An Immunomodulatory Therapeutic Vaccine Targeting Oligomeric Amyloid-β1

Abstract

Background: Aging is considered the most important risk factor for Alzheimer’s disease (AD). Recent research supports the theory that immunotherapy targeting the “oligomeric” forms of amyloid-β (Aβ) may halt the progression of AD. However, previous clinical trial of the vaccine against Aβ, called AN1792, was suspended due to cases of meningoencephalitis in patients. Objective: To develop a peptide sensitized dendritic cells (DCs) vaccine that would target oligomer Aβ and prevent an autoimmune response. Methods: Double transgenic APPswe/PS1ΔE9 (Tg) and C57BL/6J control mice were used in this study. Cytokine expression profile detection, characterization of antisera, brain GSK-3β, LC3 expression, and spatial working memory testing before and post-vaccination were obtained. Results: Epitope prediction indicated that E22W42 could generate 13 new T cell epitopes which can strengthen immunity in aged subjects and silence several T cell epitopes of the wild type Aβ. The silenced T cell epitope could help avoid the autoimmune response that was seen in some patients of the AN-1792 vaccine. The E22W42 not only helped sensitize bone marrow-derived DCs for the development of an oligomeric Aβ-specific antibody, but also delayed memory impairment in the APP/PS1 mouse model. Most importantly, this E22W42 peptide will not alter the DC’s natural immunomodulatory properties. Conclusion: The E22W42 vaccine is possibly safer for patients with impaired immune systems. Since there is increasing evidence that oligomeric form of Aβ are the toxic species to neurons, the E22W42 antibody’s specificity for these “oligomeric” Aβ species could provide the opportunity to produce some clinical benefits in AD subjects.

Alzheimer’s disease in elderly COVID-19 patients: potential mechanisms and preventive measures

“…In this regard, a recent study in the APP/PS1 mouse model of AD showed that injection of dendritic cells presenting a modified Aβ peptide triggered a specific antibody response and improved memory performance to a similar degree than that exhibited by non-transgenic, untreated mice. Importantly, the vaccine did not trigger an inflammatory response [ 70 ]. Despite past failures and the significant challenge involved in developing and testing vaccines against endogenous neurodegenerative disease proteins, these sustained efforts to harness the immune system to treat AD will hopefully bring long-awaited success.…”

An Aβ3‑10‑KLH vaccine decreases Aβ plaques and astrocytes and microglia activation in the brain of APP/PS1 transgenic mice

“…The pathogenesis of AD is complex which is characterized by a progressive loss of neurons and involves Aβ plaques formation, activation of astrocytes and microglia (Guo et al, 2020;Tiwari et al, 2019). Vaccines and active immunotherapy are being studied against AD (Bittar et al, 2018;Song et al, 2020). The aim of this study was to investigate Aβ plaques and changes of astroglia and microglia in mice injected with a new vaccine based on Aβ3-10 as the antigen.…”

“…Some strategies for AD treatment aim to consolidate the clearance of Aβ plaque and elimination of neuroinflammation reactions (Lemere, 2013), and immunotherapy against Aβ and phosphorylated tau (p-Tau) has been suggested for more than 20 years. Pre-clinical studies have shown some efficacy of vaccines and active immunotherapies against Aβ and p-Tau, but the translation to humans proved ineffective and with serious safety issues (Song et al, 2020). Among others, a vaccine against Aβ1-42 (Elan Pharmaceuticals, CA, USA) could remove amyloid plaques and improve perceptive function in transgenic animal models and AD patients (Janus et al, 2000;Vellas et al, 2009), but the clinical trial of the Aβ1-42 vaccine was suspended because of severe side effects like acute meningoencephalitis and cerebral hemorrhage (Rosenberg, 2005).…”

Neuroprotective Natural Products for Alzheimer’s Disease

“…One of the major focuses of drug discovery efforts in the AD area has been the development of drug candidates to regulate abnormal Aβ aggregation. Several synthetic drugs have been evaluated in clinical trials, including LY2886721 [ 113 ], AN1792 [ 114 ] and verubecestat [ 115 ], along with monoclonal antibody drugs such as donanemab, which targets Aβ 3–42 [ 116 ] and aducanumab (BIIB037), which targets a conformational epitope found on Aβ [ 117 ]. However, none of them have been successful in the treatment of AD.…”