The Accumulation of Tau-Immunoreactive Hippocampal Granules and Corpora Amylacea Implicates Reactive Glia in Tau Pathogenesis during Aging

Connor M Wander; Jui-Heng Tseng; Sheng Song; Heba A Al Housseiny; Dalton S Tart; Aditi Ajit; Yen-Yu Ian Shih; Rebecca Lobrovich; Juan Song; Rick B Meeker; David J Irwin; Todd J Cohen

doi:10.1016/j.isci.2020.101255

The Accumulation of Tau-Immunoreactive Hippocampal Granules and Corpora Amylacea Implicates Reactive Glia in Tau Pathogenesis during Aging

iScience. 2020 Jul 24;23(7):101255. doi: 10.1016/j.isci.2020.101255. Epub 2020 Jun 10.

Authors

Affiliations

¹ Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA.
² Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA.
³ Penn Digital Neuropathology Laboratory, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-4283, USA.
⁴ Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
⁵ Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: toddcohen@neurology.unc.edu.

Abstract

The microtubule-associated tau protein forms pathological inclusions that accumulate in an age-dependent manner in tauopathies including Alzheimer's disease (AD). Since age is the major risk factor for AD, we examined endogenous tau species that evolve during aging in physiological and diseased conditions. In aged mouse brain, we found tau-immunoreactive clusters embedded within structures that are reminiscent of periodic acid-Schiff (PAS) granules. We showed that PAS granules harbor distinct tau species that are more prominent in 3xTg-AD mice. Epitope profiling revealed hypo-phosphorylated rather than hyper-phosphorylated tau commonly observed in tauopathies. High-resolution imaging and 3D reconstruction suggest a link between tau clusters, reactive astrocytes, and microglia, indicating that early tau accumulation may promote neuroinflammation during aging. Using postmortem human brain, we identified tau as a component of corpora amylacea (CA), age-related structures that are functionally analogous to PAS granules. Overall, our study supports neuroimmune dysfunction as a precipitating event in tau pathogenesis.

Keywords: Cellular Neuroscience; Molecular Neuroscience; Neuroscience.

Abstract

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