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Quantifying the accretion of hyperphosphorylated tau in the locus coeruleus and dorsal raphe nucleus: the pathological building blocks of early Alzheimer's disease.

  • Author(s): Ehrenberg, AJ;
  • Nguy, AK;
  • Theofilas, P;
  • Dunlop, S;
  • Suemoto, CK;
  • Di Lorenzo Alho, AT;
  • Leite, RP;
  • Diehl Rodriguez, R;
  • Mejia, MB;
  • Rüb, U;
  • Farfel, JM;
  • de Lucena Ferretti-Rebustini, RE;
  • Nascimento, CF;
  • Nitrini, R;
  • Pasquallucci, CA;
  • Jacob-Filho, W;
  • Miller, B;
  • Seeley, WW;
  • Heinsen, H;
  • Grinberg, LT
  • et al.

Published Web Location

https://doi.org/10.1111/nan.12387
Abstract

Aims

Hyperphosphorylated tau neuronal cytoplasmic inclusions (ht-NCI) are the best protein correlate of clinical decline in Alzheimer's disease (AD). Qualitative evidence identifies ht-NCI accumulating in the isodendritic core before the entorhinal cortex. Here, we used unbiased stereology to quantify ht-NCI burden in the locus coeruleus (LC) and dorsal raphe nucleus (DRN), aiming to characterize the impact of AD pathology in these nuclei with a focus on early stages.

Methods

We utilized unbiased stereology in a sample of 48 well-characterized subjects enriched for controls and early AD stages. ht-NCI counts were estimated in 60-μm-thick sections immunostained for p-tau throughout LC and DRN. Data were integrated with unbiased estimates of LC and DRN neuronal population for a subset of cases.

Results

In Braak stage 0, 7.9% and 2.6% of neurons in LC and DRN, respectively, harbour ht-NCIs. Although the number of ht-NCI+ neurons significantly increased by about 1.9× between Braak stages 0 to I in LC (P = 0.02), we failed to detect any significant difference between Braak stage I and II. Also, the number of ht-NCI+ neurons remained stable in DRN between all stages 0 and II. Finally, the differential susceptibility to tau inclusions among nuclear subdivisions was more notable in LC than in DRN.

Conclusions

LC and DRN neurons exhibited ht-NCI during AD precortical stages. The ht-NCI increases along AD progression on both nuclei, but quantitative changes in LC precede DRN changes.

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