Immunotherapy for Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of dementia worldwide. In AD the normal soluble amyloid β (sAβ) peptide is converted into oligomeric/fibrillar Aβ. The oligomeric forms of Aβ are thought to be the most toxic, while fibrillar Aβ becomes deposited as amyloid plaques and congophilic angiopathy, which serve as neuropathological markers of the disease. In addition the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is a critical part of the pathology. Numerous therapeutic interventions are under investigation to prevent and treat AD. Among the more exciting and advanced of these approaches is vaccination. Active and passive Immunotherapy targeting only Aβ has been successful in many AD model animal trials; however, the more limited human data has shown much less benefit so far, with encephalitis occurring in a minority of patients treated with active immunization and vasogenic edema or amyloid-related imaging abnormalities (ARIA) being a complication in some passive immunization trials. Therapeutic intervention targeting only tau has been tested only in mouse models; and no approaches targeting both pathologies concurrently has been attempted, until very recently. The immune approaches tried so far were targeting a self-protein, albeit in an abnormal conformation; however, effective enhanced clearance of the disease associated conformer has to be balanced with the potential risk of stimulating excessive toxic inflammation. The design of future more effective immunomodulatory approaches will need to target all aspects of AD pathology, as well as specifically targeting pathological oligomeric conformers, without the use of any self-antigen.     

Tau-aggregation inhibitor therapy for Alzheimer's disease

Many trials of drugs aimed at preventing or clearing β-amyloid pathology have failed to demonstrate efficacy in recent years and further trials continue with drugs aimed at the same targets and mechanisms.The Alzheimer neurofibrillary tangle is composed of tau and the core of its constituent filaments are made of a truncated fragment from the repeat domain of tau. This truncated tau can catalyse the conversion of normal soluble tau into aggregated oligomeric and fibrillar tau which, in turn, can spread to neighbouring neurons. Tau aggregation is not a late-life process and onset of Braak stage 1 peaks in people in their late 40s or early 50s. Tau aggregation pathology at Braak stage 1 or beyond affects 50% of the population over the age of 45.The initiation of tau aggregation requires its binding to a non-specific substrate to expose a high affinity tau–tau binding domain and it is self-propagating thereafter. The initiating substrate complex is most likely formed as a consequence of a progressive loss of endosomal–lysosomal processing of neuronal proteins, particularly of membrane proteins from mitochondria. Mutations in the APP/presenilin membrane complex may simply add to the age-related endosomal–lysosomal processing failure, bringing forward, but not directly causing, the tau aggregation cascade in carriers.Methylthioninium chloride (MTC), the first identified tau aggregation inhibitor (TAI), offers an alternative to the amyloid approach. Phase 3 trials are underway with a novel stabilized reduced form of methylthioninium (LMTX) that has improved tolerability and absorption.     

Emerging and potential therapies for Alzheimer's disease

Background: The amyloid β (Aβ) peptide is critical to the development of Alzheimer's disease (AD), the major neurodegenerative disease of the elderly for which there is currently no cure. Objective: To review the literature on emerging treatments and potential therapeutic strategies for AD. Methods: Available published literature and information from pharmaceutical companies was utilised. Results/conclusion: Several of the current treatments to combat AD are aimed at inhibiting the production, blocking the oligomerisation/aggregation or enhancing the degradation of Aβ. In our opinion, albeit based on limited available data, a future potential therapeutic strategy is to mimic the mechanism by which the normal cellular form of the prion protein inhibits the β-secretase β-site amyloid precursor protein cleaving enzyme-1 (BACE1), and hence the production of Aβ.     

The complexities of the pathology–pathogenesis relationship in Alzheimer disease

Current pathogenic theories for Alzheimer disease (AD) and aging favor the notion that lesions and their constituent proteins are the initiators of disease due to toxicity. Whether this is because structural pathology is traditionally viewed as deleterious, and whether this, in turn, is a fundamental misinterpretation of the relationship between pathology and pathogenesis across the spectrum of chronic diseases, remains to be determined. As more and more detailed information about the biochemical constituents of AD lesions becomes available, it may also be argued that just as much knowledge of cellular physiology as pathophysiology has been gained. Indeed, essentially all major proteins in AD lesions are derived from molecular cascades, which are in turn highly conserved across cells, tissues, and species. Moreover, the lesions themselves are observed in the cognitively intact, and sometimes in large numbers, while major consensus criteria indicate that an extent of pathology is normal with advanced age. As the medical science community continues to pursue lesion targeting for therapeutic purposes, the notion that AD pathology is indicative of an active host response or environmental adaptation, and therefore a poor target, is becoming clearer.     

Emerging beta-amyloid therapies for the treatment of Alzheimer's disease

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder marked by loss of memory, cognition, and behavioral stability. AD is defined pathologically by extracellular neuritic plaques comprised of fibrillar deposits of beta-amyloid peptide (Abeta) and neurofibrillary tangles comprised of paired helical filaments of hyperphosphorylated tau. Current therapies for AD, such as cholinesterase inhibitors, treat the symptoms but do not modify the progression of the disease. The etiology of AD is unclear. However, data from familial AD mutations (FAD) strongly support the "amyloid cascade hypothesis" of AD, i.e. that neurodegeneration in AD is initiated by the formation of neurotoxic beta-amyloid (Abeta) aggregates; all FAD mutations increase levels of Abeta peptide or density of Abeta deposits. The likely link between Abeta aggregation and AD pathology emphasizes the need for a better understanding of the mechanisms of Abeta production. This review summarizes current therapeutic strategies directed at lowering Abeta levels and decreasing levels of toxic Abeta aggregates through (1) inhibition of the processing of amyloid precursor protein (APP) to Abeta peptide, (2) inhibition, reversal or clearance of Abeta aggregation, (3) cholesterol reduction and (4) Abeta immunization.     

Targeting p38 MAPK pathway for the treatment of Alzheimer's disease

Accumulating evidence indicates that p38 mitogen-activated protein kinase (MAPK) could play more than one role in Alzheimer's disease (AD) pathophysiology and that patients suffering from AD dementia could benefit from p38 MAPK inhibitors. The p38 MAPK signalling has been widely accepted as a cascade contributing to neuroinflammation. However, deepening insight into the underlying biology of Alzheimer's disease reveals that p38 MAPK operates in other events related to AD, such as excitotoxicity, synaptic plasticity and tau phosphorylation. Although quantification of behavioural improvements upon p38 MAPK inhibition and in vivo evaluation of p38 MAPK significance to various aspects of AD pathology is still missing, the p38 MAPK is emerging as a new Alzheimer's disease treatment strategy. Thus, we present here an update on the role of p38 MAPK in neurodegeneration, with a focus on Alzheimer's disease, by summarizing recent literature and several key papers from earlier years.     

Emerging amyloid beta (Ab) peptide modulators for the treatment of Alzheimer's disease (AD)

Background: According to the ‘amyloid cascade hypothesis’ of Alzheimer's disease (AD), abnormal processing of beta-amyloid precursor protein (βAPP) into toxic amyloid beta (Aβ)-peptides is central to the etiopathology of this uniquely human brain disorder. Objective: To review current AD drugs, pharmacological approaches and strategies aimed at modulating Aβ-peptide generation and/or aggregation in the treatment of AD. Methods: Data searches at various websites: Alzheimer Research Forum; individual drug company databases; Medline; Pharmaprojects database; unpublished research; inter-University research communications. Results/conclusion: Considerable research effort has focused on secretase-mediated mechanisms of βAPP processing, and the latest pharmacological strategies have used selective Aβ-peptide-lowering agents (SALA) to provide therapeutic benefit against Aβ-initiated neurodegenerative pathology. Currently, dedicated anticholinesterase, glutamatergic agonist and Aβ-peptide immunization have had little impact in the clinical treatment of AD. One unexpected benefit of statins (HMG-CoA inhibitors), besides their cholesterol lowering abilities, has been their ancillary effects in potentiating the enzymatic mechanisms that generate Aβ-peptides. The long-term benefits or complications of statin-based therapies for use in the clinical management of AD are not known.     

β-Amyloid peptide as a target for treatment of Alzheimer’s disease

Alzheimer’s disease is a progressive neurodegenerative disorder characterised by a series of biochemical and histological changes although the net of relations and its initial cause is far from being fully understood. The amyloid hypothesis points out the pathological processing of a physiologically normal protein, the amyloid precursor protein, to neurotoxic forms of amyloid β-peptide as the origin of the cascade of biochemical changes that lead to Alzheimer’s disease. Normal APP processing involves three proteases, α-, β- and γ-secretase, to yield physiological amyloid fragments. Familial Alzheimer’s disease patients exhibit an increased activity of β- and γ-secretases, resulting in higher than average levels of small amyloid fragments, of 40 or 42 amino acids (Aβ₄₀ and Aβ₄₂, respectively). These newly formed Aβ₄₀ and Aβ₄₂ may suffer a conformational change followed by aggregation into fibrils and finally deposition as senile plaques in a complex process named fibrillogenesis, which is associated with neurotoxicity. Modulation of this multistep process is a reasonably hopeful approach for the treatment of Alzheimer’s disease. In a general sense, this approach can be divided in three groups: first, modulating the production of Aβ promoting the non-amyloidogenic route; second, inhibiting fibrillogenesis and third, by immunisation techniques, enhancing the formation of anti-Aβ antibodies in order to mark fibrils and plaques as targets for microglial cells.     

Preclinical and clinical challenges in the development of disease-modifying therapies for Alzheimer's disease

The neurodegenerative disease first described almost 100 years ago by Alois Alzheimer is predicted to be one of the major health problems of the 21st century. Alzheimer's disease (AD) is a progressive dementia characterized by global cognitive decline and is defined pathologically by amyloid plaques and neurofibrillary tangles. Major unmet medical need has encouraged pharmaceutical companies to invest in AD drug development. Promising novel approaches are under way, assisted by recent advances in animal models and an increased understanding of pathophysiology. However, demonstration of disease modification and identification of at-risk individuals are among the significant challenges facing those working in AD drug development.     

New perspectives on the role of tau in Alzheimer's disease. Implications for therapy

Alzheimer's disease (AD) and related dementias constitute a major public health issue due to an increasingly aged population as a consequence of generally improved medical care and demographic changes. Current drug treatment of AD, the most prevalent dementia, with cholinesterase inhibitors or NMDA antagonists have demonstrated very modest, symptomatic efficacy, leaving an unmet medical need for new, more effective therapies. While drug development efforts in the last two decades have primarily focused on the amyloid cascade hypothesis, so far with disappointing results, tau-based strategies have received little attention until recently despite that the presence of extensive tau pathology is central to the disease. The discovery of mutations within the tau gene that cause fronto-temporal dementia demonstrated that tau dysfunction, in the absence of amyloid pathology, was sufficient to cause neuronal loss and clinical dementia. Abnormal levels and hyperphosphorylation of tau protein have been reported to be the underlying cause of a group of neurodegenerative disorders collectively known as ‘tauopathies’. The detrimental consequence is the loss of affinity between this protein and the microtubules, increased production of fibrillary aggregates and the accumulation of insoluble intracellular neurofibrillary tangles. However, it has become clear in recent years that tau is not only a microtubule interacting protein, but rather has additional roles in cellular processes. This review focuses on emerging therapeutic strategies aimed at treating the underlying causes of the tau pathology in tauopathies and AD, including some novel approaches on the verge of providing new treatment paradigms within the coming years.     

Alzheimer's disease and senile dementia: Biochemical characteristics and aspects of treatment

Alzheimer's disease (AD) and senile dementia (SD) are often classified together, but there are genetic, biochemical, neuropathological and clinical arguments for separating them.The well-known Alzheimer lesions in the brains of patients with AD and SD are described, as is the loss of neurons in the locus coeruleus. White matter changes in brains from patients with dementia are discussed and related to AD and SD.Biochemical changes in brains of patients with AD and SD include reduced activity of acetylcholineesterase (AChE) and choline-acetyltransferase (CAT), indicating reduced activity in the acetylcholinergic system. There is also, however, reduced activity in the dopamine (DA), noradrenaline (NA) and 5-hydroxytryptamine (5-HT) system. The active amines are decreased while the end metabolites are decreased to a lesser extent or normal. The levels of the active amines are thought to reflect the number of neurons, while the levels of end metabolites reflect the rate of turnover in the system. 3-Methoxy-4-hydroxyphenylglycol (MHPG) is increased to levels above normal, which may indicate an increased rate of turnover in the NA system.Monoamine oxidase B (MAO-B), which is increased in advanced age, is further increased in patients with AD and SD. It is assumed that this enzyme is localized in extraneuronal tissue, and therefore the increase may reflect a gliosis.In brains from patients with AD and SD neuropeptides are also studied. Only somatostatin and substance P, however, seem to be reduced, indicating selective damage to the neuropeptides.The biochemical changes can be given pathogenetic importance. Disturbances in the acetylcholinergic system may explain memory disturbances, disturbances in the DA system may explain parkinsonlike symptoms and disturbances in the NA and 5-HT systems may explain mood disturbances and emotional symptoms in the disorder. The biochemical changes may also suggest a line of treatment. At present, several attempts have been made to activate the neurotransmitter systems. The progress of these studies is, however, not very encouraging.     

Molecular approaches to the treatment, prophylaxis, and diagnosis of Alzheimer's disease: novel PET/SPECT imaging probes for diagnosis of Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disease of the brain associated with irreversible cognitive decline, memory impairment, and behavioral changes. Postmortem brains of AD patients reveal neuropathologic features, in particular the presence of senile plaques (SPs) and neurofibrillary tangles (NFTs), which contain β-amyloid peptides and highly phosphorylated tau proteins. Currently, AD can only be definitively confirmed by postmortem histopathologic examination of SPs and NFTs in the brain. Therefore, SPs and NFTs in the brain may be useful as biomarkers for the differential diagnosis of AD; the detection of individual SPs and NFTs in vivo by positron-emission tomography (PET) or single-photon emission computed tomography (SPECT) should improve diagnosis and also accelerate discovery of effective therapeutic agents for AD. Many PET/SPECT imaging probes for SPs have already been developed. Several of the PET probes have been shown in clinical trials to be useful for the imaging of β-amyloid plaques in living brain tissue. More recently, the development of PET/SPECT probes for in vivo imaging of NFTs is an active area of study in the field of molecular imaging because the appearance of NFT pathology correlates well with clinical severity of dementia. We will review current research on the development of PET/SPECT imaging probes for in vivo detection of SPs and NFTs and their application to diagnosis and therapy of AD.     

Transdermal delivery of treatment for Alzheimer's disease: development, clinical performance and future prospects

There is increasing interest in the potential of transdermal drug delivery systems for the treatment of neurological disorders, especially in the elderly. In this population, the higher incidence of chronic diseases, such as diabetes mellitus, cardiovascular disease, neurological disease and chronic pain, has dramatically increased the need for long-term medications. Additionally, elderly patients often have a combination of several chronic diseases, meaning drug delivery, drug-drug interactions, absorption/blood concentrations, toxicity and compliance are of concern for patients as well as for their caregivers and physicians. Recent efforts have focused on developing pharmaceutical preparations that overcome these issues. For example, rate-controlled drug delivery systems have been under active development. Transdermal drug delivery systems have been developed to deliver phenserine, rivastigmine, nicotine and estradiol for the management of cognitive and behavioural dysfunctions in patients with Alzheimer's disease because this form of administration has several advantages, including maintenance of sustained therapeutic plasma concentrations of drugs, easy application and reduced systemic adverse effects. Thus, transdermal drug delivery for elderly patients offers promise as the ideal therapeutic approach to treating Alzheimer's disease.This article reviews the technical principles underlying the development of transdermal drug delivery systems, focusing on cholinesterase inhibitors, and the prospects for future development. The clinical performance of transdermal patches, again with emphasis on cholinesterase inhibitors, is also reviewed.     

The role of insulin and insulin-like growth factor I in the molecular and cellular mechanisms underlying the pathology of Alzheimer's disease

Cellular and molecular processes leading to abnormal accumulation of β amyloid in the brain are slowly being uncovered. A potential involvement of insulin and insulin-like growth factor I (IGF-I) in this plausible pathogenic process in Alzheimer's disease has recently been proposed. Evidence favoring this idea stems from the ability of both hormones to stimulate β amyloid release from neurons as well as by the stimulatory effect that IGF-I exerts on brain amyloid clearance. In addition, insulin and IGF-I levels are altered in Alzheimer's patients and, probably in close association to these changes, cell sensitivity towards insulin—and possibly also IGF-I—is decreased in these patients. We now review evidence that disturbed insulin/IGF-I signaling to brain cells, initiated at the level of the blood–brain barriers is probably instrumental in development of brain amyloidosis. Furthermore, insulin and IGF-I are potent neuroprotective factors and can regulate levels of phosphorylated tau, a major component of neurofibrillary tangles found in Alzheimer's brains. Therefore, a decrease in trophic support to neurons together with increased tau phosphorylation will follow loss of sensitivity towards insulin and IGF-I. Altogether, this supports the notion that a single pathogenic event, i.e., brain resistance to insulin/IGF-I, accounts for neuronal atrophy/death, tangle formation and brain amyloidosis typical of Alzheimer's pathology.     

Development of semagacestat (LY450139), a functional γ-secretase inhibitor,for the treatment of Alzheimer's disease

Background: Alzheimer's disease is thought to be caused by increased formations of neurotoxic amyloid beta (Aβ) peptides, which give rise to the hallmark amyloid plaques. Therefore, pharmacological agents that reduce Aβ formation may be of therapeutic benefit. Objective: This paper reviews the pharmacology and chemical efficacy of an Aβ-lowering agent, semagacestat (LY450139). Methods: A review of the published literature pertaining to semagacestat was obtained using several electronic search engines; unpublished data on file at Eli Lilly and Co. were used as supplementary material. Results/conclusions: Semagacestat treatment lowers plasma, cerebrospinal fluid and brain Aβ in a dose-dependent manner in animals and plasma and cerebrospinal fluid Aβ in humans, compared with placebo-treated patients. On the basis of extant data, semagacestat seems to be well tolerated, with most adverse events related to its actions on inhibition of peripheral Notch cleavage. Thus far, clinical efficacy has not been detectable because of the short duration of the current trials. Phase III trials with 21 months of active treatment are currently underway.     

Antiamyloid strategies for the treatment of Alzheimer's disease

Although the specific causes of Alzheimer's disease have not yet been determined, considerable circumstantial evidence implicates beta-amyloid, an insoluble polypeptide made up of 39 to 42 amino acids, in the continuing destruction of brain cells that results in the progressive deterioration of the patient's mental ability. The toxic actions of beta-amyloid appear to be due to free radicals generated by a portion of the beta-amyloid molecule. These free radicals damage various parts of the neuron and lead to increased intracellular calcium which is also toxic. beta-Amyloid is formed by the aberrant processing of a much larger precursor protein that is made when cells are damaged. The normal processing of this precursor protein not only prevents the formation of beta-amyloid, but produces a soluble protein that regulates the entry of calcium into neurons and has cytoprotective actions. Interventions to prevent the destruction of neurons and the disruption of brain function by beta-amyloid include the administration of antioxidants and free radical scavengers to reduce further neural damage from deposits of beta-amyloid, the activation of various growth factors to repair damaged cells and restore their functions, and the stimulation of the normal processing of the precursor protein not only to aid in neural repair but more importantly to prevent the formation of additional beta-amyloid.