РОЛЬ ФЕРМЕНТОВ В ПАТОГЕНЕЗЕ И ТЕРАПИИ БОЛЕЗНИ АЛЬЦГЕЙМЕРА
Н. К. Михайлова, 2 курс
Научный руководитель -к. б. н., доц. Е. Н. Лебедева,к. филол. н., ст. преп. О. В. Назина
Кафедра биологической химии
Кафедра иностранных языков
Оренбургскийгосударственныймедицинскийуниверситет
ENZYMES ’ ROLE IN THE PATHOGENESIS AND THERAPY OF THE ALZHEIMER ’ S DISEASE
N. K. Mikhailova, 2nd year
Supervisor - Ph. D. in Biology, Assistant professor E. N. Lebedeva,
Ph. D.in Philology, Senior lecturer O. V. Nasina
Department of biological chemistry
Department of foreign languages
The Orenburg State Medical University
Аннотация. Болезнь Альцгеймера (БА, синоним – деменция альцгеймеровского типа) представляет собой наиболее распространенную форму первичных дегенеративных деменций позднего возраста, характеризующаяся нарушением высших корковых функций. В настоящее время ведутся разноплановые исследования, посвященные потенциальным путям терапии БА
Ключевые слова: болезнь Альцгеймера, ферменты, патогенез.
Alzheimer's disease (AD), also referred to simply as Alzheimer's, is a chronic neurodegenerative disease that usually starts slowly and gradually worsens over time. It is the cause of 60–70% of cases of dementia.[1][2] The cause for most Alzheimer's cases is still mostly unknown except for 1% to 5% of cases where genetic differences have been identified. Several competing hypotheses exist trying to explain the cause of the disease.
The oldest, on which most currently available drug therapies are based, is the cholinergic hypothesis, which proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine. The cholinergic hypothesis has not maintained widespread support, largely because medications intended to treat acetylcholine deficiency have not been very effective.
In 1991, the amyloid hypothesis postulated that extracellular amyloid beta (Aβ) deposits are the fundamental cause of the disease. Also, a specific isoform of apolipoprotein, APOE4, is a major genetic risk factor for AD. While apolipoproteins enhance the breakdown of beta amyloid, some isoforms are not very effective at this task (such as APOE4), leading to excess amyloid buildup in the brain. In 2009, this theory was updated, suggesting that a close relative of the beta-amyloid protein, and not necessarily the beta-amyloid itself, may be a major culprit in the disease. Aβ is a fragment from the larger amyloid precursor protein (APP). APP is a transmembrane protein that penetrates through the neuron's membrane. In Alzheimer's disease, gamma secretase and beta secretase act together in a proteolytic process which causes APP to be divided into smaller fragments. N-APP, a fragment of APP from the peptide's N-terminus, is adjacent to beta-amyloid and is cleaved from APP by these enzymes. N-APP triggers the self-destruct pathway by binding to a neuronal receptor called death receptor 6 (DR6, also known as TNFRSF21). [5] DR6 is highly expressed in the human brain regions most affected by Alzheimer's, so it is possible that the N-APP/DR6 pathway might be hijacked in the ageing brain to cause damage. In this model, beta-amyloid plays a complementary role, by depressing synaptic function.
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The tau hypothesis proposes that tau protein abnormalities initiate the disease cascade. In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies. When this occurs, the microtubules disintegrate, destroying the structure of the cell's cytoskeleton which collapses the neuron's transport system. This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells.
The hypotheses about the role of enzymes in pathogenesis and treatment of the AD can be divided in two parts:
·Ones considering that the enzymes’ dysfunction may play a crucial role in the AD pathogenesis and that blocking of these enzymes can be used as a treatment
·Those that suggest using enzymes to revert protein misfolding
But both sides identify Alzheimer's disease as a protein misfolding disease (proteopathy).
The enzyme called Beta-secretase 1 (BACE1 stimulates producing of beta-amyloid peptide by cleaving amyloid precursor protein. An excessive accumulation of this peptide eventually leads to the formation beta-amyloid plaques. The researches claim that collected data show that BACE1 inhibitors have the potential to treat Alzheimer's disease patients without unwanted toxicity. But BACE1 also cleaves other proteins, thus regulating important processes in the brain. Therefore, completely inhibiting it may cause some impairments as a side effect. So currently the researchers are working on reducing BACE1 more gently and gradually, in the hope that this would yield better results with fewer side effects.
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The histone deacetylase HDAC2, which negatively regulates synaptic gene expression and neuronal plasticity, is upregulated in Alzheimer’s disease (AD) patients and mouse models. The effect of HDAC is to condense chromatin, which, in turn, reduces the expression of some genes in the DNA. Compounds that inhibit HDAC2 have already been tested, but most of these have undesirable side effects. For example, they interfere with HDAC1, which is important for cell proliferation, especially in white and red blood cells. Further tests have revealed sp3, a "transcription factor" molecule that helps HDAC2 to alter chromatin and block the memory genes on the DNA. The research team also found a molecule that might serve as a basis for developing a drug that prevents sp3 from binding to HDAC2 to free up the memory genes. They showed that the molecule does not interfere with cell proliferation, as some other HDAC inhibitors do.
There is increasing evidence that deficient clearance of A-amyloid (AA) contributes to its accumulation in late-onset Alzheimer disease (AD). Several AA-degrading enzymes, including neprilysin (NEP), insulin-degrading enzyme, and endothelin-converting enzyme reduce AA levels and protect against cognitive impairment in mouse models of AD. Although it remains unproven that a decline in AA degrading enzyme activity contributes to the accumulation of AA in AD, it is clear that overexpression of AA-degrading enzymes, neprilysin in particular, can reduce amyloid deposition and ameliorate cognitive decline in AD animal models. These findings could be used as therapeutic strategies that might be suitable for use in humans. The potential ways of treatment include the administration of agents that upregulate AA degrading enzyme activity, various forms of gene therapy that increase the expression of AA-degrading enzymes in the periphery or within the brain, direct delivery of the enzymes into the brain, and, lastly, approaches based on the delivery of stem cells. [10]
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Insulin-degrading enzyme (IDE) is a protein that plays a key role in degrading Aβ monomer in vitro and in vivo. IDE is also a metalloprotease enzyme responsible for insulin degradation The results of research suggested that activators of specific signaling pathways effectively increased the expression level of IDE, decreased the accumulation of Aβ40 and Aβ42, and alleviated the spatial learning and recognition impairments in T2D and AD mice. Combine previous reporting and the present study, reasearchers found the potential role of IDE may as a target for AD with metabolic perturbations, especially when AD patients present with peripheral and central metabolic impairments.
Intrinsically disordered proteins, like tau, are enriched with proline residues that regulate both secondary structure and aggregation propensity. The orientation of proline residues is regulated by cis/trans peptidyl-prolyl isomerases (PPIases).PPIases can be considered as molecular chaperones, key enzymes that assist in folding proteins by stabilizing nascent polypeptide chains and by facilitating interactions that help stabilize a final structure. These chaperones also prevent the aggregation of newly formed proteins and can shunt misfolded proteins toward degradation pathways. In addition to interacting with newly synthesized proteins, chaperones also help to maintain cellular homeostasis by triaging toxic protein aggregates, which are responsible for causing neurodegenerative diseases. The recent research shows that cyclophilin 40 (CyP40), a PPIase, dissolves tau amyloids in vitro. Nuclear magnetic resonance (NMR) revealed that CyP40 interacts with tau at sites rich in proline residues. CyP40 was also able to interact with and disaggregate other aggregating proteins that contain prolines. Moreover, processes mediated by CyP40 are ATP-independent/ In addition to CyP40, there are currently 41 known human PPIases within the cyclophilin, FKBP, and parvulin families. Therefore, future screening may reveal additional PPIases with activities similar to CyP40, including ATP-independent disaggregation. Additionally, CyP40 and other PPIases should be further characterized for disaggregation activity against proline-containing amyloids, especially those associated with disease.
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Since the enzyme activity is essential for living organisms, any malfunction (mutation, overproduction, underproduction or deletion) of a single critical enzyme can lead to a genetic disease. On the other hand, enzymes can be used as a fixing tool for previous malfunctions. These two principles are actively studied nowadays and can be applied to the new ways of AD’s treatment. Therefore studies about blocking enzymes that play crucial role in AD’s pathogenesis or about enzymes that can reverse negative effects are very important and potentially they may be developed in the real methods of treatment.
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