apoptosis pathology

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A Brief Survey of Three Diseases Associated with Defective Programmed Cell

Death Pathways

By Victor GardnerAP Biology, Periods 6-7

Submitted to: Dr. MaduDate of Submission: 19 October 2014


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AbstractMalfunctioning apoptosis has been implicated in several diseases, including the range of

immunodeficiencies caused by HIV, Alzheimer's disease and dementia, and even psychological depression. The

present review attempts to provide a brief overview of the clinical manifestations of, role of apoptosis in, and

treatments that affect apoptosis or effect cellular regeneration for each disease. In HIV, such treatments include

those which inhibit HIV protease; in Alzheimer's, treatments focus on inhibiting the effects of

hyperphosphorylation generated by GSK3; in depression, focus is made on the regeneration of hippocampal tissue

lost to apoptosis. Present research in the treatment of each disease is then considered, and a full list of citations is

provided.1. Introduction

Apoptosis, programmed cell death, is essential to regulating the activities of cells in multicellular organisms. Forexample, the eukaryotic cells that make up multicellular organisms need signals not only to grow and proliferate, but tomerely survive. Cells that do not receive enough of such survival factors die off through apoptosis. An example of such

behavior is found in nerve cells: in the developing nervous system, nerve cells are produced in excess; however, those that

do not receive enough survival factor die out, leaving only those cells required by the organism [1].Just as cell-survival factors exist, so do cell-death factors. The best understood of these cell-death factors is

TGF-. TGF- binds to cell-surface receptors, initiating a signal transduction pathway that results in several changes in

gene expression, ultimately resulting in cell death [1].It is well understood that gene expression can affect the life-or-death status of a cell. For example, several genes

have been termed oncogenes for their roles in coding for proteins that inhibit apoptosis and thereby promote cancer

generation. Gene expression is, by extension, controlled by several transcription factors, such as those in the NFkBfamily. This family of transcription factors serves to induce the expression of several genes which produce proteins that

inhibit apoptosis, such as the caspase-8 antagonist FLIP [2].Other such inhibitors of apoptosis include the family of Inhibitor of Apoptosis Proteins (IAP), which serve to

inhibit proapoptotic caspases, which are themselves essentially proteases that induce cell death. IAPs inhibit caspaseactivity through direct binding to activated caspases; for example, the apoptosis-initiator caspase-9 is directly suppressedthrough the activity of ML-IAP. Every IAP contains at least one copy of the baculovirus iap repeat (BIR) domain; it is this

domain that most directly partakes in the inhibitory activities of IAPs. IAPs are highly selective in their inhibitoryprowess, unlike certain virus proteins, and so can only inhibit certain apoptotic pathways, but not others [3].

Most pathways for apoptosis operate through activating such caspases. For example, some of the pathwaysmoderated by Tumor Necrosis Factor (TNF) contain a "Death Domain." Ligation of this Death Domain results in theactivation of certain intracellular proteins, eventually activating the caspases [52]. By extension, certain caspases operate

through affecting the structural integrity of the mitochondrial membrane. One the outer membrane of the mitochondria iscompromised, cytochrome-c, normally used in cellular respiration, leaks out. Cytochrome-c then proceeds to aid in theassembly of a multiprotein complex known as the apoptosome, which itself proceeds to effect apoptosis in the cell [4].

In the present work, the role of apoptosis in three disease, HIV, Alzheimer's disease, and depression, is

considered. First, a general overview of the causes and clinical manifestations of each disease is provided. This overviewis then followed by a discussion of the role of apoptosis in the manifestation of the disease. Finally, a survey of treatmentoptions that either affect apoptosis or affect the loss of cells due to apoptosis is made. The article closes with a moregeneral discussion of treatment options involving apoptosis, and a list of references is provided.

2. Human Immunodeficiency Virus (HIV)(a) A Bri ef Description of the Human Immunodefi ciency Virus

Human immunodeficiency Virus, otherwise known as HIV, is a retrovirus (an enveloped virus replicating in ahost cell via reverse transcription, the process of creating DNA from an RNA template) of the family lentiviridae (a genus

of viruses in the family Retroviridae characterized by its long gestation period) [5]. The virus itself consists of the capsid,formed from a set of viral proteins themselves surrounding two RNA copies of the viral genome, surrounded by the viralenvelope, which contains several glycoproteins that enable the virus to bind to specific receptors on the target cell. After

binding to the host cell, the HIV viral envelope fuses with the plasma membrane, releasing the capsid into the cytosol. Thecapsid proceeds to release its viral RNA into the cytosol, which, due to the virus's enzyme reverse transcriptase, form

double-stranded DNA. This DNA effects the synthesis of a new HIV, which leaves the cell, surrounded by a viralenvelope converted from the plasma membrane, infect more cells [5]. Moreover, the virus has been shown to neutralize

host restriction factors such as Apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3g (A3G) using HIV-1viral infectivity factor (ViF), making the search for treatments for this disease difficult, to say the least [6].


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1 protease in causing a cell's apoptosis by inhibiting the function of that enzyme. HIV-1 protease functions either byeliminating the integrity of the mitochondrial membrane, causing apoptosis-inducing enzymes such as cytochrome c to bereleased from the mitochondria, or by its own interaction with the gene breast carcinoma-associated protein 3(BCA3),which increases the production of the protein Bax, which itself play a role in signaling apoptosis [22]. ABT-538 acts as a

symmetrical inhibitor of HIV-1 protease, effectively blocking out signals for the cell to perform apoptosis. In addition, themolecule acts as an "optimal compromise between oral viability and potency," meaning that it can be ingested orallywhile still maintaining a high efficacy as an anti-HIV medication [23]. ABT-538 does not, however, act on cells alreadyinfected with the virus; rather, it prevents new infections. Thus, the decrease in viraemia observed is effected by thosealready-infected cells dying out and no new cells taking their place, essentially "starving" the virus population [8]. Figure

1 shows the number of HIV RNA molecules per mL measured in a study where subjects were given ABT-538. Moreover,on account of a lessening concentration of HIV viruses causing apoptosis of lymphocytes, white blood cell counts in

patients treated with ABT-538 rise significantly [8] It should be noted, however, that a different study found that someindividuals reach a "plateau" in the recovery of CD4+lymphocytes, bringing into question the extent of this medication'seffectivity [24].

Another potential medicine, A-77003, also works by inhibiting HIV-protease. An in vitro study, however,revealed mixed results. On the one hand, when certain concentrations (0.5M) are given in continuous infusion to the in

vitro cells, the spread of HIV throughout the culture is severely limited, even for 72 hours after the truncation of A-77003supply; on the other hand, when 1mg a1acid glycoprotein was added to the culture, the efficacy of the medication wasablated, bringing into question the potential for clinical applications and in vivo studies [25].

3. Alzheimer's Disease

(a) A Br ief Description of Alzheimer' s DiseaseAlzheimer's disease, the fourth most common cause of death in the United

States, is also the nation's leading cause of dementia (a progressive deteriorationof cognitive function) [26]. It is characterized by neurodegenerative symptoms,

such as : neurofibrillary tangles (NFTs, aggregates of phosphorylated tau proteins,which stabilize the cell's microtubule array), amyloid core formation (inAlzheimer's, the aggregation of misfolded amyloid-beta (A) proteins, causingabnormal interactions of A with the body), and neutritic degeneration (thedegeneration of nerves through neural inflammation) [27, 28]. The structure of

amyloid-beta was determined to consist of a multimeric polypeptide which itself ismade of approximately 40 subunits, 4 kDa each; these subunits are arranged in a

fibre-like structure [29, 30]. Amyloid-beta aggregates share insolubility as a

superficial similarity with scrapie (a disease causing degeneration of the centralnervous system) polypeptides, although no actual structural similarities with

scrapie have been determined. Finally, the amyloid aggregates in Alzheimer'sshare the 4 kDa structural subunit with the disease congophilic angiopathy,

which itself is caused from amyloid deposits in the blood vessels [29].Amyloid-beta deposition is considered to be the primary factors of

Alzheimer's disease, with the aggregations ultimately resulting in cell damage

(Figure 2, sub) [31]. This position is further supported b the fact that amyloidformation (catalyzed by apolipoprotein E and antichymotrypsin) was

demonstrated to impair cognitive ability in mice [31]. However, it is still notknow exactly how amyloid-beta aggregation occurs in non-inherited

Alzheimer's disease [31, 32]. Despite this lack of precise knowledge, however,there is a consensus around the genetic mutations that cause familialAlzheimer's disease. The three genes that code for the amyloid precursor

protein, presenilin 1, and presenilin 2, when mutated, have been shown to resultin the phenotype of Alzheimer's disease [32]. The formation of neurofibrillary

tangles. by contrast, is thought to be a result, rather than a cause, of Alzheimer's; the neurons seem to be using thephosphorylation of tau proteins as a defensive barrier against amyloid-beta aggregation [32].

The onset of Alzheimer's disease is ultimately initiated years before any evidence of the characteristic dementia

(in this context, it is important to note that "Alzheimer's disease" denotes the entire pathophysiological process underlyingand preceding Alzheimer's, not simply the clinical manifestation of dementia) [33]. Individuals in the preclinical stage ofAlzheimer's include those with specific "biomarkers" for the disease. These biomarkers include an abundance of

Figure 2: Image adapted from [23].(a) Normal amyloid-beta plaqueformations. (b) Amorphous amyloid-

beta plaque formations. (c) A mixtureof both normal and amorphousamyloid-beta plaque formations; thearrow is pointing to an amorphous

formation surrounded by normal plaquestructures. (d) A close-up of an

amorphous amyloid-beta plaquestructure composed of interwovenamyloid-beta fibers.


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apolipoprotein E 4 and the presence of autosomal dominant (i.e. only needing a copy of a certain gene from one parent toinherit a disease) genetic mutations [33]. In the clinical stage, a pragmatic evaluation of the ability of a patient to perform"activities of daily living" adds to the information gained by a mere cognitive-abilities test. In other words, the cognitivedeterioration brought on by dementia in Alzheimer's disease results in a corresponding deterioration in the quality of life

for an individual living with the disease; for example, it becomes difficult to find belongings, travel outside the home, usethe telephone, or even partake in usual hobbies and games [34].

(b) The Role of Apoptosis in Al zheimer' s Di sease

Like many neurodegenerative diseases, Alzheimer's is marked by excessive neuronal apoptosis. In Alzheimer'sdisease specifically, there is an overabundance of the cell-death moderator glycogen synthase kinase-3 (GSK3) [35].

Before surveying the mechanisms by which GSK3 mis-moderates apoptosis in Alzheimer's disease, it is first necessary toprovide an overview of the mechanisms by which GSK3 moderates apoptosis in general.

GSK3 is unique in that it can both inhibit extracellular-initiated apoptosis while encouraging intracellular-initiatedapoptosis. The receptor is itself moderated by phosphorylation of certain amino acids, effecting structural alterations thateither inhibit or enhance activity. For example, the phosphorylation of serine-9 (in GSK3) or serine-21 (in GSK3)

inhibits activity, whereas the phosphorylation of tyrosin-216 (in GSK3) or tyrossine-279 (in GSK3) enhances activity.Moreover, the activity of GSK3 is indirectly controlled by the phosphorylation state of its substrate. GSK3 overexpression

encourages intracellular-initiated apoptosis through partaking in the disruption of the mitochondria, leading to cell death;the signal for apoptosis can be triggered by DNA damage, irreversible protein misfolding, or other such factors. Bycontrast, GSK3 inhibits extracellular-signaled apoptosis by protecting the cell from TNF-mediated cytotoxicity (i.e. GSK3stops tumor necrosis factors, a so-called "death receptor," from binding and signaling apoptosis) [36].

Given that the aforementioned overabundance of GSK3 in Alzheimer's disease patients results in excessive

neuronal apoptosis, thereby causing the clinical manifestation of dementia, it is now necessary to survey the methodsthrough which GSK3 effects the programmed death of so many neurons. It has been shown that amyloid-beta influencesthat PI3K-Akt intracellular signaling pathway, inhibiting the phosphorylation of serine-9 or -21 (supra). Because the

phosphorylation of this specific amino acid inhibits GSK3's ability to enhance intracellular apoptosis-signaling pathways,the inhibition of the phosphorylation of this specific amino acid thereby encourages apoptosis [35]. Co-effected by this

signaling pathway is the activation of apoptosis-promoting capase-3 [37]. This caspase operated by weakening thestructural integrity of the mitochondrial membrane, allowing cytochrome c to leak out, which then promotes the assemblyof apoptosome, an essential protein in the process of apoptosis [38].

(c) Advancements in the Treatment of Alzheimer' s Di sease

Existing treatments for Alzheimer's disease have proven ineffective, revealing the need for further study into

possible avenues of therapy for treatment[39, 40]. Given that Alzheimer's is caused by both excessive phosphorylation ofvarious proteins and amyloid-beta toxicity (itself on account of excessive GSK3 activity from the presence of amyloid-

beta), it follows that inhibiting the protein kinases implicated in this disease should be the goal of new therapeuticapproaches for treating the disease. On account of evidence that excessive tau protein phosphorylation (i.e. neurofibrillarytangles) is correlated with high amyloid-beta levels, a path for researching new therapeutic approaches have been

proposed that inhibit the phosphorylation of tau proteins. Such a therapy would target multiple kinases (including GSK3)implicated in tau phosphorylation, thereby reducing the ability of the cell to phosphorylate aggregates of tau [39].

Several inhibitors act through just such a method. Tideglusib-12 (NP-12), a non-competitive inhibitor of GSK3,

was shown to reduce both tau phosphorylation and amyloid-beta deposition. Moreover, NP-12 acts as an agonist (amolecule which initiates a physical response through binding to a receptor, i.e. a ligand which activates a specific cellular

response) for PPAP, causing several anti-inflammatory and protective properties to show in neurons [40]. In addition toNP-12, the NAD+-dependent sirtuin SIRT1 has been implicated in regulation of amyloid-beta generation. However,

researchers have suggested that a calorie-restriction diet could affect SIRT1 in such a way as to mediate excessiveamyloid-beta deposition. More importantly, however, is the fact that SIRT1 in part prevents amyloid-beta deposition

through the inhibition of ROCK1 (rho-associated, coiled-coil-containing protein kinase 1) expression, opening new doorsfor research in either ROCK1 inhibitors or SIRT1 enhancers [41]. Finally, the MAPK family of inhibitors shown promiseas an inhibitor of both tau phosphorylation and the degenerative toxicity caused by amyloid-beta [40].


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4. Depression(a) A Br ief Description of Depression

Stress is not only ever-present in human culture; it represents an essential alarm system for any individualorganism. Upon an organism's encountering a "threat to homeostasis," whether it be lack of situational information,

perceived loss of control, excessive blood loss, injury, inflammation, or excessive psychosocial demands, that organismmay feel "stressed." In other words, upon encountering any one or more of the aforementioned situations, the organism'slimbic-hypothalamo-pituitary-adrenal (HPA) brain structure, integrating several emotional, cognitive, neuroendocrine (i.e.

hormonal), and autonomic (i.e. subconscious, part of the

peripheral nervous system) pathways, mediates, along with thesympathico-adrenomedullary system, the production ofcorticotropin-releasing hormone (CRH), which in turn inducesthe production and release of adrenocorticotroph hormone

from the pituitary gland. Adrenocorticotroph in turn causes theproduction and release of glucocorticoids (a form of

corticosteroids) from the adrenal cortex [42, 43]. While undernormal situations this biological response to stress provides animpetus for the organism to address the source of stress,

prolonged hyperactivity of the HPA and concomitantcorticosteroid overproduction ultimately results in

depression [42-44]. Moreover, in depressive patients the

hippocampus, amygdala, and prefrontal cortex show alteredpatterns of activity in PET scans and demonstrate a decreasein volume; it should be noted, however, that amygdala volumeactually increases after the first episode of depression,

decreasing in later episodes, as adrenocortical steroidsproduce a wide array of effects upon the structure [43].

Patients with depression have an increased risk forcomorbid diseases to arise, further complicatingtreatment [44]. For example, although at first a controversialstance, depression has been recognized as an independent riskfactor for the development of Ischemic heart disease, as

opposed to simply a secondary by-product of feeling sad about having heart problems. Furthermore, it has been shown

that depression in patients with heart disease is an accurate indicator of mortality 6 months after a myocardial infarction(i.e. a heart attack) [44]. The relationship between sleep and depression, however, is harder to pin down, on account ofseveral "confounding variables" that must be accounted for in performing studies, such as age (increasing age results in

prolonged sleep latency, an increase in nocturnal awakenings, and pronounced early-morning wakening), gender (slow-

wave-sleep, i.e. "deep sleep," is reduced in healthy males as compared to healthy females), and severity of depression(with increasing severity of depression, sleep continuity seems to be impaired). Despite these hurdles, however, it has

been determined that, overall, that patients with depression have REM deprivation, sleep deprivation, and increased sleeplatency (the time it takes to fall asleep) as compared to healthy individuals [45]. A third pronounced symptom ofdepression is psychomotor retardation. A study performed by Bernard Sabbe et al. found that for three separate tasks, (1)

copying "simple figures" such as a circle or a diamond, (2) copying "complex figures" such as letter combinations orunknown patters, and (3) rotating figures, depressed patients presented with both a longer reaction time and a longer

motor-processing time than healthy individuals (Figure 3). The increase in reaction time can be considered revealing of a

retardation of cognitive processing in depressed patients; similarly, the increase in motor-processing time is representativeof a retardation in motor-processing [46].

(b) The Role of Apoptosis in Depression

Evidence has come to light suggesting that depression effects structural changes in certain areas of the brain, even

inducing neural apoptosis. For example, in a study funded by the Sri Lanka Council for Agriculture Research Policy, thebrain of a twenty five year old male who had committed suicide through self-immolation (namely, burning 81% of hisbody area) was observed. Researchers found that the subicular region of the man's brain contained apoptotic neurons,

caused by the overstimulation of glucocorticoid receptors on the neurons. Moreover, observed hippocampal apoptosis wasmediated through overstimulation of corticosteroid receptors in the region. It was also proposed that mineralocorticoid

Figure 3: Image adapted from [42]. In this study,patients were asked to perform a "simple task," such ascopying a circle or a diamond. These results show thatin both reaction time (RT) and motor time (MT),depressed patients took significantly longer to performthe same tasks as the controls. The data were recorded

using a Calcomp 2300 digitizer linked to a PC; the arrayhad been specially designed to measure pen pressure.An ANOVA was performed to prove the results weresignificant.


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receptors were responsible for preventing cell death, possibly acting as a protection from apoptosis-inducingcorticosteroids and glucocorticoids [47].

More evidence for apoptosis in depression was found in studies performed on both rats and tree shrews. Inexperiments in which tree shrews were subjected to psychosocial stress for extended periods of time, apoptosis was found

in the hippocampus, along with clear rises in cortisol and reductions in body weight. However, upon magnetic resonanceimaging (MRI), no significant reduction in brain mass was observed. Furthermore, it is also important to note that a largenumber of cells could have already died only a short time after the onset of stress, meaning that the researchers could notobserve the initial increased levels of neural apoptosis [42]. In rats, acute short-term stress has been shown to hinderneurogenesis, with long-term stress initiating apoptosis in the hippocampus. This heightened apoptosis continues

immediately after the removal of stress, but levels out after about three weeks without psychosocial stress [42].In addition to heightened corticosteroid levels, an overexpression of Bcl-2 proteins congregating in the outer

mitochondrial membrane also plays a role in initiating programmed cell death under stress [48]. As mentioned earlier,heart attack patients often suffer from severe depression. It has been demonstrated that morbidity may be influenced byincreased levels of programmed cell death in patients suffering from comorbid depression and cardiovascular disease [48].

Moreover, acute depression is associated with heightened apoptosis in peripheral blood lymphocytes, such as natural killercells, which results in reduced immune system efficacy [49].

(c) Advancements in the Treatment of Depression

Research into development of new therapies for depression have recently focused on the role of brain-derivedneurotrophic factor (BDNF), a neural growth factor, and its role in the plasticity (i.e. ability to form tissue) of neurons. Infact, it has been shown that a majority of antidepressants operate through increasing the activity of BDNF and its receptorTrkB, a tyrosine kinase receptor. Essentially, the stimulation of BDNF and TrkB enhances both nerve growth and neural

plasticity, allowing for the regenesis of tissue and cells lost to excessive apoptosis [50]. Before an overview of how drugsincrease the activity of BDNF, however, it is first necessary to provide an overview of how BDNF and TrkB work.

Upon being stimulated by BDNF, TrkB dimerizes and activates intracellular signal transduction pathways thatultimately result in the activation of several transcription factors. One such pathway is Phospholipase C (PLC). In this

pathway, the activation of TrkB by BDNF directly activates PLC, which in turn hydrolyzes phosphatidylinositol

4,5-biphosphate, producing the secondary messengers diacyglycerol and inositol 1,4,5-triphosphate (IP3). IP3 thenproceeds to cause the release of Ca2+, more secondary messengers, which ultimately result in nerve growth and tissuedevelopment, replacing that tissue lost to depression-induced apoptosis [51].

Antidepressants utilizing BDNF have been shown to only be effective after multiple treatments; this is likelybecause a corresponding increase in neuroregeneration can only be effected after several days of increased BDNF and

TrkB expression; furthermore, there is a need for a growth of neuronal tissue configurations in order to recover fromexcessive depression-induced neuronal apoptosis [51]. As a caveat, however, BDNF has poor blood-brain penetration,

making it difficult for the drug to be effective taken conveniently, and, on account of its interaction with p75NTR, cancause pain. To solve this, researchers have developed small ligands capable of signaling TrkB with more specificity thanBDNF. One such compound is LM22A-4, which restores motor learning after administration, and demonstrates a high

specificity and efficacy in its interaction with TrkB [52].

5. Conclusion & DiscussionIn the fight against disease, inhibiting or otherwise countering apoptosis seems to be one of the more successful

strategies for combating certain afflictions. For example, in depression, instead of actively inhibiting cell-death pathways,researchers have developed the experimental LM22A-1, LM22A-2, LM22A-3, and LM22A-4, which do nothing to inhibit

apoptosis; rather, they act as a cell growth factor and plasticity encourager, encouraging neurons to multiply and formhippocampal tissues to replace those lost to stress-induced (i.e. caused by corticosteroid overproduction) apoptosis [52]. In

fact, these medicines, as compared to the natural nerve growth factor BDNF, demonstrate a heightened efficacy due totheir ability to penetrate into the brain from the blood stream; this ability is a by-product of the fact that they are non-

proteins, and so can better diffuse through biological membranes [52].

Alternatively, in Alzheimer's and HIV, current medical research is focusing on ways to inhibit apoptosis andtherefore stop the progression of the disease in the infected individual. For example, HIV contains the protein HIV

protease, which serves to induce apoptosis in lymphocytes through its interactions with the mitochondrial membrane [22].Antiretroviral therapy, the leading treatment for HIV, attempts to halt the spread of the virus to new lymphocytes,essentially starving HIV out [25]. However, this treatment is only effective on individuals without acute HIV, and so

requires early detection of the disease, which, as HIV is a retrovirus, is characteristically difficult to do [24].Treatment for Alzheimer's disease works in a similar vein. Under current treatments, it is difficult to stop the

spread of Alzheimer's. However, research is currently underway to develop medicines that stop neuronal apoptosis by


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inhibiting amyloid-beta-plaque-induced overexpression of the tyrosine kinase receptor GSK3. Such research hopes toprevent the hyperphosphorylation of aggregates of tau proteins, which in turn would prevent neural apoptosis, slowing thespread of the disease [35]. Such research hopes to provide effective medications not only against Alzheimer's, but evenagainst less severe forms of dementia, such as mild cognitive impairment (MCI), essentially a lesser form of

Alzheimer's [33].

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