara Dunlop, Maria B. Mejia, Ana T. Alho, Renata Elaine Paraizo Leite, Roberta Diehl Rodriguez, Claudia K. Suemoto, Camila F. Nascimento, Marcus Chin, Daniel Medina-Cleghorn, Ana Maria Cuervo, Michelle Arkin, William W. Seeley, Bruce L. Miller, Ricardo Nitrini, Carlos Augusto Pasqualucci, Wilson Jacob FilhoUdo Rueb, John Neuhaus, Helmut Heinsen, Lea T. Grinberg

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Clarifying the mechanisms connecting neurofibrillary tangle (NFT) neurotoxicity to neuronal dysfunction in humans is likely to be pivotal for developing effective treatments for Alzheimer's disease (AD). To model the temporal progression of AD in humans, we used a collection of brains with controls and individuals from each Braak stage to quantitatively investigate the correlation between intraneuronal caspase activation or macroautophagy markers, NFT burden, and neuronal loss, in the dorsal raphe nucleus and locus coeruleus, the earliest vulnerable areas to NFT accumulation. We fit linear regressions with each count as outcomes, with Braak score and age as the predictors. In progressive Braak stages, intraneuronal active caspase-6 positivity increases both alone and overlapping with NFTs. Likewise, the proportion of NFT-bearing neurons showing autophagosomes increases. Overall, caspases may be involved in upstream cascades in AD and are associated with higher NFTs. Macroautophagy changes correlate with increasing NFT burden from early AD stages.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalNeurobiology of Aging
Volume61
DOIs
StatePublished - Jan 1 2018

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Keywords

  • Alzheimer's disease
  • Autophagy
  • Caspases
  • Human brainstem
  • Neurofibrillary tangles
  • Neuron counts

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Theofilas, P., Ehrenberg, A. J., Nguy, A., Thackrey, J. M., Dunlop, S., Mejia, M. B., Alho, A. T., Paraizo Leite, R. E., Rodriguez, R. D., Suemoto, C. K., Nascimento, C. F., Chin, M., Medina-Cleghorn, D., Cuervo, A. M., Arkin, M., Seeley, W. W., Miller, B. L., Nitrini, R., Pasqualucci, C. A., ... Grinberg, L. T. (2018). Probing the correlation of neuronal loss, neurofibrillary tangles, and cell death markers across the Alzheimer's disease Braak stages: a quantitative study in humans. Neurobiology of Aging, 61, 1-12. https://doi.org/10.1016/j.neurobiolaging.2017.09.007