Oligodendrocytes and their Progressive Failure to Ensure Myelination in the Aging Brain
Axons that connect neurons in the nervous system are sheathed in structures largely made of myelin. This myelin sheath is necessary for the correct function of nerves and the brain, as demonstrated by the unpleasant consequences of demyelinating conditions such as multiple sclerosis. In normal aging there is a lesser degree of loss of myelin over time, and a weight of evidence points towards this loss providing a meaningful contribution to age-related cognitive decline. Therefore it is worth keeping an eye on this area of research, and the development of therapies for demyelinating conditions, as some approaches might also be applicable to age-related myelin loss.
Myelin is maintained by the population of cells called oligodendrocytes. Like all cell populations, there is a drift away from youthful function with age. Numerous causes exist, including the usual suspects of increased inflammatory signaling and diminished stem cell and progenitor cell activity, but as is usually the case it is challenging to assign a relative importance to the many identified processes of oligodendrocyte aging. Cellular biochemistry remains an interconnected web of incompletely understood processes, only slowly mapped.
Oligodendrocytes in the aging brain
Although the exact mechanisms of cognitive decline are not yet known, it is understood that progressive breakdown of the intricate communication between neurons and glial cells, reduced efficacy of action potential conduction and processes such as neuroinflammation lead to a non-autonomous and gradual loss of cognitive function. White matter tracts functionally connect various areas of the central nervous system (CNS), and are predominantly populated by myelinated axons.
This has led to a growing field of interest and understanding of brain aging as a network deterioration, such that the loss of myelination in white matter tracts which connect cortical regions underlies the loss of cognitive functions which rely on this network connectivity and efficient neuronal transmission. Non-human primate work has found direct links between reduced myelination index, of specific corticocortical and corticobasal tracts and cognitive performance in normal aging.
Myelin is a lipid-rich membrane structure, which wraps concentrically around axons. In the CNS, myelin is provided by terminally differentiated cells of the oligodendrocyte lineage, which hereafter will be referred to as mature oligodendrocytes. Developmental myelination of the CNS takes place largely within the first 2 years of life, but white matter volume increases up until around mid-life as new axonal projections become myelinated. Adult myelination is highly plastic, modifiable by experience, and seems to have important roles in learning and memory and normal cognitive function. Oligodendrocytes are derived from specific neural progenitor cells; oligodendrocyte progenitor cells (OPCs). OPCs populate the CNS, and proliferate throughout life to self-renew, and differentiate to provide a continuous source of new mature oligodendrocytes.
It is widely accepted that there is an overall loss in white matter volume with age in non-pathologically aging human brains. Considering the widespread and specialised roles of myelin, it follows that myelin degradation leads to cognitive decline during 'normal' aging, that is in the absence of clinical age-related pathology such as dementia. This is not least as a result of leaving axons exposed and vulnerable to damage, as is well documented in demyelinating conditions such as multiple sclerosis. Longitudinal data shows that age-related myelin degeneration largely contributes to loss of cognitive function through disconnection of cortical regions, due to slowed processing speeds, which in fact appears to be independent of axonal degeneration. White matter loss and degeneration may result in age-related cognitive decline via several independent mechanisms.
The chronology of neuronal loss and myelin damage is not yet understood. Therefore, it could be hypothesised that a good understanding of the health of oligodendrocytes in the aging brain and how white matter might be protected in aging is ever more important as a potential prophylactic approach to age-associated disease.
https://elifesciences.org/articles/67604
Pharmacological rescue of impaired mitophagy in Parkinson's disease-related LRRK2 G2019S knock-in mice
Parkinson's disease (PD) is a major and progressive neurodegenerative disorder, yet the biological mechanisms involved in its aetiology are poorly understood. Evidence links this disorder with mitochondrial dysfunction and/or impaired lysosomal degradation - key features of the autophagy of mitochondria, known as mitophagy. Here, we investigated the role of LRRK2, a protein kinase frequently mutated in PD, in this process in vivo. Using mitophagy and autophagy reporter mice, bearing either knockout of LRRK2 or expressing the pathogenic kinase-activating G2019S LRRK2 mutation, we found that basal mitophagy was specifically altered in clinically relevant cells and tissues. Our data show that basal mitophagy inversely correlates with LRRK2 kinase activity in vivo. In support of this, use of distinct LRRK2 kinase inhibitors in cells increased basal mitophagy, and a CNS penetrant LRRK2 kinase inhibitor, GSK3357679A, rescued the mitophagy defects observed in LRRK2 G2019S mice. This study provides the first in vivo evidence that pathogenic LRRK2 directly impairs basal mitophagy, a process with strong links to idiopathic Parkinson's disease, and demonstrates that pharmacological inhibition of LRRK2 is a rational mitophagy-rescue approach and potential PD therapy.
https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.120.318711
Renin Cell Baroreceptor, a Nuclear Mechanotransducer Central for Homeostasis
These studies show that the enigmatic baroreceptor is a nuclear mechanotransducer that resides in the renin cells per se and is responsible for the sensing and transmission of extracellular physical forces directly to the chromatin of renin cells via lamin A/C to regulate renin gene expression, renin bioavailability, and homeostasis.
https://onlinelibrary.wiley.com/doi/10.1002/adfm.202105301
Tissue Programmed Hydrogels Functionalized with GDNF Improve Human Neural Grafts in Parkinson's Disease
The survival and synaptic integration of transplanted dopaminergic (DA) progenitors are essential for ameliorating motor symptoms in Parkinson's disease (PD). Human pluripotent stem cell (hPSC)-derived DA progenitors are, however, exposed to numerous stressors prior to, and during, implantation that result in poor survival. Additionally, hPSC-derived grafts show inferior plasticity compared to fetal tissue grafts. These observations suggest that a more conducive host environment may improve graft outcomes. Here, tissue-specific support to DA progenitor grafts is provided with a fully characterized self-assembling peptide hydrogel. This biomimetic hydrogel matrix is programmed to support DA progenitors by i) including a laminin epitope within the matrix; and ii) shear encapsulating glial cell line-derived neurotrophic factor (GDNF) to ensure its sustained delivery. The biocompatible hydrogel biased a 51% increase in A9 neuron specification-a subpopulation of DA neurons critical for motor function. The sustained delivery of GDNF induced a 2.7-fold increase in DA neurons and enhanced graft plasticity, resulting in significant improvements in motor deficits at 6 months. These findings highlight the therapeutic benefit of stepwise customization of tissue-specific hydrogels to improve the physical and trophic support of human PSC-derived neural transplants, resulting in improved standardization, predictability and functional efficacy of grafts for PD.