TY - JOUR
T1 - Probing the correlation of neuronal loss, neurofibrillary tangles, and cell death markers across the Alzheimer's disease Braak stages
T2 - a quantitative study in humans
AU - Theofilas, Panos
AU - Ehrenberg, Alexander J.
AU - Nguy, Austin
AU - Thackrey, Julia M.
AU - Dunlop, Sara
AU - Mejia, Maria B.
AU - Alho, Ana T.
AU - Paraizo Leite, Renata Elaine
AU - Rodriguez, Roberta Diehl
AU - Suemoto, Claudia K.
AU - Nascimento, Camila F.
AU - Chin, Marcus
AU - Medina-Cleghorn, Daniel
AU - Cuervo, Ana Maria
AU - Arkin, Michelle
AU - Seeley, William W.
AU - Miller, Bruce L.
AU - Nitrini, Ricardo
AU - Pasqualucci, Carlos Augusto
AU - Filho, Wilson Jacob
AU - Rueb, Udo
AU - Neuhaus, John
AU - Heinsen, Helmut
AU - Grinberg, Lea T.
N1 - Funding Information:
The authors thank the patients and their families for their invaluable contribution to brain aging neurodegenerative disease research and the staff of the Sao Paulo Autopsy Service and BBBABSG for technical support. We thank Anita Spanova and Cristina Armas for their histological assistance and Daniel Medina-Cleghorn for assistance with cell cultures. This study was supported by the National Institutes of Health R01AG040311 , P50AG023501 , P01AG019724 , K24AG053435 , Alzheimer's Association ( AARG-16-441514 ), the John Douglas French Alzheimer Foundation, UCSF - CTSI-Pilot Awards program, LIM-22/Faculdade de Medicina da Universidade de Sao Paulo, and Hospital Israelita Albert Einstein, Sao Paulo.
Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2018/1
Y1 - 2018/1
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Autophagy
KW - Caspases
KW - Human brainstem
KW - Neurofibrillary tangles
KW - Neuron counts
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U2 - 10.1016/j.neurobiolaging.2017.09.007
DO - 10.1016/j.neurobiolaging.2017.09.007
M3 - Article
C2 - 29031088
AN - SCOPUS:85030862302
SN - 0197-4580
VL - 61
SP - 1
EP - 12
JO - Neurobiology of Aging
JF - Neurobiology of Aging
ER -
