According to the
amyloid hypothesis, in the early phases of Alzheimer’s
disease (AD), small soluble prefibrillar aggregates of the amyloid
β-peptide (Aβ) interact with neuronal membranes, causing
neural impairment. Such highly reactive and toxic species form spontaneously
and transiently in the amyloid building pathway. A therapeutic strategy
consists of the recruitment of these intermediates, thus preventing
aberrant interaction with membrane components (lipids and receptors),
which in turn may trigger a cascade of cellular disequilibria. Milk
αs1-Casein is an intrinsically disordered protein
that is able to inhibit Aβ amyloid aggregation in vitro, by sequestering transient species. In order to test αs1-Casein as an inhibitor for the treatment of AD, it needs
to be delivered in the place of action. Here, we demonstrate the use
of large unilamellar vesicles (LUVs) as suitable nanocarriers for
αs1-Casein. Proteo-LUVs were prepared and characterized
by different biophysical techniques, such as multiangle light scattering,
atomic force imaging, and small-angle X-ray scattering; αs1-Casein loading was quantified by a fluorescence assay. We
demonstrated on a
C. elegans
AD model the effectiveness of the proposed delivery strategy in vivo. Proteo-LUVs allow efficient administration of the
protein, exerting a positive functional readout at very low doses
while avoiding the intrinsic toxicity of αs1-Casein.
Proteo-LUVs of αs1-Casein represent an effective
proof of concept for the exploitation of partially disordered proteins
as a therapeutic strategy in mild AD conditions.