A scFv antibody targeting common oligomeric epitope has potential for treating several amyloidoses

Abstract

Overproduction or poor clearance of amyloids lead to amyloid aggregation and even amyloidosis development. Different amyloids may interact synergistically to promote their aggregation and accelerate pathology in amyloidoses. Amyloid oligomers assembled from different amyloids share common structures and epitopes, and are considered the most toxic species in the pathologic processes of amyloidoses, which suggests that an agent targeting the common epitope of toxic oligomers could provide benefit to several amyloidoses. In this study, we firstly showed that an oligomer-specific single-chain variable fragment antibody, W20 simultaneously improved motor and cognitive function in Parkinson’s disease and Huntington’s disease mouse models, and attenuated a number of neuropathological features by reducing α-synuclein and mutant huntingtin protein aggregate load and preventing synaptic degeneration. Neuroinflammation and oxidative stress in vivo were also markedly inhibited. The proposed strategy targeting the common epitopes of amyloid oligomers presents promising potential for treating Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, and other amyloidoses.

Vaccines targeting the primary amino acid sequence and conformational epitope of amyloid‐β had distinct effects on neuropathology and cognitive deficits in EAE/AD mice

“…Therefore, oligomer‐specific epitopes have become promising targets of immunotherapeutic interventions in AD (Guerrero‐Munoz, Castillo‐Carranza, & Kayed, 2014). Indeed, our previous reports and the results of the present study demonstrated that oligomer‐specific vaccines and antibodies significantly reduced brain pathology and prevented cognitive deficits in models of AD in mice (Wang et al, 2017; Zha et al, 2016; Zhao et al, 2014).…”

“…The Morris water maze (MWM) consisted of a pool (110 cm in diameter) containing opaque water (22 ± 1°C) and a platform (10 cm in diameter) submerged 1 cm under the water (Zha et al, 2016). Hidden platform training was conducted twice per day for five consecutive days with an inter‐trial interval of 3–4 hr.…”

Antibodies against alpha‐synuclein: tools and therapies

“…, ) Recently, scFv W20 that recognizes various oligomers targeting the common epitopes of amyloid oligomers was found to reduce α‐syn and mutant huntingtin protein aggregate load in mouse models, leading to reduced synaptic degeneration, neuroinflammation, and oxidative stress, concomitant with amelioration of cognitive and motor deficits (Zha et al . ). Spencer et al .…”

“…These scFv recognized amyloid oligomers in all types of plaques, Lewy bodies, and amylin deposits in the brain tissues of AD and PD patients and in the pancreas of type 2 diabetes patients ). Other scFv antibodies, including 10H and D5, were found to recognize morphologically distinct a-syn oligomers and selectively bind to aggregates in post-mortem human PD brain tissues and inhibit toxicity in a cell model (Emadi et al 2007(Emadi et al , 2009 Recently, scFv W20 that recognizes various oligomers targeting the common epitopes of amyloid oligomers was found to reduce a-syn and mutant huntingtin protein aggregate load in mouse models, leading to reduced synaptic degeneration, neuroinflammation, and oxidative stress, concomitant with amelioration of cognitive and motor deficits (Zha et al 2016). Spencer et al (2014) fused the scFv fragment, targeting oligomeric a-syn, to low-density lipoprotein receptor-binding domain from apolipoprotein B, improving its therapeutic potential by increasing accumulation of scFv in the brain and directing scFv/a-syn complexes for degradation through the endosomal sorting pathway (Spencer et al 2014).…”

Superparamagnetic Iron Oxide Nanoparticles Conjugated with Aβ Oligomer-Specific scFv Antibody and Class A Scavenger Receptor Activator Show Therapeutic Potentials for Alzheimer’s Disease

“…ROS assay was performed as previously described [31]. Brie y, ROS production was uorometrically monitored using 2, 7-dichloro uorescein diacetate (DCFDA) mixed with the brain lysates.…”