Overview Of Sickle Cell Disease And Alzheimers Disease Biology Essay

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Human genotype is the most prominent determinant of human pathogenesis. Thus the role of human gene on the progression and development of human disease can never be neglected. A hereditary disorder might be monogenetic which occurs due to mutation in a single particular gene. For instance sickle cell disease, thalassemia, Cystic fibrosis are the examples of monogenetic disorder which are caused due to a particular genetic mutation. In contrast, in some genetic disorders, mutation in more than one gene causes or predisposes the same disease. Thus Alzheimer's disease and Parkinson's disease which are caused due to involvement of more than one gene can be designated as multigenic disorders.

A Comparative Overview of Sickle Cell Disease (SCD) and Alzheimer's Disease (AD)

Sickle Cell Disease (SCD) is a monogenetic disorder in haemoglobin causing the Red Blood Cells(RBC) to form an abnormal sickle shape. This process is called sickling which ultimately results in the loss of flexibility in RBC and other pathogenic consequences. The factor involved behind the sickling of RBC is the mutation of Beta Globin gene located in chromosome 11. This disorder is prevalent in people originated from tropical and sub tropical regions where malaria is /was common. Nearly one third indigenous people of Sub- Saharan Africa bear this mutated Beta globin gene. Sickle cell disease results into reduced life expectancy with average life being 42 years and 48 years in affected males and females respectively. (Platt OS, et al, 1994)

Alzheimer's disease (AD) is a multigenic disorder which was named after German psychiatrist Alois Alzheimer who first described it in 1906 as an incurable, neurodegenerative disease generally diagnosed in people more than 65 years of age. The survey of September 2009 shows that number of patients suffering from Alzheimer's disease worldwide are more than 35 million. This prevalence has been expected to reach up to 107 million by 2050.( Brookmeyer, R et al ,2007).Alzheimer's disease is a type of a protein misfolding disease , caused by accumulation of abnormally folded amyloid-beta and tau proteins in the brain. Hence it is also called a tauopathy due to abnormal aggregation of the tau protein in brain. The clinical picture of AD is variable, however the common feature is progressive breakdown of memory and cognitive functions like reasoning.(Nussbaum et al 2004). Confusion, irritability, language breakdown, aggression and long term memory loss are some of the symptoms that appear as the disease becomes more severe. This ultimately leads to loss of body functions and death. Most of the AD sufferers are expected to survive for around seven years after getting diagnosed. However, less than 3%sufferers remain alive even after fourteen years of diagnosis.


Pathophysiology of Sickle Cell Disease

A point mutation in the β-globin gene of chromosome 11 , which results in the substitution of hydrophilic glutamic acid to hydrophobic  valine at the sixth position gives rise to mutated beta globin sub unit. When two mutated beta globin subunits bind to two wild type alpha sub units, formation of a an aberrant haemoglobin called HbS takes place. Being benign in nature, this mutation does not cause any apparent effects on the secondary or tertiary structures of haemoglobin in conditions of normal oxygen concentration. However, this HbS has a tendency to polymerize in low-oxygen tension and causes polymerisation of the haemoglobin. In this process, the hydrophobic residues of the valine at position 6 of the beta chain of HbS associates with the hydrophobic patch, making the haemoglobin molecules to aggregate and form fibrous precipitates. The repeated episodes of polymerization and sickling causes permanent deformity on the shape of RBC and decreased elasticity. When these deformed and rigid RBCs pass through the capillaries, they get occluded there due to reduced elasticity. Thus the adhesion of abnormal red blood cell (RBC) to the endothelium has been proposed as the probable initiating event of vasoocclusion, nevertheless the variations in the endothelium activation state may modulate the unpredictable occurrence of the major complications. (Hebbel RP, 1997)Inflammation is the major catalytic agent for this process.(Kaul DK, Hebbel RP,2000). This process ultimately results in ischaemia.

The anemia in sickle cell disease is caused by hemolysis due to the destruction of the RBCs inside the spleen. The rapid destruction rate of RBC exceeds the rate of replenishment of bone marrow. Unlike healthy red blood cells typically sickle cells survive only for 10-20 days. Though the peripheral destruction of sickled RBCs have been considered to be prominent feature of sickle cell disease, potential contribution of ineffective erythropoiesis to the pathophysiology of this hemoglobinopathy is also point to be considered. (Catherine J. Wu et al,2005).

Pathophysiology of Alzheimer's disease

AD is mainly a sporadic disease and only 0.1 percent cases are familial which onset before the age of 65. Neverthless there are some genes that act as a risk factor. (Blennow K, de Leon MJ, Zetterberg H, 2006). Most of the familial autosomal dominant AD are due to mutation in one of the following genes: 1)APP (Amyloid precursor protein) gene 2)presenilin1 and 3)Presinilin 2 . Most of the mutation in APP or Presenilin gives rise to the production of AB42(Amyloid beta 42) which is the major part of senile plaques that are seen in AD.

Apolipoprotein E(APOE) is another genetic factor associated with AD. APOE is actually a common aminoacid involved in cholesterol transport. However it is also detected in both plaques and neurofibraillary tangles associated with AD. Studies have shown that at least 40 to 80 percent individuals with AD possess at least one APOE 4 allele.

Though the exact cause of onset of AD has not yet been revealed, some theories has been put forward. They are : i)Cholinergic hypothesis ii)Amyloid Hypothesis and iii)Tau Hypothesis.

The cholinergic hypothesis says that impaired synthesis of a neurotransmitter called acetylcholine is responsible for the onset of AD.( Francis PT, Palmer AM, Snape M, Wilcock GK, 1999). However this hypothesis was refuted by the evidence that medications intended to treat acetylcholine deficiency could not produce promising results.

Amyloid hypothesis holds the notion that deposition of amyloid beta protein (ABP) derived from amyloid beta precursor protein(APP) is the main basis of the AD. This APP is encoded by APP gene located on chromosome 21. According to this hypothesis, amyloid precursor protein (APP), which penetrates through the neuron's membrane, has significant role on neuronal growth, survival and post-injury repair. In Alzheimer's disease, APP is divided into smaller fragments by enzymes through proteolysis. Fibrils of beta-amyloid are derived from one of these fragments of APP. These fibrils then form clumps which deposits outside neurons and are known as senile plaques. The fibrils thus formed disrupt the cell's calcium ion homeostasis. This process ultimately results in programmed cell death or apoptosis.( Yankner BA, Duffy LK, Kirschner DA,1990)

In 2004, Tau hypothsis for AD emerged when amyloid hypothesis was challenged by the fact that amyloid plaques do not correlate with the neuron loss. (Schmitz C, Rutten BP, Pielen A, et al., 2004). As we know every neuron has a cytoskeleton, partly made up of microtubules which help in building different molecules from the body of the cell to the ends of the axon. The Tau hypothesis says that tau  protein stabilizes the microtubules when phosphorylated and undergoes chemical changes, becoming hyperphosphorylated. After that tau protein pairs with other threads and creates neurofibrillary tangles. This process disintegrate the neuron's transport system. ( Hernández F, Avila J , 2007). As a result, biochemical communication stops between the neurons leading to death of cell.


Treatment of Sickle cell disease

Dietary cyanate or derivatives can be used on the treatment of sickle cell disease. Painful crisis due to vaso-occlusion can be managed by analgesics, and opoid administration. Children born with sickle cell disease are given 1 mg dose of folic acid per day throughout the life. As a supplement they are accompanied by a dose of penicillin , till the age of five years, in order to safe guard from infections. In adult patients with acute chest pain due to vaso-occlusion, oxygen supplementation, and blood transfusion can give relief. Bone marrow transplantation has been found to be effective in children. (Walters MC, Patience M, Leisenring W, et al., 1996)

Hydroxyurea is the first approved drug for the treatment of sickle cell disease which had successfully decreased the severity of attacks in a study done by Charache et al in 1995. "To date, hydroxyurea (HU) is the only drug known to reduce the frequency of vasoocclusive crises, acute chest syndromes (ACSs), and transfusion requirements". (Malika Benkerrou et al, 2002). The possible mechanism of action of hydroxyurea has been believed to be the reactivation of fetal heamoglobin in place of HbS. Neverthless the long term use of this drug as a chemotheraupetic agent has shown some risks. ( Platt OS, 2008).In addition, gene therapy is the most novel and most promising technique for treatment of monogenetic disorder like sickle cell disease.

Treatment of Alzheimer's disease

Since Alzheimer's disease does not have any cure so far, only symptomatic treatment can be given to the sufferers.

Pharmaceutical treatment includes:

Acetylcholinesterase inhibitors that are used to reduce the rate of acetylcholine  break down.

Glutamate which is a useful excitatory neurotransmitter of the nervous system.

Memantine which  is a noncompetitive NMDA receptor antagonist. 

Antipsychotic drugs that can be used to reduce the aggressiveness in Alzheimer's patients with behavioural problems

Psychosocial intervention is complementary to pharmaceutical treatment in AD patients. Especially dementia is managed by psychosocial intervention. Similarly caregiving is very mandatory to AD patients because AD renders people incapable of fulfilling their own needs.


The comparative study of these two genetic diseases showed that Sickle cell disease (SCD) a hereditary single gene disorder caused due to mutation of beta globin gene in chromosome 11 due substitution of glutamic acid by valine at position 6, whereas alzheimer's disease is a multigenic disease caused due to mutation in multiple genes like beta APP ,PS1 , PS2 and APOE. SCD is a solely an inherited disorder, however AD is very rarely a familial. Both of these disorders involve the alteration on the structure of protein. However, SCD is basically a hemoglobinopathy due to polymerization of the abnormally synthesized hemoglobin. In contrast, AD evolves from accumulation of beta amyloid peptide in brain leading to cognitive abnormalities and degeneration of neurons.

Regarding the onset of disease, SCD occurs by birth, however most of the Alzheimer's disease initiate after the age of 65. Unlike SCD, behavior problem is the characteristic feature of AD. If the magnitude of severity concerned, SCD is very less dangerous and less severe disease in comparison to AD if hypoxia and dehydration avoided. Rather the heterozygous sickle cell trait becomes advantageous preventing the individual from malaria. In contrast , AD is a very severe and dangerous neurological disorder with very poor prognosis. Though there are symptomatic treatments available for AD, but no cure for this disorder so far. Unlike AD, SCD can be relatively managed by treatments. In addition, gene therapy has also shown promising results for the treatment of SCD. Thus, SCD and AD have plenty of contrasting features.