Enzymatic Targets for Drug Discovery Against Alzheimer's Disease

Alzheimer’s has become a common disease in aged people that leads to cognitive impairment and finally results in dementia and death. As the disease has a complicated etiology, it can hardly be prevented and cured. Hence, it turned out to be one of the menacing neurodegenerative diseases. The important concerning factor about Alzheimer’s is its unaffordable treatment cost. Also, there are only a few efficient anti-Alzheimer drugs. Now, it is a very urgent need to discover the most efficient and cost-effective anti-Alzheimer’s drugs. Nowadays, research reveals drugs based on heterocyclic scaffolds that have attributed to potent pharmacology. Quinoline-containing molecule, tacrine was recommended as an acetylcholinesterase inhibitor. However, its use has been withdrawn because of its toxicity. While research is going on designing derivatives of tacrine. Fortunately, some tacrine derivatives showed the most potent anti-Alzheimer properties. In view of this, here, anti-Alzheimer properties of recently reported tacrine-based Alzheimer’s agents are discussed and evaluated. The structure-activity relationship has been helpful in identifying potent molecules in a series of derivatives.

Alzheimer’s disease (AD) exemplifies a looming epidemic lacking effective treatment and manifests with the accumulation of neurofibrillary tangles, amyloid-β plaques, neuroinflammation, behavioral changes, and acute cognitive impairments. It is a complex, multifactorial disorder that arises from the intricate interaction between environment and genetic factors, restrained via epigenetic machinery. Though the research progress has improved the understanding of clinical manifestations and disease advancement, the causal mechanism of detrimental consequences remains undefined. Despite the substantial improvement in recent diagnostic modalities, it is challenging to distinguish AD from other forms of dementia. Accurate diagnosis is a major glitch in AD as it banks on the symptoms and clinical criteria. Several studies are underway in exploring novel and reliable biomarkers for AD. In this direction, epigenetic alterations have transpired as key modulators in AD pathogenesis with the impeding inferences for the management of this neurological disorder. The present chapter aims to discuss the significance of epigenetic modifications reported in the pathophysiology of AD such as DNA methylation, hydroxy-methylation, methylation of mtDNA, histone modifications, and noncoding RNAs. Additionally, the chapter also describes the possible therapeutic avenues that target epigenetic modifications in AD. 

Alzheimer's disease (AD) is the most prevalent form of dementia, and it is considered a dynamic cognitive decline. Neurofibrillary tangles and nerve cell injury are important neuropharmacological symptoms for one AD brain. TMP21 is an important molecule in cellular protein trafficking. TMP21, a protein involved in the production of neurotic plaques, appears to be dysregulated in AD. As a result, we want to look into TMP21 dysregulation in Alzheimer's disease, as well as the involvement of TMP21 in neurotic plaque development and the underlying mechanisms. TMP21's significance in the creation of neurofibrillary tangles, synaptic disbalance, and nerve cell death is also explored. It will shed light on the therapeutic potential of regulating TMP21 as a treatment for AD.

Alzheimer's disease (AD) is a major cause of mental disability in the elderly, accounting for 50-60% of all dementia. While β-amyloid plaques as well as neurofibrillary tangles are neuropathological markers, inflammation plays a critical role in AD development. The aberrant detachment of microtubules (MTs) from axon MTs, cellular mislocalization, and hyperphosphorylation of tau are major factors in neurodegeneration death. Tau's ability to aggregate as well as form NFTs is assumed to be regulated by post-translational changes, which are regarded to be an essential regulatory mechanism. So far, drugs that target tau phosphorylation as well as aggregation have not shown therapeutic impact. It is now clear that tubulin PTMs cause tau dysfunction. High glutamylation and detyrosination levels in the neurons affect MT surface physicochemical characteristics. Further evidence for the relevance of such an enzymatic machinery in neurobiology comes from the recent discovery of harmful mutations in enzymes involved in surface MT modification. In this chapter, we discussed that targeting tubulin-modifying enzymes pharmacologically may be useful in treating neurodegenerative disorders.

Alzheimer’s disease (AD) is the most important cause of dementia and a complex chronic neurodegenerative disease. Many of the currently marketed drugs are used to treat this disease condition, but a major issue with these drugs is their neurotoxicity. Alzheimer's treatment with the FDA approval of memantine resolves the neurotoxicity issue. Memantine acts on glutamate and its receptors in the treatment of AD. Recent studies show that NMDA receptor-acting drugs are doing well in the healing of Alzheimer's patients, because of their selectivity on receptor and neuroprotective activity. The present work is an attempt to collect updated information about memantine and glutamate antagonists used for the treatment of AD. 

Alzheimer’s Disease (AD) is a neurodegenerative disease. The disease itself is progressive and full recovery from it isn’t achievable yet. There are several hypotheses asserted (Cholinergic hypothesis, Amyloid hypothesis etc.) to explain the mechanisms behind the disease. Also, many targets have been identified for possible therapeutics and from these targets, numerous drug candidates have been evaluated in clinical trials. Unfortunately, most of these trials failed due to the enigmatic nature of this disease. Currently, there are 7103 targets associated with Alzheimer's disease listed in the Open Targets platform where 1240 of them are enzyme-related. In this chapter, enzymatic targets of the AD have been reviewed, and those claimed to have disease modifying effects were selected and presented according to their clinical significance.

The clinical manifestations of Alzheimer's disease (AD) and associated human tauopathies are driven by tau neuronal and glial abnormalities. Tau, a microtubule-associated protein is inherently disordered due to its lack of a stable structure and great flexibility. Intracellular inclusions of fibrillar tau with a sheet shape accumulate in the brains of individuals with AD and other tauopathies. As a result, tau separation from microtubules and tau transition from a disordered state to an inappropriately aggregated state are critical steps before the start of tau-related illnesses. Many studies have demonstrated that this shift is triggered by post translational changes such as hyperphosphorylation and acetylation. Before the development of tau inclusions, the misfolded tau self-assembles and forms a tau oligomer. Animal and clinical research utilising human samples has shown that tau oligomer development contributes to neuronal death. During tauopathies, tau seeds are released from cells and absorbed into neighbouring cells, resulting in the spread of abnormal tau aggregation. Thus, Tau has become both a physiological and pathological target for AD treatments during the last decade. Evidence reveals many potential techniques for preventing tau-mediated toxicity: (1) direct suppression of pathological tau aggregation; (2) inhibition of tau post-translational changes that occur before pathological tau aggregation; (3) inhibition of tau propagation; and (4) microtubule stabilisation. Aside from traditional low-molecular-weight compounds, newer drug discovery approaches, such as the development of medium-molecular-weight drugs (peptide- or oligonucleotide-based drugs) and high-molecular-weight drugs (antibody based drugs), provide alternative pathways to preventing the formation of abnormal tau. Suppression of protein kinases or protein-3-O-(N-acetyl-beta-D-glucosaminl)-L-serine/threonine hydrolase, inhibition of tau aggregation, active and passive immunotherapies, and tau silencing using antisense oligonucleotides; in several animal models, have shown the capacity to prevent or minimise tau lesions and treat either cognitive or motor impairment. Immunotherapy, which has already reached the clinical stage of drug development, is the most advanced technique for treating human tauopathies. Tau vaccines or humanised antibodies are designed to target a range of tauspecies in both intracellular and extracellular environments. Some of them recognise the amino- or carboxy-terminus, while others have proline-rich areas or microtubule binding domains that they can attach to. In this review, we examine various clinical targets for the treatment of tauopathies as well as the various molecules researched as tau inhibitors that can be used in AD. Furthermore, we explore the efficacy of some of the prominent molecules in clinical studies for tau-targeted therapies research.

Alzheimer’s disease (AD) is an attained disorder of cognitive and behavioral impingement with progressive symptoms over time. It is mostly witnessed in elderly people, and as per the World Health Organization (WHO), it has affected more than 35 million people worldwide, and this figure is presumed to double by the year 2050. The most commonly believed cause of AD is the accumulation of beta-amyloid, which forms extracellular plaques. Presently conventional therapy for treating cognitive impairments in AD relies on a neurotransmitter or enzyme modulation strategy. Conventional approved drugs, such as acetylcholinesterase inhibitors (memantine, tacrine), are widely available for the treatment of mild to moderate AD, but due to their lower bioavailability, poor solubility, and ineffective capability to surpass the blood brain barrier (BBB), they often fail to produce the desired effect. The potency of conventional AD drugs is highly dependent on various physiological aspects such as BBB; blood-cerebrospinal fluid barrier and drug efflux by P-glycoprotein, which all hampers the capabilities of AD drugs to grasp the central nervous system (CNS). So, in order to conquer the hurdle and these existing limitations faced by CNS drugs to cross the BBB, innovative pathways in drug development have become the need of the hour. Various nanocarriers based approaches profitably meet this demand by improving the efficacy as well as facilitating the sustained release of the entrapped AD drug via targeted drug delivery. The blood-brain barrier offers protection to the central nervous system and also limits the entry of therapeutic molecules to the CNS. On the other hand, nanotechnology offers the possibility to deliver small molecules against CNS disorders across BBB due to their enormous properties, such as small surface area, controllable physicochemical properties, higher drug payload, and better drug circulation time. Plenty of nanocarriers and nanoparticle prodrugs have been reported to have inconsequential cytotoxicity in preclinical studies, and these advancements have proclaimed a new juncture for the development of new classes of nano carriers’ based potent drug formulations for the treatment of AD. A plethora of nanotechnology-based approaches such as polymers, emulsions, lipo-carriers, solid lipid carriers, carbon nanotubes, and metal-based carriers have been redefined over time, and they have been successfully focusing on both neuroprotective and neurogenerative techniques for treating AD. Many researchers also reported that nanotechnological-based techniques can improve the early diagnosis of AD and enhance the therapeutic efficacy and bioavailability of drugs.

With the discovery of Carbonic Anhydrase (CA) and its isoenzymes in various Alzheimer’s disease (AD) models and the brain of AD patients, the role of CA in AD pathology has become of keen interest among scholars around the world. Several experiments were performed to investigate the same, albeit they didn’t provide us with the exact mechanism through which CAs are involved in AD progression, but they gave us an important insight into the beneficial outcomes of CA inhibition. Carbonic Anhydrase Inhibitor (CAI) administration showed a significant reduction in the release of the proapoptotic factor- Cytochrome C (cyt C) from the challenged mitochondria (under oxidative stress). Thus, a link between ageing, oxidative stress, mitochondria dysfunction and pathogenesis of Alzheimer’s disease was established. Treatment with CAI indirectly lowers neuronal loss and, thus, cognitive impairment, which are characteristic features of AD. Though, the precise functions of CA in exaggerating or mediating AD still remain hazy, with the support of various scholarships globally, the use of CAII (an isoenzyme of CA) as a potential biomarker for AD can be proposed.

Alzheimer's disease (AD) is a debilitating neurological disease that is known to worsen as people age. As a chronic illness, it has a negative impact on the health and financial well-being of patients and their families. Despite decades of research into new medications and therapy regimens, the therapeutic choices for these conditions are still limited. Although currently available medications for AD do not prevent or stop disease progression, they are used to treat symptoms and provide brief comfort to patients. The development of medications and other therapy modalities to address the unmet medical need has sparked a surge of interest in understanding the mechanism of AD in recent years. Growing bodies of evidence direct towards the treatment of AD by intercepting the Somatostatin-evoked Aβ catabolism in the brain, via the α-endosulfin-KATP channel pathway. The latter can be achieved through the repurposing or repositioning of drugs previously approved by the regulatory authorities and indicated in other diseases. With the advent of technology in the healthcare sector, these could be corroborated through various in-silico and in-vitro techniques. This article aims to explore the various aspects of the byzantine α-endosulfine-KATP channel pathway while providing information and future prospects for the development of new therapies to combat AD.

Alzheimer disease (AD) is most common cause of dementia, which is characterized by impaired cognitive and behavioural charateristics. Deposition of Aβ plaques and neurofibrillary tangs (NFTs) are the hallmark of AD. Generally it is a chronic disease where neurodegeneration, and loss of neuronal function arise earlier before it is diagnosed. Early detection of AD is important as it reduces the severity of the disease. In this regard, an effective tools/methods are available including CSF biomarkers, Magnetic Resonance imaging (MRI), Positron emission tomography (PET) but all these methods are painful and often cannot be afforded by the patients.

Therapy of AD includes inhibitors of choline esterases, and antagonists at NMDA receptors. From the studies it is shown that these drugs just offer relief from symptoms rather than alleviating the progression of disease. Multiple pathological processes contribute for AD, like oxidative stress, dysregulation of neurotransmitters, inflammation of neurons, aggregation β-amyloid, phosphorylation of tau protein. It is essential to target multiple causes for an effective outcome in the treatment of AD. Early diagnosis is also crucial as it reduces disease progression thereby cost involved in AD therapy.

This review focuses on non-invasive, patient affordable diagnosis methods and also potential targets to discover new drugs beyond conventional and available drugs.