Week 2(1) - Glial Cells (Neuroglia) Neurobiology and Clinical Aspects.pdf

Week 2 (1) Inherited Neurological Disorders (HMG 44110A ) Glial Cells (Neuroglia) Neurobiology and Clinical Aspects Dr. Merin Thomas [email protected] Office hours : Monday& Wednesday, 3.00pm to 5.00pm...

Week 2 (1) Inherited Neurological Disorders (HMG 44110A ) Glial Cells (Neuroglia) Neurobiology and Clinical Aspects Dr. Merin Thomas [email protected] Office hours : Monday& Wednesday, 3.00pm to 5.00pm Tuesday & Thursday, 1.00pm to 3.00pm 1  Learning Objectives Neuroglia – Types & their functions Neuroglia in neuropathology Neuroglia in neurodegeneration  Neuroglia The Nervous tissue comprises two types of cells Neurons - Highly specialized cells; connect all regions of body to brain & spinal cord; lost ability to undergo mitosis Neuroglia - support, nourish, and protect neurons; Much more in number than neurons; continue to divide throughout lifetime  Neuroglia Neuroglia are smaller than neurons, and they are mucg more numerous. In contrast to neurons, glia do not generate or propagate nerve impulses They can multiply and divide in the mature nervous system. Brain tumors derived from glia, called gliomas  Neuroglia The Neuroglia in the Central Nervous System (CNS) Astrocytes Oligodendrocytes Microglial cells Ependymal cells The Neuroglia in the Peripheral Nervous System (PNS) Schwann Cells Satellite Cells  Neuroglia Astrocytes: Neuroglia Astrocytes are the most abundant glial cells in the central nervous system (CNS). Play a crucial role in regulating the chemical environment around neurons. Help maintain ion balance, control the blood-brain barrier, and provide nutrients and structural support to neurons.  Neuroglia Neuroglia Oligodendrocytes: Oligodendrocytes are found in the CNS Responsible for producing myelin, a fatty substance that wraps around the axons of neurons. Myelin acts as an insulator, increasing the speed and efficiency of nerve signal transmission.  Neuroglia Neuroglia Microglia: Microglia are the immune cells of the CNS. They function as macrophages, phagocytosing dead cells, and pathogens. Play a role in the immune defense and maintaining a healthy environment in the brain and spinal cord.  Neuroglia Neuroglia Ependymal Cells: Ependymal cells line the ventricles of the brain and the central canal of the spinal cord. They produce cerebrospinal fluid (CSF), which surrounds and cushions the brain and spinal cord, providing buoyancy and protection.  Neuroglia – Why are we studying it? Neuroglia The most notable finding in neurodegenerative diseases is the progressive death of neurons. However, neuroglial changes can precede and facilitate neuronal loss. Astroglial cells maintain the brain homoeostasis, and are responsible for defense and regeneration, so that their malfunction manifest as degeneration or asthenia together with reactivity contribute to pathophysiology. Neuroglia may represent a novel target for therapeutic intervention, be that prevention, slowing progression of or possibly curing neurodegenerative diseases.  Neuroglia as a Central Element of Neuropathology The neuroglial cells are the homeostatic and defensive arm of the nervous system, which ensures proper organ internal environment associated with brain function. Conceptually, neurological diseases can be defined as homeostatic failure, often associated with the inability of neuroglia to provide full homeostatic and neuroprotective support.  Neuroglia as a Central Element of Neuropathology The responses of neural cells to the damage are fundamentally different: Neurons become stressed and lose their primary function of information transfer and information processing Neuroglial cells actively respond by increasing an evolutionary conserved defensive response, collectively known as reactive gliosis.  Neuroglia in Neurodegeneration Neurodegenerative diseases, which affect almost exclusively humans, are chronic neurological disorders that lead to a progressive loss of function, structure and number of neural cells, ultimately resulting in the atrophy of the brain and profound cognitive deficits. Underlying mechanisms remain largely unknown although neurodegeneration is often associated with abnormal protein synthesis with an accumulation of pathological proteins (such as β-amyloid or α-synuclein) either inside the cells or in the brain parenchyma.  Neuroglia in Neurodegeneration Extracellular protein aggregates form disease-specific histopathological lesions (plaques and Lewy bodies). Neuroglial alterations in neurodegeneration are complex and include both glial-degeneration with a loss of glial function and glial reactivity  Neuroglia in Neurodegeneration In many neurodegenerative processes, asthenic (weakness) and degenerative changes in astroglia precede astrogliosis, most likely, by specific lesions and the appearance of damaged or dying neurons. In amyotrophic lateral sclerosis (ALS) for example, astrodegeneration and astroglial atrophy occur before clinical symptoms and neuronal death.  Neuroglia in Neurodegeneration In Huntington’s disease (HD), a decreased astroglial l-glutamate uptake as well as an aberrant release of L-glutamate from astrocytes contributes to neurotoxicity. Astroglial reactivity also contributes to HD. Suppression of astrogliotic response by inhibition of JAK/STAT3 signalling cascade increases the number of huntingtin aggregates, thus worsening pathological progression.  Neuroglia in Neurodegeneration In Parkinson’s disease (PD), astrocytes are supposed to play a neuroprotective role. Astrocytes contribute to the metabolism of dopamine; Astrocytes were shown to convert L-DOPA to dopamine. In the striatum, astrocytes act as a reservoir for L-DOPA, which they release to be subsequently transported to neurons. The level of glial fibrillary acidic protein (GFAP) expression was decreased in astrocytes in PD human tissue, indicating astroglial atrophy and reduced astrogliotic response, which may reflect compromised astroglial neuroprotection.  Neuroglia in Neurodegeneration Oligodendrocytes also undergo degenerative changes in the context of neurodegeneration. The progression of AD, for example, is accompanied by substantial shrinkage of the white matter. Degenerative changes are also observed in oligodendroglial precursors/NG2 glial cells that may reflect a reduction in their remyelinating capacity.  Astrocytes in Alzheimer's Disease The pathological potential of astroglia in the context of dementia was realized by Alois Alzheimer, who often observed activated glial cells in close contact with pathologically altered neurons. He also described glia as a cellular component of the senile plaque. Subsequent studies frequently mentioned astroglial reactivity in the context of AD, although detailed analysis of astroglial pathology started to be investigated only very recently. Astrocytes in Alzheimer's Disease - Astrodegeneration Atrophic astrocytes fail to provide adequate homeostatic support, thus further worsening neuronal function. These changes may, therefore, account for the early cognitive impairment, which results from loss and weakening of synapses, rather than from neuronal death. Astrodegenerative changes may contribute to the development of early AD pathology.  Astrocytes in Disease - Astroglial Reactivity Astrocytes become reactive in response to injury and inflammation. There are at least two distinct categories of reactive astrocytes: hypertrophic reactive astrocytes and scar-forming astrocytes. Reactive astrocytes are found in many neurological diseases, such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), epilepsy, stroke and traumatic brain injury (TBI). Upregulation of glial fibrillary acidic protein (GFAP) is widely used as a marker of reactive astrocytes. Reactive astrocytes show hypertrophy with thicker processes.  Astrocytes in Disease - Astroglial Reactivity Roles of reactive astrocytes can be neuroprotective or neurotoxic, depending on the context. In brain or spinal cord injuries (SCIs), astrocytes become reactive astrocytes with morphological changes. At the site of injury, scar-forming astrocytes form glial scars. Preventing glial scar formation leads to infiltration of circulating immune cells and subsequent neuronal cell damage. Astroglial reactivity is observed both in human post-mortem tissues and in the brains of AD animal models.  Calcium Signaling and Astroglial Reactivity The regulation of astroglial reactivity is one of the key components of the defensive response of the CNS to all types of neuropathology. Although molecular cascades involved in the initiation of astrogliosis are far from being completely understood, there is growing evidence of the critical importance of cytosolic Ca2+ signalling particularly that of Ca2+ release from the endoplasmic reticulum (ER). Deletion of InsP3R type II, an ER Ca2+ release channel, in astrocytes greatly reduces astroglial reactive response to various lesions.  Astrocytes in Alzheimer's Disease - Astroglial Reactivity - aberrant Ca2+ signals Astrocytes respond rapidly to injury and hyperexcitability to generate Ca2+ signals For example, astrocytes rapidly increase their Ca2+ in response to hyperexcitability in drug-induced seizure model. Aberrant Ca2+ signals are preferentially observed in the area where the tissue is strongly affected and where hypertrophic astrocytes are located. For example, in an in vivo adult mouse model of familial AD, reactive astrocytes displayed frequent Ca2+ signals near amyloid plaques and Ca2+ waves that originated from plaques  Vesicular Trafficking and Secretion in Astrocytes Are Altered in AD Pathological changes in astroglia (for example, signs of astrogliotic activation) have been observed at the pre-symptomatic phase of AD before the formation of β-amyloid deposits and hence changes in astroglial signalling may also occur early in the disease. Gliosignalling molecules, stored in membrane-bound vesicles, are secreted by astrocytes through the stimulation-secretion coupling that involves exocytotic release. These molecules are delivered to the plasma membrane by vesicle traffic. This brings vesicles from the Golgi complex, deep in the cytoplasm, to the cell surface.  Vesicular Trafficking and Secretion in Astrocytes Are Altered in AD This traffic is maintained by an elaborate system regulated by increases in [Ca2+]i. Astrocytes from 3xTg-AD mice isolated in the pre-symptomatic phase of the disease exhibit alterations in vesicle traffic.  Oligodendroglia in Disease In the human brain the central myelination is provided by oligodendrocytes which are present in both white and grey matter. Degeneration and death of oligodendrocytes with a subsequent decrease in CNS myelination and the shrinkage of the white matter are observed in the most (if not all) diseases of the brain and of the spinal cord including stroke, perinatal ischemia, multiple sclerosis, psychiatric disorders, traumatic injury and AD. The loss of myelin is a characteristic feature of the aging CNS; decreased myelination and oligodendroglial demise has been identified in the cerebral cortex, in areas related to cognition and memory including the frontal lobes.  Oligodendroglia in Disease In the progress of human life, the myelination of the CNS profile steadily increases during postnatal development, peaks at around 45 years and subsequently decreases in centenarians to levels comparable to those observed in infancy. In the primary visual cortices of the rhesus monkey, age-dependent myelin deterioration has been characterized, and it appeared that the length of paranodes is decreased in aging indicating some shortcomings in demyelination. These changes in the myelin developed in parallel with the decrease in the self-renewal capacity of oligodendroglial precursors/NG2 cells.  Oligodendroglia in Alzheimer’s Disease Oligodendroglial cell death and myelin shortages are associated with abnormal Ca2+ homeostasis and signalling, which is caused by either extracellular (neurotransmitter dyshomeostasis) or cellular factors (alterations in the Ca2+ homeostatic cascades such as channels, transporters and pumps). Oligodendrocytes express several types of ionotropic receptors, including l-glutamate and P2X receptors, which are permeable to Ca2+.  Oligodendroglia in Alzheimer’s Disease Prolonged or excessive activation of these receptors induces cytosolic Ca2+ overload, accumulation of Ca2+ within mitochondria, increased production of reactive oxygen species, and release of pro- apoptotic factors, which all, acting in concert, trigger oligodendrocyte death and myelin destruction. Excitotoxicity mediated by l-glutamate and ATP may also contribute to oligodendroglia death in the context of AD. In AD, the white matter degenerates and the number of oligodendrocytes is decreased.  White matter atrophy in AD. Postmortem coronal slices of the left cerebral hemisphere from patients with (A) normal aging or (B) advanced AD. Panels A and B show approximately the same coronal slice levels depicting the cingulate gyrus, corpus callosum, basal ganglia (bg), central and periventricular posterior frontal white matter (wm) and lateral ventricle. Note the markedly atrophic white matter and associated ex vacuo enlargement of ventricles (V) in (B) AD relative to (A) control. de la Monte SM, Grammas P. Insulin Resistance and Oligodendrocyte/Microvascular Endothelial Cell Dysfunction as Mediators of White Matter Degeneration in Alzheimer’s Disease. In: Wisniewski T, editor. Alzheimer’s Disease [Internet]. Brisbane (AU): Codon Publications; 2019 Dec 20. Figure 1, [White matter atrophy in AD...]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK552145/figure/Ch8-f0001/ doi: 10.15586/alzheimersdisease.2019.ch8  Oligodendroglia in Alzheimer’s Disease Myelin and oligodendrocyte defects in AD occur before the onset of symptoms and may be considered as early markers. White matter lesions are also quite prominent in the early-stage AD in periventricular and deep white matter. In 3xTg-AD mice marked morphological atrophy and decreased numbers of NG2 glia were detected at the early stages; in the later phase, the NG2 glia associates themselves with senile plaques and infiltrate the latter with processes. A similar decrease in the NG2-positive profiles was observed in human AD post-mortem tissue.  Oligodendroglia in Alzheimer’s Disease All these alterations in myelin, oligodendroglia as well as degenerative changes in oligodendroglial precursors/NG2 cells may contribute to pathological remodeling of the connectome and hence to cognitive deficiency.  Microglia in Alzheimer’s Disease Microglial changes, both reactive and degenerative, are now considered to be an important part of AD progression. Activated microglial cells (together with astrocytes) are closely associated with senile plaques; they secrete numerous proinflammatory factors that may contribute to neuronal damage. At the same time, the loss of microglial function has also been observed. In APP/PS1 mice, appearance of senile plaques coincided with the loss of microglial phagocytotic function (which, arguably, reduced β- amyloid clearance and facilitated plaque formation).  Microglia in Alzheimer’s Disease In the ageing human brain, degeneration of microglia can define neural tissue vulnerability to the AD pathology. Activation of microglia can be triggered by β-amyloid, either soluble or oligomeric. In vivo imaging of transgenic mice demonstrated that microglia are activated and recruited to Aβ plaques only after the plaques had been formed. Microglial status does change in the progression of AD.  In conclusion Pathological changes in neuroglia, including but not restricted to astrocytes, oligodendrocytes, NG2 cells and microglia, are omnipresent in neurodegenerative diseases. These neuroglial changes include cellular degeneration and asthenic responses at earlier stages of a disease, and, as disease progresses, evident by occurring neuronal damages, neuroglia turns to reactive phenotypes. The specific morphofunctional changes in glia not only occur during distinct temporal domains, but also are region-specific.  In conclusion Since the changes in neuroglia precede those in neurons, it is likely that the neuroglial cells failure to maintain CNS homeostasis is a malefactor causative to neuronal death. Neuroglia therefore may represent an opportunistic target for therapeutic intervention directed towards prevention and conceivably curing neurodegenerative diseases.  REFERENCES Beart, P., Robinson, M., Rattray, M., & Maragakis, N. J. (2017). Neurodegenerative diseases: Pathology, Mechanisms, and Potential Therapeutic Targets. Springer. Shigetomi, E., Saito, K., Sano, F., & Koizumi, S. (2019). Aberrant calcium signals in reactive astrocytes: a key process in neurological disorders. International Journal of Molecular Sciences, 20(4), 996. https://doi.org/10.3390/ijms20040996 Tortora, G. J., & Derrickson, B. H. (2020). Principles of anatomy and physiology. John Wiley & Sons