Widespread tau seeding activity at early Braak stages

Jennifer L. Furman, Jaime Vaquer-Alicea, Charles L. White, Nigel J. Cairns, Peter T. Nelson, Marc I. Diamond

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Transcellular propagation of tau aggregates may underlie the progression of pathology in Alzheimer’s disease (AD) and other tauopathies. Braak staging (B1, B2, B3) is based on phospho-tau accumulation within connected brain regions: entorhinal cortex (B1); hippocampus/limbic system (B2); and frontal and parietal lobes (B3). We previously developed a specific and sensitive assay that uses flow cytometry to quantify tissue seeding activity based on fluorescence resonance energy transfer (FRET) in cells that stably express tau reporter proteins. In a tauopathy mouse model, we have detected seeding activity far in advance of histopathological changes. It remains unknown whether individuals with AD also develop seeding activity prior to accumulation of phospho-tau. We measured tau seeding activity across four brain regions (hippocampus, frontal lobe, parietal lobe, and cerebellum) in 104 fresh-frozen human AD brain samples from all Braak stages. We observed widespread seeding activity, notably in regions predicted to be free of phospho-tau deposition, and in detergent-insoluble fractions that lacked tau detectable by ELISA. Seeding activity correlated positively with Braak stage and negatively with MMSE. Our results are consistent with early transcellular propagation of tau seeds that triggers subsequent development of neuropathology. The FRET-based seeding assay may also complement standard neuropathological classification of tauopathies.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalActa Neuropathologica
DOIs
StateAccepted/In press - Nov 22 2016

Fingerprint

Tauopathies
Alzheimer Disease
Fluorescence Resonance Energy Transfer
Parietal Lobe
Frontal Lobe
Hippocampus
Brain
tau Proteins
Limbic System
Entorhinal Cortex
Detergents
Cerebellum
Seeds
Flow Cytometry
Enzyme-Linked Immunosorbent Assay
Pathology

Keywords

  • Alzheimer’s disease
  • Braak staging
  • Neuropathology
  • Propagation
  • Seeding
  • Tau

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Widespread tau seeding activity at early Braak stages. / Furman, Jennifer L.; Vaquer-Alicea, Jaime; White, Charles L.; Cairns, Nigel J.; Nelson, Peter T.; Diamond, Marc I.

In: Acta Neuropathologica, 22.11.2016, p. 1-10.

Research output: Contribution to journalArticle

Furman, Jennifer L. ; Vaquer-Alicea, Jaime ; White, Charles L. ; Cairns, Nigel J. ; Nelson, Peter T. ; Diamond, Marc I. / Widespread tau seeding activity at early Braak stages. In: Acta Neuropathologica. 2016 ; pp. 1-10.
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