TitleProbing the correlation of neuronal loss, neurofibrillary tangles, and cell death markers across the Alzheimer's disease Braak stages: a quantitative study in humans.
Publication TypeJournal Article
Year of Publication2018
AuthorsTheofilas P, Ehrenberg AJ, Nguy A, Thackrey JM, Dunlop S, Mejia MB, Alho AT, Leite RElaine Par, Rodriguez RDiehl, Suemoto CK, Nascimento CF, Chin M, Medina-Cleghorn D, Cuervo AMaria, Arkin M, Seeley WW, Miller BL, Nitrini R, Pasqualucci CAugusto, Filho WJacob, Rueb U, Neuhaus J, Heinsen H, Grinberg LT
JournalNeurobiol Aging
Date Published2018 Jan
KeywordsAged, Aged, 80 and over, Alzheimer Disease, Autophagosomes, Autophagy, Brain, Caspase 6, Cell Death, Disease Progression, Female, Humans, Male, Middle Aged, Neurofibrillary Tangles, Neurons

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.

Alternate JournalNeurobiol. Aging
PubMed ID29031088
PubMed Central IDPMC5705284
Grant ListP50 AG023501 / AG / NIA NIH HHS / United States
U54 NS100717 / NS / NINDS NIH HHS / United States
K24 AG053435 / AG / NIA NIH HHS / United States
R01 AG040311 / AG / NIA NIH HHS / United States
P01 AG019724 / AG / NIA NIH HHS / United States
RF1 AG054108 / AG / NIA NIH HHS / United States
P30 AG038072 / AG / NIA NIH HHS / United States
T32 GM007175 / GM / NIGMS NIH HHS / United States
P01 AG031782 / AG / NIA NIH HHS / United States