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

• Published in: Neurobiology of aging Vol. 61; pp. 1 - 12
• Main Authors: Theofilas, Panos, Ehrenberg, Alexander J., Nguy, Austin, Thackrey, Julia M., Dunlop, Sara, Mejia, Maria B., Alho, Ana T., Paraizo Leite, Renata Elaine, Rodriguez, Roberta Diehl, Suemoto, Claudia K., Nascimento, Camila F., Chin, Marcus, Medina-Cleghorn, Daniel, Cuervo, Ana Maria, Arkin, Michelle, Seeley, William W., Miller, Bruce L., Nitrini, Ricardo, Pasqualucci, Carlos Augusto, Filho, Wilson Jacob, Rueb, Udo, Neuhaus, John, Heinsen, Helmut, Grinberg, Lea T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2018
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - etiology; Alzheimer Disease - pathology; Alzheimer's disease; Autophagosomes; Autophagy; Autophagy - physiology; Brain - pathology; Caspase 6 - metabolism; Caspase 6 - physiology; Caspases; Cell Death; Disease Progression; Female; Human brainstem; Humans; Male; Middle Aged; Neurofibrillary tangles; Neurofibrillary Tangles - pathology; Neuron counts; Neurons - pathology; Human brainstem; Neurofibrillary tangles; Neuron counts; Caspases; Alzheimer's disease; Autophagy
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2017.09.007

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.