Gene Editing Using Crispr-Cas9 for the Treatment of Alzheimer’s disease

Gene Editing Using Crispr-Cas9 for the Treatment of Alzheimer’s disease

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. Introduction

1.1 Alzheimer’s Disease

Alzheimer’s disease is the most common cause of dementia; there are, however, numerous. Alzheimer’s disease accounts for 50% to 70% of people with dementia suffer. Alzheimer’s disease is a degenerative process that slowly and progressively destroys brain cells.

It is named after Alois Alzheimer, a German neurologist, who in 1907 first described the symptoms and neuropathological features of Alzheimer’s disease, such as plaques and tangledneuro-fibrils in the brain. It is a disease that affects memory and mental functions (for example, thinking, speaking, etc.), but it can cause other problems such as confusion, changes in mood and disorientation in space-time.

Early symptoms i.e. some difficulty remembering and loss of intellectual abilities may be as mild as to pass unnoticed by the person, family members and friends. But, as the disease progresses, the symptoms become more and more obvious, and they begin to interfere with daily activities and social relations.Gene Editing Using Crispr-Cas9 for the Treatment of Alzheimer’s disease

Difficulty in the practice of the very common everyday activities, such as dressing, bathing and using the toilet, becomes gradually so severe as to result, over time, in the complete dependence on others. Alzheimer’s disease is neither infectious nor contagious. It can be considered in all respects a terminal illness, which causes a general deterioration of health.

Gene Editing Using Crispr-Cas9 for the Treatment of Alzheimer’s disease. The most common cause of death is pneumonia, because the progress of the disease leads to deterioration of the immune system and weight loss, increasing the risk of infections of the throat and lungs. In the past, use of the term “Alzheimer’s disease” was in reference to a form of pre-senile dementia, as opposed to senile dementia.

It is now believed, however, the disease affects both people below 65 years of age to people above 65 years. As a result, today, It is often referred to as Alzheimer’s dementia, specifying, if necessary “early onset.”

1.2  Characteristics:

Alzheimer’s disease is histo-pathologically characterized by massive synaptic loss and Neuronal death observed in the brain regions responsible for cognitive functions, Including the cerebral cortex, the hippocampus, the entorhinal cortex, and the ventral striatum.Gene Editing Using Crispr-Cas9 for the Treatment of Alzheimer’s disease

The histopathological characteristics present in the cerebral parenchyma of patients with Alzheimer’s disease include amyloid fibrillar deposits located on the walls of Blood vessels, associated with a variety of different types of senile plaques, accumulation of Abnormal filaments of the tau protein and consequent formation of neurofibrillary tails (NFT), Neuronal and synaptic loss, glial activation and inflammation.

Based on these neuropathological markers, two main hypotheses were proposed, to explain the etiology of the disease. According to the hypothesis of the amyloid cascade, Neurodegeneration in Alzheimer’s disease begins with proteolytic cleavage of the protein. Amyloid precursor protein (APP) results in the production, aggregation, and deposition of β- Amyloid (Aβ) and senile plaques.

According to the cholinergic hypothesis, the dysfunction of the cholinergic activity is sufficient to produce a memory deficit in animal models, which is similar to Alzheimer’s disease. Brains of patients with Alzheimer’s disease showed degeneration of cholinergic neurons, also depicted by cholinergic markers including choline acetyltransferase and acetylcholinesterase having reduced activity in the cerebral cortex of patients with Alzheimer’s disease.

In most cells, phospholipase A2 (PLA2) contributes to the release of arachidonic acid of phospholipid membranes, which is a fundamental step in the synthesis of the main mediators of the inflammatory response. As phosphatidylcholine is one of the substrates of PLA2, reduction of the activity of this enzyme could produce a decline in the catabolism of Phosphatidylcholine, reducing the amount of choline for the synthesis of acetylcholine, further contributing to the Cholinergic deficiency in Alzheimer’s disease.

In brains of patients with Alzheimer’s disease, the reduction of acetylcholinesterase activity in the frontal and parietal cortex was related to the onset of dementia, the number of senile and NFT plaques, and early death of these patients. Thus, the reduction of PLA2 activity in patients with the Alzheimer’s disease is directly related to the severity of dementia and the level of Cognitive impairment. But the reduction in the activity of this enzyme was not related to the symptoms of Alzheimer’s disease which were being treated with antipsychotics and acetylcholinesterase.

1.3 Genetic Aspects:

The genetic factor is considered to be preponderant in the etio-pathogenesis of Alzheimer’s disease. In addition to the genetic component, toxicity, infectious agents, aluminum, reactive oxygen substances (ROS) and amino acids.Neurotoxicity, and the occurrence of damage in microtubules and associated proteins are one of the most widely accepted pathogenic mechanism of the disease.

It is important to point out that these agents may still act for direct damage in the genetic material, leading to somatic tissue mutation. About 1/3 of the cases of Alzheimer’s disease present familiarity and behave according to an autosomal dominant monogenic inheritance pattern. These cases, in general, are of early involvement, and extended families have been periodically studied.

The Patients affected by Alzheimer’s disease have a 50% chance of having children affected by the pathology. Moreover, an association between Alzheimer’s disease and Down’s syndrome is evidenced in the literature.Discovery of the first Alzheimer’s disease gene on chromosome 21, which has an extra copy of chromosome in Down syndrome patients.

Individuals with Down syndrome presented premature aging, and practically all had Alzheimer’s, clinically and neuro-pathologically confirmed, between 40 and 50 years of age. The first case to be identified in Alzheimer’s disease, the person responsible for APP was which accumulates intensely in the senile plaques of the brains of patients with Alzheimer’s disease.

Although the various genetic risk factors – APP, PS1 and PS2 – are associated with Alzheimer’s disease, the presence of the allele of the apolipoprotein E gene type 4 (apoE4) demonstrated association with the number of senile plaques and vascular plaques, as well as a reduction of Cholinergic function in brains of patients with this pathology.

The APP gene Located on the chromosome and its pathogenic role have been extensively investigated in The accumulation of Aβ protein in the brains of patients with Alzheimer’s. The presence of the apoE4 gene in the long arm of chromosome 19 was associated with Risk factors for Alzheimer’s disease.

The inheritance of the apoE4 gene increases four times the risk for the development of Alzheimer’s disease, and this risk is more if the patient inherits the allele of both parents.

In relation to PS, more than 40 mutations have been described for PS1 (whose gene is located On chromosome 14), which may subsequently result in the sporadic form of Alzheimer’s disease. Mutations in PS 1 and 2 selectively increased Substance Aβ in cell culture and in transgenic mouse brains and were related to the development of sporadic forms of Alzheimer’s disease…………………………………………………………continued