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-β Pathology

Abstract

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-β (Aβ) pathology and precede neurofibrillary tangle formation in the early stage of AD; however, the relationship between p-tau181 and Aβ-mediated pathology is less well understood. We recently reported that p-tau181 represents axonal abnormalities in mice with Aβ pathology (AppNLGF). 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 AppNLGF 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, vesicular GABA transporter, or parvalbumin in the brains of 24-month-old AppNLGF and control mice without Aβ 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-positive GABAergic interneurons but not of glutamatergic neurons. Interestingly, the density of unmyelinated axons was 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 AppNLGF 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 Aβ pathology.

Recognizing Alzheimer's disease from perspective of oligodendrocytes: Phenomena or pathogenesis?

“…While most researchers focused on neuronal tau, Hirota et al. reported that AD‐related p‐tau181 signals localized to demyelinated axons of parvalbumin‐positive GABAergic interneurons in an App knock‐in mouse model of AD 109 . Of note, oligodendroglial tau could propagate along WM tracts, resulting in the loss of OLs.…”

“…reported that AD-related p-tau181 signals localized to demyelinated axons of parvalbumin-positive GABAergic interneurons in an App knock-in mouse model of AD. 109 Of note, oligodendroglial tau could propagate along WM tracts, resulting in the loss of OLs. Moreover, this process was independent of neuronal tau.…”

Delineating mechanisms underlying parvalbumin neuron impairment in different neurological and neurodegenerative disorders: the emerging role of mitochondrial dysfunction

“…The PNN is one of the master regulators of E/I balance [ 154 ], and reduced PNN expression has been observed in human AD brains and rodent models [ 155 , 156 ], while astrocytes and resident macrophages of the brain called microglia also regulate PV+ cell excitability ( Figure 1 ) [ 157 , 158 ]. In addition, PV+ cell axons are highly myelinated [ 159 ] and one recent report found evidence of demyelination of PV+ axons, but not excitatory neurons, at early disease stages in an AD mouse model [ 160 ]. While the causes of PV cell vulnerability in diseases have often focused on their high energy demands, as discussed in this review, changes in the PNN and/or myelination levels would also have profound effects on PV+ neuron's firing properties and function [ 161 ].…”