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

Publication date: Available online 20 September 2017
Source:Neurobiology of Aging
Author(s): 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 Filho, Udo Rueb, John Neuhaus, Helmut Heinsen, Lea T. Grinberg
Clarifying the mechanisms connecting NFT neurotoxicity to neuronal dysfunction in humans are likely to be pivotal for developing effective treatments for Alzheimer's disease. 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 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 aCasp-6 positivity increases both alone and overlapping with neurofibrillary tangles (NFT). 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.



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