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Neurobiol Aging. 2018 Jan;61:1-12. doi: 10.1016/j.neurobiolaging.2017.09.007. Epub 2017 Sep 20.

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

Author information

1
Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
2
Hospital Albert Einstein, São Paulo, Brazil; Department of Pathology, LIM-22, University of São Paulo Medical School, São Paulo, Brazil.
3
Division of Geriatrics, LIM-22, University of São Paulo Medical School, São Paulo, Brazil.
4
Department of Pathology, LIM-22, University of São Paulo Medical School, São Paulo, Brazil.
5
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
6
Departments of Developmental and Molecular Biology, Anatomy and Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
7
Department of Neurology, University of São Paulo Medical School, São Paulo, Brazil.
8
Dr. Senckenbergisches Chronomedizinisches Institut, Department of Anatomy, J. W. Goethe University Frankfurt am Main, Frankfurt, Germany.
9
Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
10
Department of Pathology, LIM-22, University of São Paulo Medical School, São Paulo, Brazil; Department of Psychiatry, University of Wuerzburg, Wuerzburg, Germany.
11
Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Department of Pathology, LIM-22, University of São Paulo Medical School, São Paulo, Brazil. Electronic address: lea.grinberg@ucsf.edu.

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.

KEYWORDS:

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

[Indexed for MEDLINE]
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