Immunization in Alzheimer's disease: naïve hope or realistic clinical potential?

Abstract

There has been considerable recent interest in vaccination of patients by immunotherapy as a potentially clinically useful methodology for combating histopathological changes in Alzheimer's disease (AD). The focus of the majority of this research has been on (1) active immunotherapy using the pre-aggregated synthetic b-amyloid (Ab) 42 preparation AN1792 vaccine (QS-21), or (2) passive immunization using injections of already prepared polyclonal anti-Ab antibodies (intravenous immunoglobulin). These two clinical approaches to the treatment of patients with AD represent the focus of this review. We conclude here that, with certain caveats, immunization offers further potential as a technique for the treatment (and possible prevention) of AD. New studies are seeking to develop and apply safer vaccines that do not result in toxicity and neuroinflammation. Nevertheless, caution is warranted, and future clinical investigations are required to tackle key outstanding issues. These include the need to demonstrate efficacy in humans as well as animal models (especially with respect to the potentially toxic side effects of immunotherapy), and fine-tuning in safely guiding the immune response. The issue of defining necessary and sufficient criteria for determining clinical efficacy remains an additional important issue for future immunization trials. The vaccination methodology appears to offer substantial current promise for clearing both soluble and aggregated amyloid in AD. However, it remains to be determined whether this approach will help to repair already damaged neural systems in the disease, and the extent to which vaccination-driven amyloid clearance will impact beneficially on patients' neurocognitive capacity and their functional status. The outcomes of future studies will be important both clinically and scientifically: an important further test of the validity of the amyloid hypothesis of AD is to evaluate the impact of an effective anti-amyloid strategy on the functional status of patients with this disease.

Mechanisms of U87 Astrocytoma Cell Uptake and Trafficking of Monomeric versus Protofibril Alzheimer’s Disease Amyloid-β Proteins

“…Its effects at the cellular level and within the nervous system have been pressing issues for those attempting to develop diagnostic and therapeutic approaches. Vaccines to enhance Aβ clearance are currently under investigation in several clinical trials [37]. However, the mechanisms underlying constitutive and enhanced clearance have not been completely elucidated.…”

Inhibition of RhoA GTPase and the subsequent activation of PTP1B protects cultured hippocampal neurons against amyloid β toxicity

“…Therapeutic approaches aimed at clearing Aβ plaques have received special attention, and methods for active or passive immunisation have proven effective in reducing Aβ content in the brain. Nevertheless, these strategies have failed to conclusively ameliorate or retard cognitive deterioration in AD patients [4,5]. …”

Alzheimer's disease vaccine development: A new strategy focusing on immune modulation

“…Yet, while studies with pre-symptomatic AD mouse and other animal models have shown promising results (Schenk et al, 2004;Wilcock et al, 2009;Lemere et al, 2004;Head et al, 2006), those results have not been translated into positive results in clinical trials (Delrieu et al, 2012;Karran, 2012). This situation has raised questions about the concept behind this approach (Morris et al, 2014;Lee et al, 2007;Foster et al, 2009), but with little consideration of the differences between the vaccines used in the AD mouse models and humans and the disparities in immunoresponse between species. Yet, passive immunotherapy has provided strong evidence that the immunological approaches may be the most effective and safe ways to deal with this disease.…”