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What Is The Role Of The Myelin Sheath

Although Alois Alzheimer described myelin breakdown in Alzheimer’s disease (AD) as early as 1911, his observation has since eluded researchers. Alzheimer’s disease has been considered primarily a gray matter disorder; nevertheless, recent evidence suggests that myelin damage may play an important role in AD pathology. Classic neuropathological changes in AD, e.g. accumulation of aggregated Aβ 42 and the presence of neurofibrillary tangles cause neuronal loss, but they can also induce oligodendrocyte death and myelin damage. There is also evidence that myelin pathology may even precede Aβ and tau pathologies in AD. The state of the art does not allow us to determine whether myelin damage is a primary or secondary injury in AD subjects. The article reviews the current knowledge on the role of myelin in AD pathology and its interactions with Aβ and tau pathologies.

Chapter 12 Nervous Tissue Diagram

Alzheimer’s disease (AD) is known to cause some well-characterized pathological changes, such as extracellular accumulation of amyloid plaques, neuronal occurrence of neurofibrillary tangles, glial hypertrophy, and neuronal death [ 1 – 3 ]. The disease is primarily associated with neuronal damage; however, there is evidence that myelin fibers are also damaged in AD. Myelin pathology in AD patients has not been widely studied to date, although Alois Alzheimer described myelin disruption in AD as early as 1911 [ 4 , 5 ]. It is unclear why the phenomenon of myelin damage has been forgotten for over 100 years. Classic neuropathological changes in AD, e.g. the deposition of amyloid plaques and the presence of neurofibrillary tangles in the brain lead to neuronal damage and synapse loss, but oligodendroglial degeneration and myelin damage have also been observed in the brains of AD patients [6–9].

The myelin sheath is a lipid-rich multi-layered membrane wrapped around axons. Damage to myelin is thought to cause neuronal dysfunction and cognitive decline. Myelin is necessary for impulse propagation along axons. In addition, there is evidence from neuroimaging and postmortem studies of the human brain that myelin damage may be associated with amyloid-β (Aβ) plaques and tau hyperphosphorylation, both of which have been found in AD [ 6 , 7 , 10 , 11 ]. Interestingly, the distribution of AD pathology inversely reflects the pattern of myelination [12]. In later myelinated brain regions, such as temporal and frontal lobes, AD pathology develops before early myelinating regions, mainly motor and sensory systems, which may remain intact in AD until very late stages of the disease [13–16]. Some studies also suggest that AD is a developmental disorder that may only appear when myelination is complete [ 13 , 14 ]. One recent study has also revealed a defect in myelin lipid biosynthesis in the preclinical stage of AD, which significantly contributes to the deterioration of synaptic function and cognitive decline [16]. Interestingly, impaired myelin sheath formation even appears to prevent neurofibrillary tangle pathology in AD patients, indicating that myelin damage may be the first neuropathological abnormality in AD [16]. The above data suggest that AD may be a demyelinating disorder. Over time, myelin damage can contribute to synaptic dysfunction and cognitive decline. The article presents current knowledge on the role of myelin in AD, as well as its interactions with amyloid deposition in the brains of AD patients.

Myelin wraps around the axons of neurons and forms structures called nodes of Ranvier, where action potentials are generated and then propagate along the myelinated axons [17]. Conduction velocity along myelinated axons is not only dependent on axon diameter, but is also regulated by the number and geometry of nodes of Ranvier [17]. Myelin damage can affect the transmission of action potentials in neurons. Neuropathological animal data showed impaired synaptic staining and synaptic transmission in the demyelinated hippocampus of experimental autoimmune encephalitis (EAE) mice [18, 19]. This finding confirms that myelin plays an important role in synaptic transmission.

In addition, proteins such as neurite outgrowth inhibitor-A (Nogo-A), myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (MOG), which are expressed in oligodendrocytes and myelin, act as inhibitors of axon sprouting, which is important. to form synapses [20]. However, in addition to these proteins, many other factors may contribute to the deterioration of synapse structure and function. Dysfunction of axonal transport can occur as a result of demyelination. Proper function of myelin also has beneficial effects on neuronal function. Damage to myelin can impair neuronal function because myelin supports the survival of axons. Oligodendrocytes have the ability to secrete trophic factors such as insulin-like growth factor-1 (IGF-1), glial cell-derived neurotrophic factor (GDNF) and nerve growth factor (NGF), which have beneficial effects on neuronal survival [ 21 ]. –23]. Clinically, this means impaired cognition, as various myelination disorders cause cognitive decline.

Myelinated Motor Neurons

Data from experimental animal models of AD also suggest that focal demyelination can be found primarily near Aβ plaques in the neocortex [ 10 , 11 , 24 ]. Schmued et al. found evidence of complete disruption of myelinated fibers passing through or near Aβ plaques in the hippocampus region of rats [ 24 ]. Thus, various animal model data suggest that demyelination can lead to neuronal and axonal degeneration. Both factors may underlie the cognitive impairment observed in AD.

Data from animal models also provide evidence for an interaction between tau pathology and myelin damage. Myelin damage has been found to precede the deposition of Aβ plaques and neurofibrillary tangles in the brains of mouse models of AD [ 25 , 26 ]. Defects in myelin biosynthesis have been found in AD subjects even in the very early, preclinical stages of the disease, e.g. Braak stage I/II in the temporal cortex, which also confirms that myelin dysfunction precedes amyloid pathology [16]. Cuttas et al. a significant decrease in the activity of ceramide synthase 2, which is responsible for the synthesis of very long chain ceramides included in the lipids of the myelin sheath, was observed. This finding may support the hypothesis that demyelination may play a role in the pathogenesis of AD [16].

Myelin damage is likely to be an early feature of AD pathology, preceding the appearance of typical pathological changes such as Aβ plaques and neurofibrillary tangles. Interestingly, there is also evidence that tau protein hyperphosphorylation may occur later, during the remyelination process [27]. It should be noted here that hyperphosphorylated tau protein as a marker of axonal and neuronal loss has also been found in other demyelinating disorders [28]. It is still unclear whether myelin damage really triggers the occurrence of AD pathology.

Myelin development progresses from childhood and adolescence to adulthood [29]. Myelination of the central nervous system is completed at different times in different parts of the brain. In humans, the development of myelin in the corpus luteum, in contrast to the formation of neurons, ends only in the second decade of life [30] and in the frontal lobes only around the age of forty [31]. . Myelination is directly related to the development of cognition and motor function.

Question Video: Describing The Structure Of The Myelin Sheath

Data from animal models show that the expression of myelin basic protein (MBP), an essential compound of the myelin sheath, is significantly higher in rats trained to perform learning tasks than in untrained rats, and MBP levels are directly related to learning speed [32, 33]. Interestingly, the presence of new oligodendrocytes and myelin in the corpus luteum was found in adult mice that had to learn complex motor skills [34, 35].

The integrity of the myelin sheath decreases with age and so does the amount of myelin in the brain. Myelin content peaks in middle age and gradually declines in later years [ 14 , 36 ]. There is evidence that age-related cognitive decline is associated with changes in white matter [37] that may be caused by marked demyelination and loss of oligodendrocytes. Age-related changes in white matter integrity are associated with cognitive decline in healthy elderly individuals [38]. It is worth noting that there is evidence that memory training can increase the integrity of white matter in the elderly while improving their cognitive performance [39]. In conclusion, aging-related myelin damage may contribute to cognitive decline in healthy elderly individuals (Figure 1).

The role of myelin in cognition. The figure shows the results of myelin damage for cognition. Myelin is responsible for the transmission of action potentials. Myelin proteins are involved in the formation of synapses and their proper functioning. Myelin damage impairs neuronal function, increases neuronal energy consumption, and impairs trophic factor transport and rapid axonal transport

The amyloid hypothesis as a correlate needs to be tested

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