Alzheimer’s disease biomarker‐related phospho‐tau 181 signals localize to demyelinated axons of parvalbumin‐positive GABAergic interneurons in App knock‐in mouse
Yu Hirota, Yasufumi Sakakibara, Kimi Takei, Risa Nishijima, Koichi M. Iijima, Michiko Sekiya- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Tau proteins phosphorylated at Thr181 (p‐tau 181) in cerebrospinal fluid and blood is a sensitive biomarker for Alzheimer’s disease (AD). An increase in p‐tau 181 level well correlates with Aβ pathology and precedes neurofibrillary tangle formation in the early stage of AD, though the relationship between p‐tau 181 and Aβ‐mediated pathology is less well understood. We have recently reported that p‐tau 181 signals are detected in the axonal structures and represent axonal abnormality around Aβ plaques in the cortex of App knock‐in mouse model of Aβ amyloidosis (AppNLGF mice). However, from which neuronal subtype(s) these p‐tau 181‐positive axons are originated remains elusive. In this study, we aimed to determine which neuronal subtype(s) express p‐tau 181 in the axons.
Method
To investigate the localization of p‐tau 181 signals in the brains of aged (24‐month‐old) AppNLGF and wild‐type mice, we prepared frozen brain sections and co‐immunostained with antibodies against p‐tau 181 and myeline basic protein (MBP), the glutamatergic neuronal vesicle marker vesicular glutamate transporter 1 (VGLUT1), the GABAergic neuronal vesicle marker vesicular GABA transporter (VGAT), the inhibitory neuron marker parvalbumin, the cholinergic neuronal vesicle marker vesicular acetylcholine transporter (VAChT), or the noradrenergic neuronal vesicle marker norepinephrine transporter (NET).
Result
Histochemical analyses revealed that p‐tau 181 signals were not overlapped with axons of unmyelinated cholinergic nor noradrenergic neurons, but well colocalized with myelinated axons of parvalbumin‐positive GABAergic interneurons, but not of glutamatergic neurons. Interestingly, the density of unmyelinated axons was significantly decreased in AppNLGF mice, while that of glutamatergic, GABAergic or p‐tau 181‐positive axons was less affected. Instead, myelin sheaths surrounding p‐tau 181‐positive axons were significantly reduced in AppNLGF mice.
Conclusion
This study suggests that p‐tau 181 signals may represent axonal abnormality of parvalbumin‐positive GABAergic interneurons with disrupted myelin sheaths in brains of mouse model of Aβ pathology.