Aged Microglia in Neurodegenerative Diseases: Microglia Lifespan and Culture Methods

Microglia have been recognized as macrophages of the central nervous system (CNS) that are regarded as a culprit of neuroinflammation in neurodegenerative diseases. Thus, microglia have been considered as a cell that should be suppressed for maintaining a homeostatic CNS environment. However, microglia ontogeny, fate, heterogeneity, and their function in health and disease have been defined better with advances in single-cell and imaging technologies, and how to maintain homeostatic microglial function has become an emerging issue for targeting neurodegenerative diseases. Microglia are long-lived cells of yolk sac origin and have limited repopulating capacity. So, microglial perturbation in their lifespan is associated with not only neurodevelopmental disorders but also neurodegenerative diseases with aging. Considering that microglia are long-lived cells and may lose their functional capacity as they age, we can expect that aged microglia contribute to various neurodegenerative diseases. Thus, understanding microglial development and aging may represent an opportunity for clarifying CNS disease mechanisms and developing novel therapies.

Pathophysiology of Lipid Droplets in Neuroglia

In recent years, increasing evidence regarding the functional importance of lipid droplets (LDs), cytoplasmic storage organelles in the central nervous system (CNS), has emerged. Although not abundantly present in the CNS under normal conditions in adulthood, LDs accumulate in the CNS during development and aging, as well as in some neurologic disorders. LDs are actively involved in cellular lipid turnover and stress response. By regulating the storage of excess fatty acids, cholesterol, and ceramides in addition to their subsequent release in response to cell needs and/or environmental stressors, LDs are involved in energy production, in the synthesis of membranes and signaling molecules, and in the protection of cells against lipotoxicity and free radicals. Accumulation of LDs in the CNS appears predominantly in neuroglia (astrocytes, microglia, oligodendrocytes, ependymal cells), which provide trophic, metabolic, and immune support to neuronal networks. Here we review the most recent findings on the characteristics and functions of LDs in neuroglia, focusing on astrocytes, the key homeostasis-providing cells in the CNS. We discuss the molecular mechanisms affecting LD turnover in neuroglia under stress and how this may protect neural cell function. We also highlight the role (and potential contribution) of neuroglial LDs in aging and in neurologic disorders.

SARS-CoV-2 infects human GnRH neurons and tanycytes, disrupting hypothalamic-pituitary hormonal axes

Neuroinvasion by SARS-CoV-2 is now accepted. To investigate whether low testosterone levels observed in men with severe COVID-19 could be of central origin, we retrospectively analyzed blood samples from 60 male intensive-care patients and explored SARS-CoV-2 brain entry using animal and cellular models as well as adult COVID-19 patient and fetal human brains. Most hypotestosteronemic patients displayed hypogonadotropic hypogonadism or abnormal hypothalamic-pituitary-gonadal axis regulation. Neurons producing gonadotropin-releasing hormone (GnRH), the master molecule controlling fertility, expressed angiotensin-converting enzyme 2 and neuropilin-1, two host-cell factors mediating infection, and were infected and dying in all COVID-19 patient brains. Tanycytes - hypothalamic glia that regulate GnRH secretion - were also infected. Additionally, human fetal olfactory and vomeronasal epithelia, from which GnRH neurons arise, richly expressed both the above host-cell susceptibility factors and formyl peptide receptor 2, a putative vomeronasal receptor that also appeared involved in SARS-CoV-2 pathogenesis in humans and mice. Finally, a fetal human GnRH cell line expressing all these receptors could be infected by a SARS-CoV-2-like pseudovirus. Together, our findings suggest that GnRH neurons, which may be implicated in brain development and aging in addition to reproduction, are particularly vulnerable to SARS-CoV-2 in both adults and fetuses/newborns, with potentially devastating long-term consequences.

Dynamic spreading of chromatin-mediated gene silencing and reactivation between neighboring genes in single cells

In mammalian cells genes that are in close proximity are coupled transcriptionally: silencing or activating one gene can affect its neighbors. Understanding these dynamics is important for natural processes, such as heterochromatin spreading during development and aging, and when designing synthetic gene regulation. Here, we systematically dissect this process in single cells by recruiting and releasing repressive chromatin regulators at dual-gene synthetic reporters, and measuring how fast gene silencing and reactivation spread as a function of intergenic distance and configuration of insulator elements. We find that silencing by KRAB, associated with histone methylation, spreads between two genes within hours, with a time delay that increases with distance. This fast KRAB-mediated spreading is not blocked by the classical cHS4 insulators. Silencing by histone deacetylase HDAC4 of the upstream gene can also lead to downstream gene silencing, but with a days-long delay that does not change with distance. This slower silencing can sometimes be stopped by insulators. Gene reactivation of neighboring genes is also coupled, with strong promoters and insulators determining the order of reactivation. We propose a new model of multi-gene regulation, where both gene silencing and gene reactivation can act at a distance, allowing for coordinated dynamics via chromatin regulator recruitment.

Internet use and cognitive engagement in older adulthood

Internet use is increasingly ubiquitous among older adults and may buffer against declines in cognitive engagement. We examined longitudinal associations between three types of internet use (media, social, and instrumental) and two indicators of cognitive engagement (Openness to Experience and Need for Cognition) in a nationally representative sample of Dutch older adults (N=2,922 aged 65+) assessed annually from 2008-2017. Pre-registered analyses indicated that older adults who were more cognitively engaged used the internet more frequently, especially for instrumental purposes like search and email. Those who increased in their use of online media declined less in Need for Cognition than their peers. These associations remained constant over time even as internet use became more common. We benchmarked our findings against null associations between cognitive engagement and TV/radio use and tested associations in younger comparison samples. Findings bolster our understanding of the role that technology use plays in personality development and aging.

SIRT6 Through the Brain Evolution, Development, and Aging

During an organism’s lifespan, two main phenomena are critical for the organism’s survival. These are (1) a proper embryonic development, which permits the new organism to function with high fitness, grow and reproduce, and (2) the aging process, which will progressively undermine its competence and fitness for survival, leading to its death. Interestingly these processes present various similarities at the molecular level. Notably, as organisms became more complex, regulation of these processes became coordinated by the brain, and failure in brain activity is detrimental in both development and aging. One of the critical processes regulating brain health is the capacity to keep its genomic integrity and epigenetic regulation—deficiency in DNA repair results in neurodevelopmental and neurodegenerative diseases. As the brain becomes more complex, this effect becomes more evident. In this perspective, we will analyze how the brain evolved and became critical for human survival and the role Sirt6 plays in brain health. Sirt6 belongs to the Sirtuin family of histone deacetylases that control several cellular processes; among them, Sirt6 has been associated with the proper embryonic development and is associated with the aging process. In humans, Sirt6 has a pivotal role during brain aging, and its loss of function is correlated with the appearance of neurodegenerative diseases such as Alzheimer’s disease. However, Sirt6 roles during brain development and aging, especially the last one, are not observed in all species. It appears that during the brain organ evolution, Sirt6 has gained more relevance as the brain becomes bigger and more complex, observing the most detrimental effect in the brains of Homo sapiens. In this perspective, we part from the evolution of the brain in metazoans, the biological similarities between brain development and aging, and the relevant functions of Sirt6 in these similar phenomena to conclude with the evidence suggesting a more relevant role of Sirt6 gained in the brain evolution.

Troponin Variants as Markers of Skeletal Muscle Health and Diseases

Ca2+-regulated contractility is a key determinant of the quality of muscles. The sarcomeric myofilament proteins are essential players in the contraction of striated muscles. The troponin complex in the actin thin filaments plays a central role in the Ca2+-regulation of muscle contraction and relaxation. Among the three subunits of troponin, the Ca2+-binding subunit troponin C (TnC) is a member of the calmodulin super family whereas troponin I (TnI, the inhibitory subunit) and troponin T (TnT, the tropomyosin-binding and thin filament anchoring subunit) are striated muscle-specific regulatory proteins. Muscle type-specific isoforms of troponin subunits are expressed in fast and slow twitch fibers and are regulated during development and aging, and in adaptation to exercise or disuse. TnT also evolved with various alternative splice forms as an added capacity of muscle functional diversity. Mutations of troponin subunits cause myopathies. Owing to their physiological and pathological importance, troponin variants can be used as specific markers to define muscle quality. In this focused review, we will explore the use of troponin variants as markers for the fiber contents, developmental and differentiation states, contractile functions, and physiological or pathophysiological adaptations of skeletal muscle. As protein structure defines function, profile of troponin variants illustrates how changes at the myofilament level confer functional qualities at the fiber level. Moreover, understanding of the role of troponin modifications and mutants in determining muscle contractility in age-related decline of muscle function and in myopathies informs an approach to improve human health.