Accelerated dystrophy and decay of oligodendrocyte precursor cells in the APP/PS1 model of Alzheimer’s-like pathology

Abstract

Myelin disruption is a feature of natural aging and of Alzheimer's disease (AD). In the CNS, myelin is produced by oligodendrocytes, which are generated throughout life by oligodendrocyte progenitor cells (OPCs). Here, we examined age-related changes in OPCs in APP/PS1 mice, a model for AD-like pathology, compared with non-transgenic (Tg) age-matched controls. Analysis was performed in the CA1 area of the hippocampus following immunolabelling for NG2 with the nuclear dye Hoescht, to identify OPC and OPC sister cells, a measure of OPC replication, together with Gpr17 and Olig2 for oligodendrocytes and myelin basic protein (MBP) immunostaining as a measure of myelination. The results indicate a decrease in the number of OPCs between 9 and 14 months in natural ageing and this occurred earlier at 9 months in APP/PS1 mice, without further decline at 14 months. The number of OPC sister cells was unaltered in natural aging, but declined significantly at 14-months in APP/PS1 mice. The number of GPR17+ and Olig2+ oligodendrocytes was not altered in APP/PS1, whereas MBP immunostaining increased between 9 and 14 months in natural ageing, but not in APP/PS1 mice. Notably, OPCs displayed marked morphological changes at 14 months in APP/PS1 mice, characterized by an overall shrinkage of OPC process domains and increased process branching, characteristic of reactive pathological changes. The results indicate that OPC and myelin disruption are pathological signs in the APP/PS1 mouse model of AD.

The synaptic blocker botulinum toxin A decreases the density and complexity of oligodendrocyte precursor cells in the adult mouse hippocampus

“…Here, we show that BoNT/A, which silences synaptic activity in the hippocampus, results in a decrease in OPC numbers and cellular atrophy. Notably, similar changes in OPCs are associated with synaptic dysregulation in AD‐like pathology in mice (Chacon‐De‐La‐Rocha et al, 2020; Vanzulli et al, 2020). The results support a role for synaptic signaling in maintaining adult OPC numbers and integrity, which is relevant to neuropathologies in which neuronal activity is altered, such as AD, MS, and traumatic injury, as well as age‐related cognitive decline.…”

“…Time‐lapse imaging demonstrates that NG2 + OPCs processes are highly motile and respond rapidly to changes in their environment (Hughes et al, 2013). Hence, it is possible that OPC processes are retracted from silent synapses following BoNT/A treatment, resulting in decreased coverage by OPCs, which is comparable to early atrophy of OPCs observed in mouse models of AD that are characterized by synaptic dysregulation (Chacon‐De‐La‐Rocha et al, 2020; Vanzulli et al, 2020). The overall extent of synaptic disruption in neuropathology is unlikely to be as extensive as that of the hippocampus following BoNT/A injection, and the changes observed in the present study are more likely to reflect those that occur focally within lesions.…”

“…Furthermore, motor learning has been shown to drive OPC differentiation, and failure to generate new oligodendrocytes impairs myelination of newly formed neuronal connections and learning ability (McKenzie et al, 2014; Xiao et al, 2016). Hence, it is proposed that decreased synaptic activity may result in disruption of OPC regenerative capacity in neurodegenerative diseases, such as Multiple Sclerosis (MS) and Alzheimer's disease (AD) (Chacon‐De‐La‐Rocha et al, 2020; Rivera et al, 2016; Vanzulli et al, 2020).…”

27-Hydroxycholesterol Promotes Oligodendrocyte Maturation – Implications for Hypercholesterolemia Associated Brain White Matter Changes

“…Furthermore, along with ageing, properties and functionality of OPCs alternate both inter-and intraregionally in the brain resulting in a heterogeneous group of OPC subtypes (40), which subsequently may in uence the remyelinating capacity of these cells. Regarding impacts of Aβ on oligodendroglia, contradictory results exist; in several studies, Aβ has been observed to induce proliferation and maturation of oligodendrocytes, and even remyelination of myelin lesions in cell and animal models (41,42), while in others OPCs have been observed to lose their ability to proliferate in Aβ plaque environment (43,44). Exogenous agents may also affect OPCs.…”