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«Alzheimer’s disease (AD) is a common human neurodegenerative disorder. It is basically occurs in elderly people (age more than Abstract 60). Till ...»

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Review Article

Different Therapeutic Approaches Against Alzheimer’s Disease and Usefulness

of Drosophila as AD Model

Sandeep Kumar Singh*

Department of Biochemistry, Banaras Hindu University, Varanasi

*Corresponding Author: Sandeep Kumar Singh Department of Biochemistry, Banaras Hindu University, Varanasi Received: January 19, 2016; Published: April 20, 2016.

Alzheimer’s disease (AD) is a common human neurodegenerative disorder. It is basically occurs in elderly people (age more than Abstract 60). Till date very less understanding about causes of AD that’s why there is no cure of the same occurs. People are focusing to find out suitable therapeutic potential for the treatment of AD by using different approaches. People are using different model system for the study and validation of different synthetic as well as herbal compounds against treatment of AD. Even AD etiology is not well known yet. So this review basically discusses the fundamental about AD and different therapeutic approaches for treatment of AD using Drosophila model system.

Keywords: Alzheimer’s disease; Drosophila model system; Neurodegenerative disorder Alzheimer’s disease is a neurodegenerative disorder [1]. It is the most common form of dementia [2,3]. AD is characterized by the Introduction memory loss, irritability and mood swings[4]. It has no any cure till today. It was first described by German psychiatrist Alos Alzheimer in 1906[4].AD is basically associated with aging[5].The cause of the AD is not well understood. There are basically two hallmark of the AD; one is extracellular deposition of senile plaques and other intracellular formation neurofibrillary tangles (NFT) in the brain [6, 7].The treatments available at present only help with the symptoms of the disease but do not stop the progression of the disease. So the differ- ent therapeutic approaches in search of suitable drug target for the treatment of AD are demanding. Nowadays people are using different synthetic as well as herbal compounds for the treatment of AD. Earlier studies from our group reported the anti-Aβ activity of a novel flavonoid derivative [8] as well as showed neuroprotective role of a novel copper chelator against copper mediated Aβ toxicity [9]. Fur- thermore, Zhang et. al. showed dual effect of a synthetic molecule having anti-Aβ as well as copper chelation property [10].Several other groups are also focusing to find out the suitable therapeutic potential against AD using anti-Aβ approaches [11-14].In this review, we have discussed different therapeutic approaches used for the treatment of AD using drosophila model system with brief description of other model system used in AD study.

The disease is characterized into four stages:

Pre-dementia: It is related to aging and stress. Memory-loss and apathy are commonly found in this stage [15,16].

Early: Language problem appears. Patient feel problem in planning [16] Moderate: It is characterized by wandering, irritability and labile effect, leading to crying, aggression and resistant towards care giver [16] Advanced: In this last stage, person becomes completely dependent on the care giver. Complete loss of speech and ability to feed by themselves occurs. Extreme apathy and exhaustion are commonly found [16].

Citation: Sandeep Kumar Singh. “Different Therapeutic Approaches Against Alzheimer’s Disease and Usefulness of Drosophila as AD

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Cause: The exact cause of Alzheimer’s is still unknown [17]. Several hypotheses are given to explain the cause. Some prominent hypotheses are: Cholinergic hypothesis, tau hypothesis, amyloid hypothesis, apoE gene related hypothesis and age-related myelin breakdown in the brain [18,19,20,21,and22].But amyloidal hypothesis is the most accepted one [23, 24, 25].

In 1991, this hypothesis postulated that amyloid beta deposits were the main cause of the disease [26].It was supported by the postuAmyloid hypothesis late that gene for amyloid beta precursor protein (APP) is located on chromosome 21 and APOE4 which is the major genetic risk factor leads to excess synthesis of β-amyloid (Aβ) in the brain [27].Researchers have assumed that Aβ oligo mers are the primary pathogenic form of Aβ. These toxic Aβ oligomers are also referred to as amyloid derived-diffusible ligands (ADDLs) which bind to the surface receptors on neurons and alter the structure of the synapse, by disrupting the neuronal communication [28].In 2009the theory was updated, which suggests that some age-related processes may also cause the neuronal withering. N-APP, a fragment of APP from the N-terminus, is cleaved from the APP peptide by one of the same enzyme which cleaves beta amyloid from the APP peptide, triggers the self-destructing pathway by binding to the neuronal receptor called death receptor6 (DR6).DR6 is expressed highly in the human brain region affected by Alzheimer’s disease. So it is possible that the N-APP/DR6 pathway may be blocked by the aging brain to cause the defect [29,30].

AD is considered as protein mis folding disease, caused by the accumulation of mis folded Aβ and tau proteins in the brain[31]. Plaques Biochemistry of AD found are made up of small peptides of 39-43 amino acids in the brain known as beta-amyloid [32,33]. Aβ is the fragment of larger peptide APP, which is the trans-membrane protein that is found in the neuron’s membrane [34,35].During AD, APP undergoes proteolytic processing by two different pathways namely: amyloidgenic pathway by the action of β and γ-secretase and non-amyloidgeinc pathway by α- and γ-secretase [36, 37, and 38]. In the amyloidogenic pathway, APP undergoes cleavage by β-secretase, encoded by BACE gene. This cleavage produces a soluble extracellular fragment of APP (sAPPβ) and a membrane spanning C-terminal fragment (βCTF/C99).The γ-secretase then cleaves βCTF to produce Aβ peptides and the APP intracellular domain (AICD).Aβ peptides of variety of lengths are produced but Aβ40 and Aβ42 are the major is forms produced in the CNS.Aβ42 is subjected to more oligomerization and is more neurotoxic [39-42].

In non-amyloidogenic pathway, α-secretase cleaves APP to produce a soluble extracellular/luminal fragment of APP (sAPPPα) and a membrane spanning C-terminal fragment (αCTF/C83). Againγ-secretase complex cleaves αCTF to produce the P3 peptide and AICD[43].

Figure 1 : Showing both the amyloidogenic and non-amyloidogenic pathway of Aβ proteolytic cleavage. Adapted from Annaert and De Strooper (2002).

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Study of Alzheimer’s disease using different model organisms:

Use of mice for AD research is very popular. In a study using transgenic mice as model organism for Alzheimer’s disease, it was found Mice that active immunization with the amyloid β(Aβ)peptide decrease Aβ deposition in brain and certain peripherally administered anti– Aβ antibodies also show similar effect. On finding the cause of Aβ clearance and metabolism,it was found that a monoclonal antibody (m266) directed against the central domain of Aβ was able to bind and completely hinder plasma Aβ. On peripheral administration of m266 to PDAPP transgenic mice, in which Aβ is generated specifically within the central nervous system (CNS),result in a rapid 1000-fold increase in plasma Aβ, due to which Aβ equilibrium changes between the CNS and plasma. The peripheral administration of m266 in the transgenic mice effectively reduces the Aβ deposition, but m266 did not bind to Aβ deposits in the brain. Thus,m266 reduces the brain Aβ burden by altering CNS and plasma Aβ clearance[44,45,46].The “central domain” anti-Aβ antibody, monoclonal antibody 266 (m266), rapidly sequesters all plasma Aβ present in PDAPP mice and causes a large accumulation of centrally derived Aβ in the plasma. Peripherally administered m266 also causes rapid increases in CSF Aβ, part of which does not appear due to entry of the antibody into the CNS.

Finally, chronic parenteral treatment with m266 results in marked suppression of Aβ deposition in brain, suggesting that certain anti-Aβ antibodies suppress AD-like pathology by altering Aβ clearance from CNS to plasma [47].

In C. Elegans the study of Alzheimer’s disease was done by studying the effect of oxidative stress and relation of Aβ fibril formation with Caenorhabditis elegans the disorder. A temperature inducible Aβ expression system was employed in C. elegans to create a transgenic strain of worms,CL4176,in which Aβ (1-42) is expressed at a temperature of 23⁰C.The transgenic strain helps in studying the relation between Aβ expression, oxidative stress, and Aβ fibril formation.CL4176 were under high oxidative stress as compared to the control animal[48,49,and 50]. The increased oxidative stress occurred in the absence of Aβ fibril formation, showing that the toxic component in Aβ toxicity is pre-fibrillar Aβ and not the Aβ fibril. The elevated oxidative stress increases the protein carbamoyl formation which inturn increases the Aβ expression but in the absence of the Aβ fibril formation, suggesting that pre-fibrillar Aβ is the Aβ toxic species. This resulted in a hypothesis that fibrils are not required for neurotoxicity[51, 52, 53, and 54].Aβ toxicity involves a mulitimer, which serve as an intermediate in fibril formation [55].

Alzheimer’s disease is also studied using zebra fish as the model organism.Zebra fish is used frequently because of the higher producZebra fish tion of eggs per spawning, transparent embryos and external development. Zebra fish contain most genes similar in function to genes known to involve in AD. It has two genes similar to human APP, app a and app b [56]. Orthologs of the β-secretase and γ-secretase complexes are found in it and expressed in CNS [57, 58, 59, 60].

To understand how the microtubule-associated protein tau (MAPT) contributes to tau pathology and how tau form pathogenic neurofibrillary tangles, a zebra fish model transiently expressing mutant human tau has been reported [61]. In this study, human tau carrying mutations at sites associated with hereditary dementias was fused to GFP under the control of the zebra fish pan-neural–specific GATA-2 promoter. GFP-positive neurons were found in the brain, retina, and spinal cord. In the brain, there was evidence which was significant for AD-associated cytoskeletal pathology that includes disruption of tau trafficking and cytoskeletal filaments in the axon, accumulation of tau in the cell near the axon, and hyper phosphorylated tau [62, 63, 64].

In an another study using zebra fish model to study methods of treating Alzheimer’s disease is by diverting APP away from the late endosomal pathway by a SORL1-dependent switch, which sequesters APP into recycling endosomes, preventing the formation of Aβ[65].

This genetic association between AD and SORL1 expression is a result of single nucleotide polymorphisms (SNPs) found within the SORL1 gene[66]. It has been demonstrated that SORL1 binds directly to APP and differentially regulates the sorting of APP into the late endosomal pathway leading to the production of cytotoxic Aβ or into the retromer recycling pathway, sequestering APP from the β- and γ-secretases. The overexpression of SORL1 in HEK cells reduces Aβ production by 82%, likely by diverting APP into the retromer recycling pathway [67,68].

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Drosophila melanogester belongs to the family Drosophilidae, of the order Diptera. It is commonly known as fruitfly.

Drosophila as model organism Kingdom: Animalia Scientific Classification Phylum: Arthropoda Class: Insecta Order: Diptera Family: Drosophilidae Genus: Drosophila Subgenus: Sophophora Species group: melanogaster group Species subgroup: melanogaster subgroup Species complex: melanogaster Complex Species: D. melanogaster Wild type fruit flies have brick red eyes, are yellow-brown in colour, and have black rings across their abdomen. They exhibit sexual

Physical appearance:

dimorphism: females are about 2.5 mm long while males are slightly smaller and back of their bodies are darker. Males can be easily distinguished from females on the basis of colour difference, distinct black patch at the abdomen and also the presence of sex combs on four legs.

Furthermore, males have a cluster of spiky hairs (claspers) surrounding the reproducing parts used to attach to the female during mating.

Drosophila is the most commonly used model organism in present days because of the following reasons: It has large reproducing capacity, which varies widely according to the species. It can be easily cultured in lab and culture requires simple B. O. D and uses little space even when using large cultures and the overall cost is low. It is small and their morphology is easy to identify once they are anesthetized (usually with ether, carbon dioxide). It has a short generation time (about 10 days at room temperature) so several generations can be studied within a few weeks.

Males and females are readily distinguished and virgin females are easily isolated, facilitating genetic crossings. Males do not show meiotic recombination, facilitating genetic studies Recessive lethal balancer chromosomes carrying visible genetic markers which can be used to keep stocks of lethal alleles in a heterozygous state without recombination due to multiple inversions in the balancer. Its complete genome is sequenced[69,] About 75% of known human disease genes is homologues to the genome of the fruit flies and 50% of fly protein sequences are found Similarity to human to be homologous to mammalian protein sequences. An online database called Homophila is available to search for human disease gene homologues in flies and vice versa. Drosophila is being used as a genetic model for several human diseases including the neurodegenerative disorders Parkinson’s, Huntington’s, Spinocerebellartaxia and Alzheimer’s disease. The fly is also being used to study mechanisms underlying aging and oxidative stress, immunity, diabetes, and cancer, as well as drug abuse[70, 71].

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