White Matter and Neuroprotection in Alzheimer's Dementia

Abstract

Myelin is the main component of the white matter of the central nervous system (CNS), allowing the proper electrical function of the neurons by ensheathing and insulating the axons. The extensive use of magnetic resonance imaging has highlighted the white matter alterations in Alzheimer's dementia (AD) and other neurodegenerative diseases, alterations which are early, extended, and regionally selective. Given that the white matter turnover is considerable in the adulthood, and that myelin repair is currently recognized as being the only true reparative capability of the mature CNS, oligodendrocyte precursor cells (OPCs), the cells that differentiate in oligodendrocyte, responsible for myelin formation and repair, are regarded as a potential target for neuroprotection. In this review, several aspects of the OPC biology are reviewed. The histology and functional role of OPCs in the neurovascular-neuroglial unit as described in preclinical and clinical studies on AD is discussed, such as the OPC vulnerability to hypoxia-ischemia, neuroinflammation, and amyloid deposition. Finally, the position of OPCs in drug discovery strategies for dementia is discussed.

Keywords: amyloid; drug screening; oligodendrocyte precursor cells; oxygen-glucose deprivation.

Figure 1

Age-related variation of oligodendrocyte lineage markers. (A) platelet-derived growth factor alpha receptor (PDGFαR) gene expression in Wt and Tg2576 at different age timepoints; (B) myelin basic protein (MBP) gene expression in Wt and Tg2576 at different age time points. Relative expression has been normalized to 1 month matched for each genotype. Statistical analysis has been performed through 2-way ANOVA, considering age (months) and genotype (Wt and Tg2576) as variables; n = 3–5. Results are significant when p < 0.05.

Figure 2

Age-related variation of oligodendrocyte precursor cells to oligodendrocyte transcription factors. The graphs show the expression profile of Olig-1 (A), Olig-2 (B), and Klf-9 (C) transcription factors. Relative expression has been normalized to 1-month for each genotype and given the value of 100%. Results are expressed as the % of variation compared to the 1-month genotype-matched, Wt and Tg2576, groups of animals. Statistical analysis has been performed through 2-wayANOVA, considering age (months) and genotype (Wt and Tg2576) as variables; n = 3–5. Results are significant when p < 0.05.

Figure 3

Lineage specific vulnerability to oxygen-glucose deprivation in in vitro models. The graph shows vulnerability to the in vitro model of hypoxia/ischemia, the oxygen-glucose deprivation (OGD), analyzed in three different in vitro models: pure neuronal, mixed neuronal/astroglial and neural stem cells (NSCs)-derived OPCs cultures. This is a summary chart of already published data [45,46], measured by cell-based high content screening and represented as percentage of condensed nuclei. Statistical analysis has been performed by Student’s t-test and asterisks represent the differences between normoxia and OGD exposed cells of the same lineage (* p < 0.05, ** p < 0.01, *** p = 0.001).

Figure 4

From the precursor to the mature oligodendrocyte: impact of noxious stimuli on differentiation and viability. Schematic representation of the physiological differentiation from the oligodendrocyte precursor cell (OPC) to myelinating OL. T3, the active form of the thyroid hormone, is the trigger of the process, driving the cell out of the cell cycle and starting the differentiation machinery. Neurotransmitters (such as GABA, glutamate and NO) directly contribute to regulating the process and the interaction between the axon and its activity and the OPCs/OLs. In the table are summarized the different component of neurodegenerative and demyelinating diseases affecting the different differentiation stages. Abbreviations: Aβ, amyloid beta; OL, oligodendrocyte; OPC, oligodendrocyte precursor cell; PDGF, platelet derived growth factor; T3, triiodothyronine.