Tau oligomers associate with inflammation in the brain and retina of tauopathy mice and in neurodegenerative diseases

Ashley N. Nilson, Kelsey C. English, Julia E. Gerson, T. Barton Whittle, C. Nicolas Crain, Judy Xue, Urmi Sengupta, Diana L. Castillo-Carranza, Wenbo Zhang, Praveena Gupta, Rakez Kayed

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

It is well-established that inflammation plays an important role in Alzheimer's disease (AD) and frontotemporal lobar dementia (FTLD). Inflammation and synapse loss occur in disease prior to the formation of larger aggregates, but the contribution of tau to inflammation has not yet been thoroughly investigated. Tau pathologically aggregates to form large fibrillar structures known as tangles. However, evidence suggests that smaller soluble aggregates, called oligomers, are the most toxic species and form prior to tangles. Furthermore, tau oligomers can spread to neighboring cells and between anatomically connected brain regions. In addition, recent evidence suggests that inspecting the retina may be a window to brain pathology. We hypothesized that there is a relationship between tau oligomers and inflammation, which are hallmarks of early disease. We conducted immunofluorescence and biochemical analyses on tauopathy mice, FTLD, and AD subjects. We showed that oligomers co-localize with astrocytes, microglia, and HMGB1, a pro-inflammatory cytokine. Additionally, we show that tau oligomers are present in the retina and are associated with inflammatory cells suggesting that the retina may be a valid non-invasive biomarker for brain pathology. These results suggest that there may be a toxic relationship between tau oligomers and inflammation. Therefore, the ability of tau oligomers to spread may initiate a feed-forward cycle in which tau oligomers induce inflammation, leading to neuronal damage, and thus more inflammation. Further mechanistic studies are warranted in order to understand this relationship, which may have critical implications for improving the treatment of tauopathies.

Original languageEnglish (US)
Pages (from-to)1083-1099
Number of pages17
JournalJournal of Alzheimer's Disease
Volume55
Issue number3
DOIs
StatePublished - 2017

Fingerprint

Tauopathies
Encephalitis
Neurodegenerative Diseases
Retina
Inflammation
Frontotemporal Dementia
Poisons
Alzheimer Disease
Brain
Pathology
HMGB1 Protein
Aptitude
Microglia
Astrocytes
Synapses
Fluorescent Antibody Technique
Biomarkers
Cytokines

Keywords

  • Alzheimer's disease
  • frontotemporal lobar dementia
  • neuroinflammation
  • oligomer
  • retinal degeneration
  • tau protein
  • tauopathy

ASJC Scopus subject areas

  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

Cite this

Tau oligomers associate with inflammation in the brain and retina of tauopathy mice and in neurodegenerative diseases. / Nilson, Ashley N.; English, Kelsey C.; Gerson, Julia E.; Barton Whittle, T.; Nicolas Crain, C.; Xue, Judy; Sengupta, Urmi; Castillo-Carranza, Diana L.; Zhang, Wenbo; Gupta, Praveena; Kayed, Rakez.

In: Journal of Alzheimer's Disease, Vol. 55, No. 3, 2017, p. 1083-1099.

Research output: Contribution to journalArticle

Nilson, AN, English, KC, Gerson, JE, Barton Whittle, T, Nicolas Crain, C, Xue, J, Sengupta, U, Castillo-Carranza, DL, Zhang, W, Gupta, P & Kayed, R 2017, 'Tau oligomers associate with inflammation in the brain and retina of tauopathy mice and in neurodegenerative diseases', Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 1083-1099. https://doi.org/10.3233/JAD-160912
Nilson, Ashley N. ; English, Kelsey C. ; Gerson, Julia E. ; Barton Whittle, T. ; Nicolas Crain, C. ; Xue, Judy ; Sengupta, Urmi ; Castillo-Carranza, Diana L. ; Zhang, Wenbo ; Gupta, Praveena ; Kayed, Rakez. / Tau oligomers associate with inflammation in the brain and retina of tauopathy mice and in neurodegenerative diseases. In: Journal of Alzheimer's Disease. 2017 ; Vol. 55, No. 3. pp. 1083-1099.
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AB - It is well-established that inflammation plays an important role in Alzheimer's disease (AD) and frontotemporal lobar dementia (FTLD). Inflammation and synapse loss occur in disease prior to the formation of larger aggregates, but the contribution of tau to inflammation has not yet been thoroughly investigated. Tau pathologically aggregates to form large fibrillar structures known as tangles. However, evidence suggests that smaller soluble aggregates, called oligomers, are the most toxic species and form prior to tangles. Furthermore, tau oligomers can spread to neighboring cells and between anatomically connected brain regions. In addition, recent evidence suggests that inspecting the retina may be a window to brain pathology. We hypothesized that there is a relationship between tau oligomers and inflammation, which are hallmarks of early disease. We conducted immunofluorescence and biochemical analyses on tauopathy mice, FTLD, and AD subjects. We showed that oligomers co-localize with astrocytes, microglia, and HMGB1, a pro-inflammatory cytokine. Additionally, we show that tau oligomers are present in the retina and are associated with inflammatory cells suggesting that the retina may be a valid non-invasive biomarker for brain pathology. These results suggest that there may be a toxic relationship between tau oligomers and inflammation. Therefore, the ability of tau oligomers to spread may initiate a feed-forward cycle in which tau oligomers induce inflammation, leading to neuronal damage, and thus more inflammation. Further mechanistic studies are warranted in order to understand this relationship, which may have critical implications for improving the treatment of tauopathies.

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