Probing the Correlation of Neuronal Loss, Neurofibrillary Tangles, and Cell Death Markers Across the Alzheimer's Disease Braak Stages: a Quantitative Study in Humans

Overview

Journal Neurobiol Aging

Publisher Elsevier

Specialties Geriatrics
Neurology
Physiology

Date 2017 Oct 15

PMID 29031088

Citations 51

Authors

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

Affiliations

Soon will be listed here.

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.

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