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
Affiliations
Connor M. Wander
Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA
Jui-Heng Tseng
Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA
Sheng Song
Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA
Heba A. Al Housseiny
Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA
Dalton S. Tart
Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA
Aditi Ajit
Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA
Yen-Yu Ian Shih
Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA
Rebecca Lobrovich
Penn Digital Neuropathology Laboratory, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-4283, USA
Juan Song
Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA; UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA
Rick B. Meeker
Department of Neurology, University of North Carolina, Chapel Hill, NC 27599, USA
David J. Irwin
Penn Digital Neuropathology Laboratory, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-4283, USA
Todd J. Cohen
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; Corresponding author
Summary: 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.
