Alzheimer's disease immunotherapy: From in vitro amyloid immunomodulation to in vivo vaccination
ABSTRACT Site-directed antibodies which modulate conformation of amyloid-beta peptide (Abeta) became the theoretical basis of the immunological approach for treatment of Alzheimer's disease (AD). Indeed, antibodies towards the EFRH sequence, located between amino acids 3-6 of the N-terminal region of Abeta, found to be a key position in modulation of Abeta conformation, prevent formation of fibrillar Abeta and dissolve already formed amyloid plaques. The performance of anti-Abeta antibodies in transgenic mice models of AD showed they are delivered to the central nervous system (CNS), preventing and/or dissolving Abeta. Moreover, these antibodies protected the mice from learning and age-related memory deficits. Development of such antibodies via active and/or passive immunization against Abeta peptide fragments has been proposed for AD immunotherapeutic strategies. Experimental active immunization with fibrillar Abeta 1-42 in hu-mans was stopped in phase II clinical trials due to unexpected neuroinflammatory manifestations. In spite of the fact that it will take considerable effort to establish a suitable immunization procedure, these results clearly strengthen the hypothesis that Abeta plays a central role in AD, stimulating a new area for development of Alzheimer's immunotherapeutics.
- [Show abstract] [Hide abstract]
ABSTRACT: Pharmacological treatment in Alzheimer's disease (AD) accounts for 10-20% of direct costs, and fewer than 20% of AD patients are moderate responders to conventional drugs (donepezil, rivastigmine, galantamine, memantine), with doubtful cost-effectiveness. Both AD pathogenesis and drug metabolism are genetically regulated complex traits in which hundreds of genes cooperatively participate. Structural genomics studies demonstrated that more than 200 genes might be involved in AD pathogenesis regulating dysfunctional genetic networks leading to premature neuronal death. The AD population exhibits a higher genetic variation rate than the control population, with absolute and relative genetic variations of 40-60% and 0.85-1.89%, respectively. AD patients also differ in their genomic architecture from patients with other forms of dementia. Functional genomics studies in AD revealed that age of onset, brain atrophy, cerebrovascular hemodynamics, brain bioelectrical activity, cognitive decline, apoptosis, immune function, lipid metabolism dyshomeostasis, and amyloid deposition are associated with AD-related genes. Pioneering pharmacogenomics studies also demonstrated that the therapeutic response in AD is genotype-specific, with apolipoprotein E (APOE) 4/4 carriers the worst responders to conventional treatments. About 10-20% of Caucasians are carriers of defective cytochrome P450 (CYP) 2D6 polymorphic variants that alter the metabolism and effects of AD drugs and many psychotropic agents currently administered to patients with dementia. There is a moderate accumulation of AD-related genetic variants of risk in CYP2D6 poor metabolizers (PMs) and ultrarapid metabolizers (UMs), who are the worst responders to conventional drugs. The association of the APOE-4 allele with specific genetic variants of other genes (e.g., CYP2D6, angiotensin-converting enzyme [ACE]) negatively modulates the therapeutic response to multifactorial treatments affecting cognition, mood, and behavior. Pharmacogenetic and pharmacogenomic factors may account for 60-90% of drug variability in drug disposition and pharmacodynamics. The incorporation of pharmacogenetic/pharmacogenomic protocols to AD research and clinical practice can foster therapeutics optimization by helping to develop cost-effective pharmaceuticals and improving drug efficacy and safety.Methods in Molecular Biology 02/2008; 448:213-357. DOI:10.1007/978-1-59745-205-2_10 · 1.29 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Diverse age-associated neurodegenerative disorders are featured at a molecular level by depositions of self-aggregating molecules, as represented by amyloid beta peptides (Abeta) and tau proteins in Alzheimer's disease, and cascade-type chain reactions are supposedly commenced with biochemical aberrancies of these amyloidogenic components. Mutagenesis and multiplication of the genes encoding Abeta, tau and other pathogenic initiators may accelerate the incipient process at the cascade top, rationalizing generations of transgenic and knock-in animal models of these illnesses. Meanwhile, these genetic manipulations do not necessarily compress the timelines of crucial intermediate events linking amyloidogenesis and neuronal lethality, resulting in an incomplete recapitulation of the diseases. Requirements for modeling the entire cascade can be illustrated by a side-by-side comparison of humans and animal models with the aid of imaging-based biomarkers commonly applicable to different species. Notably, key components in a highly reactive state are assayable by probe-assisted neuroimaging techniques exemplified by positron emission tomography (PET), providing critical information on the in-vivo accessibility of these target molecules. In fact, multispecies PET studies in conjunction with biochemical, electrophysiological and neuropathological tests have revealed putative neurotoxic subspecies of Abeta assemblies, translocator proteins accumulating in aggressive but not neuroprotective microglia, and functionally active neuroreceptors available to endogenous neurotransmitters and exogenous agonistic ligands. Bidirectional translational studies between human cases and model strains based on this experimental paradigm are presently aimed at clarifying the tau pathogenesis, and would be expanded to analyses of disrupted calcium homeostasis and mitochondrial impairments. Since reciprocal causalities among the key processes have indicated an architectural interchangeability between cascade and network connections as an etiological representation, longitudinal imaging assays with manifold probes covering the cascade from top to bottom virtually delineate the network dynamics continuously altering in the course of the disease and its treatment, and therefore expedite the evaluation and optimization of therapeutic strategies intended for suppressing the neurodegenerative pathway over its full length.Biochimica et Biophysica Acta 04/2010; 1802(4):373-88. DOI:10.1016/j.bbadis.2010.01.003 · 4.66 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Alzheimer's disease (AD) is the 6th leading cause of death in United States afflicting >5 million Americans. This number is estimated to triple by the middle of the century if effective treatments are not discovered. Current therapy for AD is mainly symptomatic. Effective disease-modifying treatments are needed that would eliminate the cause rather than the symptoms of the disease. Polymerization of monomeric beta-amyloid peptide (Aβ) into dimers, soluble oligomers and insoluble fibrils is considered the prime causative factor in triggering AD pathogenesis. Based on these facts, removal/reduction of Aβ has gained importance as a primary therapeutic target in treating the cause of the disease. In that regard, passive immunotherapy with direct delivery of anti-Aβ antibodies to the brain has shown great promise, but awaits the challenge of overcoming greater influx of anti-Aβ antibody into the brain. This investigation was undertaken to maximize direct delivery of immunotherapeutics to the brain by using wheat germ agglutinin (WGA) as a novel axonal transporter-carrier to be conjugated with anti-Aβ antibody (6E10) raised against EFRHDS 3-8 amino acid (aa) epitopes of Aβ known to react with 1-16 aa residues of mono-/di-/oligomeric Aβ. This is the first report showing the use of WGA as an efficient axonal transporter carrier that not only enhanced the influx of anti-Aβ antibody directly into the brain but also resulted in greater reduction of cerebral Aβ compared to the unconjugated anti-Aβ antibody delivered intranasally in Alzheimer's 5XFAD model.Vaccine 08/2011; 29(44):7631-7. DOI:10.1016/j.vaccine.2011.08.009 · 3.49 Impact Factor