Plant-based chimeric HPV-virus-like particles bearing amyloid-β epitopes elicit antibodies able to recognize amyloid plaques in APP-tg mouse and Alzheimer’s disease brains

Abstract

The main amyloid-beta (Aβ) variants detected in the human brain are full-length Aβ1-40 and Aβ1-42 peptides; however, a significant proportion of AD brain Aβ consists also of N-terminal truncated/modified species. The majority of the previous immunotherapeutic strategies targeted the N-terminal immunodominant epitope of the full-length Aβ; however, most of the pathological N-truncated forms of Aβ lack this critical B cell epitope. Recently, virus-like particles (VLPs), self-assembled structures with highly ordered repetitive patterns on their surface and capable of inducing robust immune responses, were applied as a promising platform for various antigen expressions. In this study, we expressed in plants two chimeric HPV16 L1 capsid proteins obtained by introduction of the β-amyloid 11-28 epitope (Aβ 11-28) into the h4 helix or into the coil regions of the L1 protein. The Aβ 11-28 epitope was chosen because it is present in the full-length Aβ 1-42 as well as in the truncated/modified amyloid peptide species. After expression, we assembled the chimerical L1/Aβ 11-28 into a VLP in which the Aβ 11-28 epitope is exposed at very high density (360 times) on the surface of the VLP. The chimeric VLPs elicited in mice Aβ-specific antibodies binding to β-amyloid plaques in APP-tg mouse and AD brains. Our study is the first to demonstrate a successful production in plants and immunogenic properties in mice of chimeric HPV16 L1 VLPs bearing Aβ epitope that may be of potential relevance for the development of multivalent vaccines for a multifactorial disease such as AD.

Plant Viruses and Bacteriophage-Based Reagents for Diagnosis and Therapy

“…In the context of neurological disorders, a VLP based on HPV displaying the β-amyloid 11-28 epitope (Aβ 11-28) was recently used as a multivalent scaffold to develop a candidate vaccine against a mouse model of Alzheimer's disease. The chimeric VLP elicited Aβ-specific antibodies that bound to βamyloid plaques in a mouse model (172). In other examples, a cucumber mosaic virus (CuMV)-based vaccine displaying recombinant nerve growth factor (NGF) generated antibodies against NGF, a key factor underlying the chronic pain associated with osteoarthritis.…”

Current Advances of Plant-Based Vaccines for Neurodegenerative Diseases

“…The L1 protein is a popular VLP and one of the major capsid proteins of HPV; hence, it was used for plant expression of the Aβ11-28 epitope, which is present in both the full-length and modified species of Aβ1-42. The abovementioned epitope was inserted simultaneously in the h4 helix and in the coil region of the VLP, yielding two chimeric molecules (VLP-L1a and VLP-L1b) [ 100 ]. Both vectors were successfully transformed in plants, as reported by Uribe-Campero et al [ 101 ] in N .…”

“…Overall, this report demonstrates the successful plant-based production of a prospective vaccine that does not require adjuvants to induce robust immunogenic properties, since the VLP itself has adjuvating properties. Indeed, the use of VLP as a carrier for an Aβ epitope showed relevant insights into the design of plant-made vaccines for AD [ 100 ].…”

Expression of Chimeric HPV-HIV Protein L1P18 in Pichia pastoris; Purification and Characterization of the Virus-like Particles

“…HPV genotype 16 L1 is the major structural protein of the virus capsid. Five of the L1 proteins form a pentamer and 72 of the pentamers self-assemble into a VLP [30][31][32]. HPV L1 VLPs have been already used as HPV vaccines and the vaccinations led to the stimulation of humoral immune responses [33][34][35].…”