Alzheimer's Disease-Related Phospho-Tau181 Signals Are Localized to Demyelinated Axons of Parvalbumin-Positive GABAergic Interneurons in an App Knock-In Mouse Model of Amyloid- Pathology

Background: The tau protein phosphorylated at Thr181 (p-tau181) in cerebrospinal fluid and blood is a sensitive biomarker for Alzheimer's disease (AD). Increased p-tau181 levels correlate well with amyloid-beta (A beta) pathology and precede neurofibrillary tangle formation in the early stage of AD; however, the relationship between p-tau181 and A beta-mediated pathology is less well understood. We recently reported that p-tau181 represents axonal abnormalities in mice with A beta pathology (App(NLGF)). However, from which neuronal subtype(s) these p-tau181-positive axons originate remains elusive. Objective: The main purpose of this study is to differentiate neuronal subtype(s) and elucidate damage associated with p-tau181-positive axons by immunohistochemical analysis of App(NLGF) mice brains. Methods: Colocalization between p-tau181 and (1) unmyelinated axons positive for vesicular acetylcholine transporter or norepinephrine transporter and (2) myelinated axons positive for vesicular glutamate transporter, vesicularGABAtransporter, or parvalbumin in the brains of 24-month-old App(NLGF) and control mice without A beta pathology were analyzed. The density of these axons was also compared. Results: Unmyelinated axons of cholinergic or noradrenergic neurons did not overlap with p-tau181. By contrast, p-tau181 signals colocalized with myelinated axons of parvalbumin-positiveGABAergic interneurons but not of glutamatergic neurons. Interestingly, the density of unmyelinated axonswas significantly decreased in AppNLGF mice, whereas that of glutamatergic, GABAergic, or p-tau181-positive axons was less affected. Instead, myelin sheaths surrounding p-tau181-positive axons were significantly reduced in App(NLGF) mice. Conclusion: This study demonstrates that p-tau181 signals colocalize with axons of parvalbumin-positive GABAergic interneurons with disrupted myelin sheaths in the brains of a mouse model of A beta pathology.