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

AimsHyperphosphorylated 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 qu...

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Published in:	Neuropathology and applied neurobiology Vol. 43; no. 5; pp. 393 - 408
Main Authors:	Ehrenberg, A. J., Nguy, A. K., Theofilas, P., Dunlop, S., Suemoto, C. K., Di Lorenzo Alho, A. T., Leite, R. P., Diehl Rodriguez, R., Mejia, M. B., Rüb, U., Farfel, J. M., Lucena Ferretti‐Rebustini, R. E., Nascimento, C. F., Nitrini, R., Pasquallucci, C. A., Jacob‐Filho, W., Miller, B., Seeley, W. W., Heinsen, H., Grinberg, L. T.
Format:	Journal Article
Language:	English
Published:	England Wiley Subscription Services, Inc 01-08-2017
Subjects:	Adult Aged Aged, 80 and over Alzheimer disease Alzheimer Disease - metabolism Alzheimer Disease - pathology Alzheimer's disease brain stem Cortex (entorhinal) Disease Progression Dorsal raphe nucleus Dorsal Raphe Nucleus - metabolism Dorsal Raphe Nucleus - pathology Female Human Humans Inclusion bodies Inclusion Bodies - pathology Locus coeruleus Locus Coeruleus - metabolism Locus Coeruleus - pathology Male Middle Aged Neurodegenerative diseases Neurons Raphe nuclei Tau protein tau Proteins - metabolism unbiased stereology Human dorsal raphe nucleus unbiased stereology Alzheimer disease locus coeruleus brain stem
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Summary:	AimsHyperphosphorylated 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.MethodsWe 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.ResultsIn 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.ConclusionsLC 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. Stereological analysis of tau pathology in the locus coeruleus and dorsal raphe nucleus in early Alzheimer's disease demonstrate that early involvement of brain stem nuclei has important functional implications.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0305-1846 1365-2990
DOI:	10.1111/nan.12387