Targeting β-Amyloid Pathology in Alzheimer's Disease with Aβ Immunotherapy

Abstract

Summary:More than 10 clinical trials of A␤ immunotherapy are currently underway in patients with Alzheimer's disease (AD). The aim is to identify safe approaches for the efficacious antibody-mediated removal of brain ␤-amyloid or its neurotoxic oligomeric precursors consisting of aggregated amyloid ␤-peptide (A␤). Initial experimental and neuro-pathological evidence for clearance of brain ␤-amyloid in response to A␤ immunotherapy is associated with structural and functional rescue of neurons, as well as initial signs of clinical stabilization and reduced rates of dementia progression. For the next steps in the future improvement of A␤ immunotherapy, major challenges in pharmacokinetics, safety, and tolerability need to be addressed. These include the low penetrations rates of IgG molecules through the blood-brain barrier, possible reductions in brain volume, the possibility of autoimmune disease related to unwanted crossreactivity with endogenous antigens on physiological structures, micro-hemorrhages related to cross-reaction with preexisting vascular amyloid pathology, possible relocalization of A␤ from ␤-amyloid plaques to brain blood vessels resulting in increased amyloid angiopathy, and the lacking activity of A␤ antibodies on pre-existing neurofibrillary tangle pathology, as well as the lacking molecular identification of the forms of A␤ to be therapeutically targeted. The solutions to these problems will be guided by the fine lines between tolerance and immunity against physiological and pathological structures, respectively, as well as by the understanding of the pathogenic transition of soluble A␤ into toxic oligomeric aggregation intermediates in the dynamic equilibrium of ␤-amyloid fibril assembly. Provided that the ongoing and planned clinical trials address these issues in a timely manner, there is a good chance for A␤ immunotherapy to be one of the first disease-modifying therapies of Alzheimer's disease to be introduced into clinical practice. Key Words: Humanized monoclonal antibody, neurodegeneration, vaccination, clinical trial, APP, passive immunization. PROOF OF CONCEPT IN EXPERIMENTAL ANIMALSThe concept of A␤ immunotherapy was first introduced by Schenk et al.1 who showed that vaccination with A␤1-42 and Freund's adjuvant prevented ␤-amyloid formation in brains of young transgenic mice and removed ␤-amyloid in older mice with pre-existing pathology. Subsequent active vaccinations in transgenic mice, nonhuman primates, and other species confirmed these findings 2-6 (For review, see references 7-10 ). Moreover, the passive transfer of antibodies against A␤ can efficiently reduce ␤-amyloid pathology.11-19 The immunotherapy-mediated clearance of ␤-amyloid pathology is paralleled by the recovery of neuronal and cytoskeletal morphology, 20,21 by the rescue of synaptic electrophysiological functions and neurotransmission, [22][23][24] and by signs of neuroprotection, 25 as well as by restored behavioral functions. 2,26 -28 While many antibodies show signs of efficacy in experimental animals, the...

Developing Therapeutic Antibodies for Neurodegenerative Disease

“…2a; [32][33][34][35]). The reason for such intense efforts is based on compelling human genetic and pathologic findings.…”

“…Removing Amyloid Via Anti-Aβ Treatment Numerous reviews have addressed the immunotherapeutic approaches to target Aβ [4,34,[55][56][57]; thus, we will focus on the debate around the mechanism(s) of anti-Aβ action ( Fig. 2b) and the most recent clinical advances.…”

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“…1,2 However, recent studies pointed to their limited performance in patients with clinically overt dementia. 3,4 To date, the identification of patients at high risk for rapid cognitive decline is considered a prerequisite for future curative strategies in AD.…”