ALZHEIMER’S DISEASE AND PATHOLOGICAL ANGIOGENESIS

ALZHEIMER’S DISEASE AND PATHOLOGICAL ANGIOGENESIS

Mrunalini Devi Kotagiri * and Abhisek Pal

Department of Pharmacology, GITAM Institute of Pharmacy, Gandhinagar, Rushikonda, Vishakapatnam, Andhra Pradesh, India.

ABSTRACT: In spite of huge investigations, the pathology of Alzheimer’ sdisease (AD) is uncertain. Vessels dysfunction is a critical mark of AD. Research has stated like beta-amyloid (Aβ) results augmented vascular development in brains, a pathway observed in AD patients. In AD, cerebral endothelium releases pro substances for β-amyloid plaque and neurotoxins that kill cortical neurons. Vascular vulnerable features and neural, vascular dysfunction related through hypo or hypertension, hypercholesterolemia, diabetes mellitus, smoking, oxidative stress, and iron overload have been invented to play essential parts in the pathogenesis of stroke and AD. Antiangiogenic agents and small molecule kinase blockers are being examined and approved for anticancer therapy and showed normal blood vessel growth in the affected areas. Endothelial cells (EC) are triggered by the angiogenesis of cerebral ischemia and hypoxia. Outcomes of epidemiological research show that chronic administration of NSAIDs, statins, H₂ antihistamines, or calcium-channel blocker sappearstoavert AD. This is mainly due to the ability of the drugs to prevent angiogenesis. Many previous reviews on pathogenesis on AD have explained neuronal degeneration, but this review focuses on the effect of angiogenesis on the pathology of AD, which is believed to be the root cause for neuronal degeneration. This review attempts to launch a relation between vascular damage and AD pathology. If AD is anangiogenes is-related condition, then antiangiogenic drugs aiming at the abnormal cerebral EC will stop and treat the disease. Also, treating the disease from the root cause decreases the side effects of treatment.

Keywords:Alzheimer's disease, Amyloid beta, Bloodbrain barrier, Antiangiogenesis

INTRODUCTION: AD is one of the usual illnesses of current civilization. Disturbing 10% of the global people, this progressive

neurodegenerative ailment results in expressible human misery and consumes US$ 100 billion annually in health inessca recharges. Though amyloid plaque has been recognized as a chief cause of AD, yet these plaques formed in cerebral region is uncertain.

In heritance, genetic polymorphism, reduced perfusion, endothelial inflammation, and lesions are recommended as possible pathways ¹. Still, a combined thoughtfulness of the illness and strong references for interferences are absent. Subsequently, therapy is limited to amelioratethde signs of memory loss by growing cerebral concentration of acetylcholine by drug sliket acrine, donepezil, rivastigmine, or galantamine. In 1906, Dr. Alois Alzheimer ² observed pathological neurological conclusions, categorized and additionally recognized as marks of AD; neural plaques, that are masses which are chiefly made of beta‐amyloid (Aβ) peptides; ^{3, 4} and neurofibrillary tangles, that chief lycalmas intra neuronal hyperphosphorylated tau-masses ⁵.

Aβ, which is a 4 kDa peptide, a proteolytic destruction product of amyloid precursor protein (APP) by the function of α and γ secretase enzymes ^{6, 7}. Mutations in APP gene or in the secretase enzyme results in β secretase breakdown, making an abnormal Aβ mass (Aβ1‐42). Such Aβ masses to produce oligomers, that multimerize to protofibrils by the creation of solid core amyloid plaques ^8-10. A barrier is present amidst the blood vessels in the cerebral area and other parts of the central nervous system, limiting fluid and particles from moving into the brain from the blood circulation called the blood-brain barrier (BBB) ^{11, 13}. Disfunction of this BBB was initially observed in animal experiments of AD 14 and was then recognized as the prime, yet the unclear path of AD ^{15, 20}. Hence, the pathway resulting to BBB disruption is a budding target for AD treatment.

Involvement of Angiogenesis and Not Apoptosis: Vascular hypothesis as specified presently guards that vessel disruption is a result of reduced perfusion to the brain, resulting in ischemia and hypoxia leading to BBB dysfunction ^{21, 25}. Succeeding amalgamation of Aβ, neuroinflammation, and final breakdown of neural vessels are observed, ending in vessel death ^{27, 28}. In the condition of hypoperfusion, the hypoxia‐inducible features start angiogenesis by up-regulation of proangiogenic agents ²⁹. The key performers in angiogenesis is Vascular endothelial growth factor (VEGF), which encourages the division and multiplication of ECs from progenitor cells, hemangioblast, and angioblast. Further causes an incompetently formed primitive vessel plexus ³⁰. This vascular plexus experiences re-modeling, which is activated by angiopoietin‐1 (Ang‐1), to a matured vessel recognized through EC tubing and pericyte employment as in normal angiogenesis. Contritely to the above steps in AD, down-regulation of cell signalling factors to VEGF, angiopoietin‐2 (Ang‐2), weakens walls of established vessels ^{31, 32}. Dormant EC turns out to be subtle to VEGF, divide extensively, and move into small vessels that will not mature and then result in leaky vasculature ³². This process is named pathological angiogenesis, a commonly seen step in the development of tumors. In accord with the present kind of vascular hypothesis, BBB damage is because of vessel death produced from programmed cell death and angiogenesis will safeguard tissue renewal and will be restricted in replacing injured tissue and confirm oxygenation of cerebral region.

Though, this function of apoptosis in BBB dysfunction is extremely is cussed. Current researches have exposed that EC proliferation in pathological angiogenesis leads to hypervascularity. AS an alternate path to the decreased blood circulation by leaky vessels, remodeling and structural variations occur in the anatomical plan of tight junctions (TJ), ensuing in conceded BBB veracity. The research of Biron et al. considered an association among amyloid generation and BBB integrity, although variations in the TJ anatomy in Tg2576 AD mouse. They noted Tg2576 AD mice show no superficial vessel apoptosis yet have significant TJ damage that was observed linking to pathological angiogenesis, ensuing in an important growth of blood vessel density in AD brain. So, this information supports that TJ disturbance outcomes raised vessel permeability which occurs in widespread angiogenesis ^{33, 40}. At least five imbricating paths initiate angiogenic in the cerebral region.

Is chemiainaged brain results in less oxygen supply, aprovocation that starts release of vaso-active elements like nitricoxide, hypoxia inducible factor 1a (HIF1a.) and VEGF, one of the ut most controlling pro angiogenic cyto kines. Amplified VEGF release is observed in active astrocytes and perivascular accumulation of AD people ^{41, 42}. Neurofibrillary tangles in AD, believed to be subordinate to β-amyloidgathering, comprise heparin sulphate proteoglycans, an agent which fixes keenly to rudimentary fibroblast growth factor (bFGF), other angiogenic cytokine ^{43, 44}. Thrombin in spires angiogenes is in areas of wounded vessel endothelium ⁴⁵. Inflammatory inter media riespresent in brains of AD, like TNFa, interleukin 6, and monocyte chemoattra 00c tant protein-1, stimulate angiogenesis. Attacking macrophages and monocytes to secrets angiogenic growth factors VEGF, bFGF, and platelet-derived growth factor (PDGF). Gene expression of endogenicanti angiogenic agent, thrombo spond in, is condensed near by focal AD lesions, resulting in proangiogenic conditions such locations ⁴⁶. Such undesirable signals for angiogenesis are extra ordinarily similar to an excess of stimuli resulting in tumor angiogenesis ⁴⁷. Brain EC in AD owns unique genetic and phenotypic characters which are not seen in healthy brains. These EC heterogeneous are seen in contrast to abnormal with normal cell groups ⁴⁸. Subsequently, while angiogenesis happens in answer to brain-reduced oxygen supply, inflammation of AD and stroke patients, separate compulsive variations result in AD.

The hypothesis taken up in this review clarifies all puzzles stood by apparently unrelated therapeutic agents that discuss protection against AD. Anti-inflammatory agents, anti-H2-receptor, antihypertensive agents, and statins will cause antiangiogenesis ^{49, 50}. We endorse that an important decrease in hazard of AD stated in outcomes of population-based researches is primarily owing to antiangiogenic functions of the above medicines on EC. This pathway will not discard other significant paths of drugs, like NSAIDs and statins, which will straightly reduce the neuronal synthesis of β amyloids. Numerous of them may have moderate lyminor angiogenic inhibitory actions associated with strong and precise antiangiogenic drug sin studies for the tumor therapy, retinopathies, and psoriasis ⁵¹. Though AD is a multifaceted ailment, cerebral neovascularisation will develop a new emphasis for clinical research. Even researchers rem aintountie pathways behind AD, patientsatriskmaygain from judicialutility of frequently used medicines that result in antiangiogenic process.

Angiogenesis: Inflammation and Vascular Stimulation: Growing proofs advocate vessel agitation seems like a character of AD pathology as its marks: amyloid and neurofibrillary tangles. Aβ in AD, as a consequence of reduced clearance from brain, is thought to be accountable for beginning of intellectual failure ^{52, 55}. Absurd to this hypothesis, accumulated Aβ can be broadly existing in brain in nonappearance of AD signs ^{55, 59}. Though Aβ theatres a vital character in AD, it is either essential or by itself adequate to result in complete AD pathology ⁶⁰. Another idea is that simple manufacture of Aβ, endorses wide spread compulsive angiogenesis, causing the rearrangement of TJs, that then result in disruption of BBB veracity, thus cumulative vascular penetrability, following hyper vascularization and ultimate AD pathology.

Hemostaticpathways In Relation To AD Angiogenesis: Conservation of flow of blood and restricting its harm on vessels is vital biological course called haemostasis ⁶¹. It is likely wing to the being of a subtle equilibrium among procoagulation and anticoagulation along with many pathways ^{61, 62}. This process has three separate stages, firstly adhering platelets to spot of damage, making a platelet-plug ⁶³. Secondly includes the initiation of coagulation cascade, terminating in fibrin clot formation; the last phase is fibrinolysis, or dissolution of clot ⁶⁴. Escorted with vessel disfunction, a changed hemostatic situation is progressively concerned in AD.

FIG. 1: ANGIOGENESIS IN THE ALZHEIMER’S BRAIN

Antiangiogenics: Small Molecule Tyrosine Kinase Blockers: Antiangiogenic agents and small molecule kinase blockers are being examined and approved for anticancer therapy and were showing normal blood vessel growth in the affected areas ⁶⁵. Sunitinib is a broad-spectrum tyrosine-kinase blocker. It inhibits the phosphorylation of numerous receptor tyrosine kinases and efficiently blocks VEGF and also platelet-derived growth factor (PDGF‐β). Presently, sunitinib is in usage for gastric tumors, cancers, and pancreas cancers. It was known to cut amyloid problem and converse intellectual weakening in AD mice, if researchers aim angiogenesis, they can relapserise in the gathering of Aβ and decrease intellectual weakening related to AD ⁶³. Drugs resulting in indirect antiangiogenesis in AD Consequences of epidemiologic trials propose that long time use of certain medicines meaning fully reductions risk of AD invulnerable people Table 1. These drugs contain NSAIDs, lipid-lowering drugs, H2 antihistamines and calcium-channel blockers. The clinical information is very convincing. Brain inflammation has developed in to a key emphasis for AD research.

Cerebral inflammation can not explain risk drop consulted by medicines that deficit considerable anti-inflammatory action. EC reply to reduced oxygen level and inflammation is by angiogenesis. Interceded by cytokine growth factors, angiogenesis includes initiating EC from existing vessels to form tube-like structures that supplement resident microcirculation by delivering oxygen and nutrients to tissues suffering from hypoxia. The EC also employs straight local actions by making a minimum of 20 paracrine agents which function on surrounding cells. Though most of these agents are anti-apoptotic survival signals, neovessels in injured cells release toxins like neurotoxins and amyloid precursors ⁶⁰.

TABLE 1: DRUGS ASSOCIATED WITH DECREASED RISK OF ALZHEIMER’S DISEASE OR DECREASED FORMATION OF 13-AMYLOID PEPTIDE

+and – denote the biological activity of each agent.

Testing the Hypothesis: The title role of vessel formation in AD could be examined in lab and clinical studies. The neovascular neurotoxin could be examined by studying EC develop menton tissue culture taken from AD brains. Gene studies of AD EC can recognize genes exclusively expressed in AD, which will be novel molecular marks for treatment.

Concluding Marks: AD characterizes an illness that can place the important problem on features of society. This problem chiefly plays on caretakers in a family and has projected billions in missing efficiency and healthcare pricing. Overages, incomplete development made with respect to the amyloid hypothesis in the therapy of AD, so new rationale towards AD pathogenesis is compulsory. Vascular vulnerable features and neural vasculard are related to hypo or hypertension, hypercholesterolemia, diabetes mellitus, smoking, oxidative stress, and iron overload have been invented to play essential parts in the pathogenesis of stroke and AD. Explanations present in augmented cerebral vascular ture penetrability former to the arrival of milestones of AD, sprouts new example in participating vessels modeling with the pathophysiology of the illness.

Based on this investigation engrossed on considering molecular pathways behind and pathophysiology of neovascularization resulting in AD. Clinical inhibition lessons should be undertaken in a high-risk population for AD by the usage of angiogenic blockers. Numerous oral angiogenic blockers are undertaking oncological studies, like thalidomide, AE-941, PTK787, endo stat in, and BMS275291. Patients getting antiangiogenic blockers will be predictable have ales ser frequency of AD, in comparison with placebo. Intervention studies can be made with predictable termination of illnesses tea diness. An agent can exist that gives defense against AD and also for cancer. Such studies will provide extensive and multifaceted management and so need strong, helpful preclinical results from lab experimentations. The sheer scale of AD in aging people encourages research investigators and industrial experts.

CONFLICTS OF INTEREST: The authors declare no conflict of interest.

ACKNOWLEDGEMENT: We thank the Management of CMR College of Pharmacy for their support in performing the literature review in the institution.

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    How to cite this article:

    Kotagiri MD and Pal A: Alzheimer’s disease and pathological angiogenesis. Int J Pharm Sci & Res 2021; 12(12):6202-08. doi: 10.13040/IJPSR.0975-8232.12(12).6202-08.

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