*2.2.3 Huntington's disease*

Huntington's disease (HD) is another neurological disorder. It is passed down to progeny as "autosomal dominant" manner. The trigger in IT15 gene (found on the short arm of chromosome 4) results in HD. Mutated IT15 gene encodes "Huntingtin" (HTT) protein that builds up inside tissues, causing the deterioration of nerve cell, which eventually leads to death. The mutation increases the amount of "CAG repeats", that causes the prolonged chain of glutamine (Q) giving polychain Q of greater than 36 toward its anionic terminal. The number of repetitions is inversely proportionate to the age at which the sickness manifests itself. After around 15–20 years, the condition causes cachexia and death. Chorea-like motions, cognitive impairment, and mood disturbances are among the symptoms [25]. It has been discovered that in HD, there is a decline in the production of genes and proteins in this system, rather than a loss of cholinergic neurons. It was demonstrated that AChE activity was lowered in mouse models of HD (R6/1), and as a result, they showed cognitive abnormalities in the middle stage of the illness. Activation of microglial cells has been observed in the carriers of mutation that can be diagnosed 15 years prior to the beginning of HD. Furthermore, activation of these cells coincides with striatal neuron dysfunction. By secreting proinflammatory cytokines, microglia may activate A1 astrocytes [26]. Furthermore, it has been demonstrated that thalamostriatal degeneration may lead to dystonia in HD. It has also been proposed that the cholinergic system is implicated in dystonia. Cholinergic transmission has been established repeatedly in HD. However, it has been proposed that therapy with AChE inhibitors is not recommended in HD [27].

#### *2.2.4 Multiple sclerosis*

Multiple sclerosis is an usual de-myelinating disorder of the central nervous system (CNS). Multiple, diffuse autoimmune inflammatory alterations contribute to myelin and oligodendrocyte destruction in SM. T-lymphocytes (mostly CD8+) dominate the inflammatory cell infiltrates. Neurotransmission has been disrupted. Axons are preserved at an initial phases of illness, but they have been irreparably destroyed with increasing time. Inflammatory alterations are dynamic and occur mostly in the substantia alba, also called as white matter. Remyelination occurs at all phases of SM, although mostly during the quiescent period [28]. SM causes a rise in proinflammatory cytokines. AChE activity was shown to be higher for those that possessed this condition compared to the reference healthy population. The effect of AChE has been linked to low levels of ACh and persistent inflammatory diseases. According to investigations, periphery acetyl-cholinesterase action has been a supplementary metric for assessing the "non-neuronal cholinergic system's" functionality in inflammation regulation. The patients suffering from relapsing-remitting SM type (RR-SM), lower ACh levels were associated with higher levels of pro-inflammatory cytokines such as IL-17 and IL1 in both CSF and blood. There is an inverse relation reported between the Ach and AChE in RR-SM patients. More the activity of AChE, less the level of Ach. Furthermore, AChE transcript expression increased. When the individuals with RR-SM were differentiated by the reference group, the enzyme level rose by more than 60%. The enhanced serum AChE activity was caused by its G4 form. Every element that is required for the production of Acetylcholine was unchanged in SM patients, demonstrating that cholinesterases are to blame in generating low levels of Ach. Moreover, greater effect of AChE was linked to elevated concentrations of variety of interleukins (IL-12, 18 and 23) and Tumor necrosis factor. The inflammation of myelin sheath promotes cholinergic dysfunction, which contributes to SM. Because ACh levels alter cytokine levels, uncontrolled metabolism of acetylcholine could be an another pathogenic cause of SM [29]. An imbalance of cholinergic activity has also been detected in the hippocampus of SM patients. This is consistent with some persons experiencing a range of cognitive deficits as a result of this medical issue. In the hippocampus of the patients investigated, ACh levels were lower, ChAT activity was lower, but AChE activity remained same. These diseases may be caused by hyper action of AChE in proportion to the chemical messenger (Ach). Another research found that AChE activity remained constant upon comparing to the reference population. Individuals suffering from SM, on the other hand, showed considerable intellectual disability already. The hike in glial AChE levels has been hypothesized for the cognitive decline that compensated for neuronal AChE's drop. That might explicate the negative association between AChE activity and the neuropsychological examination results, that could suggest a increased response of glial cells in individuals with larger cognitive impairments, according to these researchers. Furthermore, cholinergic equilibrium within AChE & ChAT has been well recognized during the remission period [30]. There is a rise in ChAT and a reduction in AChE at this stage of SM. This balance is reversed in the acute phase of the illness, with AChE hike and reduced ChAT.

#### *2.2.5 Amyotrophic lateral sclerosis*

Amyotrophic lateral sclerosis (ALS) is a neurological disorder. The degeneration of nerves occurs in the brain stem, pathways of the cortico-spinal route, and in the horn

*Role of Acetylcholine in Chronic Diseases DOI: http://dx.doi.org/10.5772/intechopen.110663*

cells of the anterior region, which results in manifestations that are either motor or non-motor. However, the illness' etiology is still unclear. ALS is more prominent in individuals of ages between 50 and 75 years. The risk of ALS reduces beyond the age of 75 years. Neuronal loss was accompanied by the responses of inflammation entailing the growth of microglial and astrocytic cells in both ALS patients and animals. The defining hallmark of ALS is accumulation of the malfunctioning protein, TDP-43. This protein is generally found in the nucleus of the cell. TDP-43 abnormal folding results in the deposition of aggregates in the cytoplasm, resulting in the motor deficits and disrupted transcriptional process. The condition begins locally and later spreads [31, 32]. This enzyme was created as a consequence of overactive motor neurons. An inflammatory response is prevalent as ALS progresses which leads to an increase in pro-inflammatory cytokines including Interleukins (IL-1, 6), Tumor necrosis factoralpha, and Interferon alpha [33]. Further, in ALS, there is a presence of microglial cells and reactive astrocytes. Excessive oxidative stress is also present in ALS [34]. R-AChE plays an important function in oxidative stress; however, its source might be reactive astrocytes. This molecular type of AChE may have a role in the development and pathophysiology of ALS.
