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Am J Pathol. 2017 Jul;187(7):1601-1612. doi: 10.1016/j.ajpath.2017.03.011. Epub 2017 May 10.

Enhanced Tau Aggregation in the Presence of Amyloid β.

Author information

1
Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
2
Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts; C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
3
McLaughlin Research Institute, Great Falls, Montana.
4
Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts. Electronic address: bhyman@mgh.harvard.edu.

Abstract

Amyloid plaques and neurofibrillary tangles co-occur in Alzheimer disease, but with different topological and temporal patterns. Whether these two lesions are independent or pathobiologically related is uncertain. For example, amyloid deposition in the neocortex precedes the spread of tau neurofibrillary tangles from the limbic areas to the cortex. We examined the aggregation properties of tau isolated from human cases with early tau pathology (Braak II) with and without plaques. Using a well-established HEK cell biosensor assay, we show that tau from cases with plaques has an enhanced ability to induce tau aggregates compared to tau from cases without plaques. To further explore this effect, we combined mice carrying the APP/PS1 transgene array that develop plaques with rTg4510 mice carrying the P301L mutant human tau transgene that develop extensive tau pathology with age. The resulting APP/PS1-rTg4510 mice had a threefold increase in tau seeding activity over the rTg4510 strain, without change in tau production or extracellular release. Surprisingly, this effect was observed before overt amyloid deposition. The enhancement of tau aggregation was also apparent by an increase in histological measures of tau pathology in young APP/PS1-rTg4510 mice and an increase in high-molecular-weight tau. Overall, these data provide evidence that amyloid β acts to enhance tau pathology by increasing the formation of tau species capable of seeding new aggregates.

PMID:
28500862
PMCID:
PMC5500829
DOI:
10.1016/j.ajpath.2017.03.011
[Indexed for MEDLINE]
Free PMC Article

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