Recent advances in the treatment of Alzheimer’s disease: An Immunotherapeutic approach

Antony Justin, Chennu Manisha, Tenzin Choephel, Peet Thomas, Victoria Jeyarani, Sayani Banerjee, Sunil Mani

Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamil Nadu, India.

*Corresponding Author E-mail: justin@jssuni.edu.in

ABSTRACT:

Alzheimer’s disease (AD) is a chronic, slowly progressive neurodegenerative disorder and most common in elderly patients. According to World Health Organization (WHO) report 2016, about 44 million people are affected with Alzheimer’s disease (AD) worldwide. Currently, FDA approved treatment for AD is merely providing symptomatic relief rather than complete cure. The fact that AD responsible for almost 70% of dementia, it is enough to depict the depth of the situation. Hence, this brought to the new investigations respect to novel array of therapeutic options like immunotherapeutic approach for AD. Primarily it involves two approaches, namely; active immunotherapy and passive immunotherapy. Active immunotherapy approach involves the administration of antigen in order to stimulate the activation of release of antibodies. The passive immunotherapy is based on the use of antibodies directed to the C-terminus, N-terminus as well as the mid-domain of Amyloid β peptide. Although these approaches seem to be a solution to the current therapeutic barriers, the applicability of immunotherapeutic approaches in practical scenario is far from being full filled mainly because of the numerous challenges faced. The immune reactions like meningoencephalitis, the very low penetrability of antibodies into the Blood-Brain Barrier (BBB) and lack of effective animal models pose biggest demerits. The current review investigates details of the history of clinical trials and the details of ongoing and promising trials in the field of immunotherapy for AD.

KEYWORDS: Immunotherapy, Alzheimer’s disease, Challenges, Monoclonal antibodies, Vaccines

INTRODUCTION:

AD was once considered a rare disorder but recently it is considered as a great threat and risk factor to the elderly community [1]. In one among nine people of age 65 and above has Alzheimer's disease[2].AD is responsible for most dementia cases reported worldwide and is marked by the loss of memory and aggregation of Amyloid beta-peptide (AßP) and Neurofibrillary tangle (NFT)[3]. Dementia is used to describe a broad set of symptoms like loss of memory and difficulties in problem-solving as well as thinking. It is a matter of concern because of the large percentage of population falling prey to the condition and the lack of effective care provided to the suffering patients [2, 4]. According to World Health Organization (WHO) data, it has been estimated that 50 million people suffer from dementia. Interestingly, Alzheimer’s disease (AD) is responsible for almost 60-70% of the total cases of dementia [5].Most recent World Alzheimer Report 2016 has found that only 50% of patients in developed countries receive proper diagnosis and the diagnosis rate in middle as well as low income countries fall as low as 10% [7]. The fact that proper medical care and treatment is unattainable for a vast number of patients even in highly developed countries is a matter of great concern.

The neuropathological characteristic of AD is marked by intracellular neurofibrillary tangles (NFT) and extracellular aggregated amyloid fibrils and amyloid-β plaques, this pathology increases with aging [7, 8]. The Neuropsychiatric symptoms (NPSs) are a characteristic feature of AD and can prove to be distressing for both the patients as well as the caregivers. These symptoms manifest in three phases; the first phase is marked by depression and irritability, second phase marked by anxiety and agitation followed by hallucination and delusion in third phase [9].

The manifestation and progression of the disease have been subject of multiple studies over the years, in spite of this fact, the manifestations, progression and the way in which individuals respond to the treatment remains as a matter of debate [10]. The current and widely used therapeutic strategy approved by United States Food and Drug Administration (U.S.F.D.A) consists of the use of N-methyl D-aspartate (NMDA) receptor antagonists, and Cholinesterase Inhibitors (ChEIs) in order to alleviate the symptoms [11, 12, 13]. The failure of these therapies is partly due to them being merely symptomatic and the use of ChEIs has not provided any convincing evidence of neuroprotective effect in patients with AD.

The limitations of existing therapy have led to the need for exploring more cost-effective and therapeutically useful methods. Interestingly, Immunotherapeutic approach is an effective alternative to the currently existing problems. This review article will be focused on the genesis, development, and challenges in this particular therapeutic strategy.

Immunotherapeutic strategy aims at treating the AD through active and passive immunization, by modulating the immune system of individuals.

PATHOGENESIS OF AD:

AD is a neurodegenerative disorder which is caused by several mutations in causative proteins like Amyloid Precursor Protein (APP), Presenilin1 (PSEN1), and Presenilin2 (PSEN2). Mutations in presenilin 2 lead to the overproduction of amyloid beta-peptide which gets accumulated in the brain and causes neuron death [14]. The brain of individuals with AD usually shows increased accumulation of senile plaques and neurofibrillary tangles (NFTs) [15]. Even though the causes and progression of AD remains to be not well understood, abnormally folded accumulation of β-amyloid in plaques and tau protein tangles in the brain or proteopathy is argued to be the prime reason [16, 17]. Inflammation in the brain has also been known to play a role in the changes that occur in Alzheimer’s disease [1]. Evidently, accelerated deterioration of neuronal plasticity is also observed in individuals with AD. Longitudinal structured MRI studies showed loss of ~0.5% in the brain mass/year in individuals of normal age [18] and ApoE derived from various cellular sources has distinct roles in both pathophysiological and physiological pathways [19].

Many theories are put forward in the pathogenesis of AD, Neveda Baskeran interpreted that Iron deficiency causes many pathophysiological problems in the brain which may lead to Alzheimer’s disease and other neurodegenerative disorders [20]. One of the most convincing theories put forward to explain pathogenesis AD is Amyloid Cascade Hypothesis (ACH). Extensive neuronal dysfunction including signal transmission deficits and cell death ultimately leads to dementia [21]. Initially, Aβ load was assumed to be responsible for neuronal death and dysfunction. The recent study demonstrated altered production of Aβ along with impaired elimination [22]. Aβ is thought to be formed by amyloidogenic pathway [23]. Interestingly, pathological, biochemical and genetic evidence suggest the important role of amyloid-β (Aβ) peptide in the disease and they act as an important target [24, 25]. In the initial stages of AD, cerebral isocortex is found to be a part of the sequence of both plaque and Cerebral Amyloid Angiopathy (CAA), followed by the allocortex in hippocampus and its related structures, and followed by involvement of the thalamus and basal ganglia [26].

It has been found with genetic studies that AD can be differentiated as the Early Onset AD (EOAD) form (with onset at age <65yrs) and sporadic Late-Onset AD (LOAD) form, with onset at age >65yrs) which is a more common form [27]. Generally, cerebral spinal fluid biomarker and the imaging of brain structure and amyloid deposition help for predicting individual development of Alzheimer's disease [28]. The transgenic models were as a result of the gene identification responsible for the familial form of AD [29]. The initiation of Positron Emission Tomography (PET) imaging of amyloid is a groundbreaking development in the clinical diagnosis [30].

RECENT APPROACHES IN THE TREATMENT OF AD:

Various strategies including natural remedies and drug therapy are being used and are emerging to treat and to prevent AD. Radha Mahendran (2017) proposed in their study; it is identified that the protein neurotrophin enhances the level of neurotrophin which will aid in the treatment of neurodegenerative disease [31].Senthil Venkatachalam put forward in their study that A signifying category of the drugs reuse in the management of the AD among them the prominent category is the anticancer, antiepileptic, antibiotics, antidiabetic, etc. [32]. Statins have also been contemplated in the therapy of CNS Disorders like AD, Cerebral Ischemia, Parkinson’s disease, trauma and tumor on accountability to upgrade the Nitric Oxide Synthase [33]. Omega 3 fatty acids have also been used in the treatment of AD as it prevents quick progression of dementia and AD, slows down aging and reduces the depression levels in the patient [34]. Certain natural elixirs like Garcinia Hanburyi Extract and Terminalia Chebula Extract have shown some Anti-Alzheimer properties as Garcinia Hanburyi could inhibit the activity of AchE and Terminalia Chebula that modulate the oxidative stress and be involved in the protective effect against oxidative damage and neurodegenerative diseases like AD [35, 36].

As the above-listed treatment strategies fail to provide promising outcomes and also do not improve the patient's quality of life, Immunotherapy can be advised for patients with AD.

IMMUNOTHERAPY OF AD:

The failure of the existing therapy to address effectively, the problem of disease progression has led to the search for novel approaches. Immunotherapy is one such approach that is promising. The immunotherapeutic intervention in AD is directed at two of its pathophysiological hallmarks, amyloid plaques composed of amyloid-beta 1–42 (Aβ42) and neurofibrillary tangles (NFTs), which are formed by aberrant self-proteins [25]. The revolutionary discovery came to light in an article in Nature by Schenk et al in 1999. They demonstrated that a transgenic mouse with a human AD mutation was injected with β-amyloid peptides with Freund’s adjuvant effectively led to reduced β-amyloid plaque pathology [37]. Subsequent studies conducted in transgenic mouse also revealed that the vaccinated groups exhibited behavior improvement when compared to the untreated groups [38].

The actual mechanisms through which the vaccination can affect the disease process remain uncertain. However, possible mechanisms involve the macrophage of the central nervous system (CNS) and the activation of microglia [39].

Immunotherapy of AD involves two types of vaccination; the active vaccination against Aβ42 involves injecting the patient with the antigen itself whereas anti-Aβ mAbs are injected in passive vaccination [15].

Active Immunotherapy:

This approach usually involves an adjuvant that is given along with the antigen to stimulate the antibody release. Typically, these adjuvants consist of bacterial fragments. For example, Freund's adjuvant is composed of mycobacterium tuberculosis in an inactivated form [40]. Notably, this approach provides a sustained immune response which in turn is refined through affinity maturation. Hence, this method ensures a limited number of immunization and thereby making it accessible to larger population [41].

The pioneer active immunization protocol to reach clinical trial was AN1792, during 2002 [30]. Unfortunately, the clinical studies were aborted following the observation of meningoencephalitis in about 6% of the subjects [15]. Later observations from the postmortem of the patients who participated in the discontinued trial, evidently showed removal of β amyloid plaques, even though the disease progression was not arrested [37].

The damage to brain vasculature caused by T-cell is said to attribute to the observed side effects. Simultaneously, β amyloid plaques release induced by antibody also contribute to this [39].

Following this, efforts for the development of immunotherapy which avoids the induction of T-cells were hastened. The vaccine CAD106that harbors a B cell epitope peptide, Aβ1–6 was successfully tested in AD patients of Sweden [39, 42]. Although certain side effects like nasopharyngitis have been reported, the results are promising. Lydia Giménez-Llort et al reports the use of single-chain variable fragments (scFv), in which the Fc portion is absent as a potential option [43]. Alternatively, a DNA based immunizing approach is reported to be safer than existing methods [42].

Tau protein, which is less targeted when compared to Aβ42, because they are chiefly present intracellularly and hence difficult to access [44]. However, ACImmune-35 (ACI-35) is a vaccine that is currently under clinical trials and was found to target the tau protein [15].

Passive Immunotherapy:

The passive immunotherapy in AD is characterized by the use of antibodies directed at the C-terminus, N-terminus as well as the mid-domain of Amyloid β peptide ^[14]. Recent studies suggest that immunotherapy can also play a key role in preventing the accumulation of tau, which is also a hallmark of the disease [45]. The studies in passive immunization for AD were initiated by Bard et al by using various antibodies like 16C11, 3D6 targeting various epitopes in Aβ peptide, and representing different IgG isotypes [48]. Numerous passive immunization studies are being carried out in the current scenario, partially owing to the various challenges faced in active immunization therapy [46].

Passive immunization in PDAPP mouse with anti-Aβ monoclonal antibody (m266) recognized an epitope on the mid-portion of Aβ13–28 peptide. As a result, the plaque deposition and formation were decreased and the levels of Aβ–anti-Aβ antibody complex were increased in blood [20]. Passive Immunization studies carried out in APPswe/PS1∆E9 mice using a highly specific Pyroglutamate-3 Amyloid- β mAb showed reduced deposition of general Aβ, pE3-Aβ, and fibrillar amyloid in the hippocampus, cortex as well as the cerebellum, during prevention as well as therapeutic study. However, more clearance was witnessed in the cerebellum when compared to hippocampus [49].

The pioneer efforts in clinical trials of monoclonal antibodies were of Bapineuzumab specific for an N-terminal Aβ epitope (Aβ1-5). Even though the phase II did not present with promising clinical benefits, phase III was initiated based on the observation of mild clinical benefits. Unfortunately, the trials were eliminated due to the absence of evident benefits along with occurrence of reversible and transient edema termed as amyloid-related imaging abnormalities with parenchymal edema (ARIA-E) [41]. Solanezumab is another humanized mAb which selectively binds to soluble Aβ by recognizing mid-domain epitope, which is different from the target of Bapineuzumab. This possibly explains the lack of ARIA-E in Solanezumab [49].

A human IgG1 mAb developed from a B-cell library, Aducanumab is a promising candidate for the passive immunization in AD. Based on the promising results, the study advanced to phase III, in order to evaluate its efficacy and is scheduled to be concluded by 2022. Crenezumab and BAN-2401 are also two humanized antibodies that continue through their initial stages of clinical trials [22].

Chai et al., reported that the immunization of the P301S mice with antibodies that specifically recognize the pathological form of tau, reduced the detectable tau pathology. This is important because tau is an important clinical characteristic in AD and various tauopathies like Pick disease [48]. Immunization with oligomeric antibodies in 3xTg-AD mice, evidently showed reduced levels of soluble and insoluble Aβ42 and Aβ40 [50]. Immunotherapeutic treatment has shown to increase the structural plasticity of dendrites, which can possibly lead to neuronal recovery [51].

CHALLENGES IN IMMUNOTHERAPY OF AD:

Although significant developments have been observed in the immunotherapy of AD in past decade, there are some issues or challenges that are required to be addressed. The lack of ability in effectively identifying the people with risk of AD, apart from the individuals bearing genetic abnormality in APP or the presenilin genes prove to be one of the hurdles in developing immunization therapy [24, 52]. The development of sensitive biomarkers in-order to detect the earliest changes in AD is necessary for better patient selection for clinical trials and to obtain more sensitive results [15].

Notably, in both passive and active immunization, only a minute percentage of antibodies are able to cross the blood-brain barrier (approximately 0.1%), but the percentage varies in AD subjects (approximately 0.5–1.0%). Thus, the penetration of antibody in the brain is critically low [28]. In addition, active vaccination demands particular attention to immunosenescence and other immune effects especially in the elderly.

The failure in clinical trial AN1792 was partly due to the absence of improvement in cognitive benefits in the long term, in addition it triggered an immune reaction via T-cell resulting in meningoencephalitis. Even though transgenic mouse models are useful to the study of AD, they are observed to be inadequate due to some significant dissimilarity between mice and humans, especially the immune response [40]. Cerebral Amyloid Angiopathy (CAA) has also been found to be augmented following the immunization. Most importantly, the effectiveness of immunotherapy in curbing AD remains in question due to absence of notable improvement in cognitive functions, despite the removal of Aβ plaques from the brain [26].

The shortcomings in active immunotherapy have given fuel to the rise in more research on passive immunotherapy and it resulted in the introduction of mAbs like Bapineuzumab and Solanezumab. Bapineuzumab seemed promising in initial stages but was stopped at phase III due to absence of considerable therapeutic benefits. Aducanumab is another antibody that is promising, and phase III is scheduled to be completed by 2022. Even if the challenges are addressed, the heavy economic burden associated with a process like immunotherapy will lead to the unequal distribution of the benefit of this novel method especially to the patients in developing countries.

CONCLUSION:

Since the inception of immunotherapy in AD by Schenk et al., in 1999, there has been promising and substantial development in the field. The importance of immunotherapy is enhanced by the drawbacks in the current therapy followed. Immunotherapy is focused on the two hallmarks of AD, namely amyloid plaques composed of amyloid-beta 1–42 (Aβ42) and neurofibrillary tangles (NFTs). The two main approaches include active immunotherapy in which the antigens are stimulated to release antibody and the passive immunotherapeutic approach that includes the use of monoclonal antibodies (mAbs). The active immunotherapy exhibited a series of drawbacks including meningoencephalitis by a T-cell mediated mechanism. However, the vaccine CAD106 that harbors a B cell epitope peptide was developed to avoid the side effects mediated by T-cell. A DNA based immunizing approach is found to be effective as well.

Although immunotherapy seems to be an alternative to the existing treatment of AD, the hurdles faced by this approach are enormous. The lack of ability of antibodies to permeate through BBB and inflammatory responses is of major concern. In addition, the shortfall of an effective animal model to mimic the AD conditions like humans poses a huge barrier to the development of an effective therapy. However, the removal of Aβ plaque does not confirm the curing or attenuation of AD beyond doubt. This remains to be the prime reason for concern in the immunotherapeutic approach. Hence, the need of the hour is the development of more efficient, economical and sustainable ways to implement the idea immunotherapy in patients with AD.

CONFLICT OF INTEREST:

The authors declare the there is no conflict of interest.

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Received on 21.08.2019 Modified on 13.09.2020

Research J. Pharm. and Tech 2020; 13(4):2057-2062.

DOI: 10.5958/0974-360X.2020.00370.4