A nanomedicine-based therapeutic approach restores memory and ameliorates amyloid pathology in Alzheimer's mouse models

Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by deposition of the β-amyloid (Ab) peptide in the brain. Although many Ab-centric therapies have been attempted, they all failed and no efficacious therapy is available yet. Objectives. Main objectives of this study were to investigate the efficacy of multifunctional liposomes (Lip), designed to target the brain, to 1. promote disaggregation of brain Ab assemblies in AD mouse brain, 2. reduce brain Ab burden and 3. restore mouse memory, at a post-symptomatic stage. 4. Arrest pathology progression at a presymptomatic stage. Methods. Functionalized Lip with a peptide derived from apolipoprotein-E receptorbinding domain (mApoE) for blood-brain barrier targeting, and with phosphatidic acid (PA) for Ab binding (mApoE-PA-Lip) were administered (I.P.) for 3 weeks in post- and 4 months in pre-symptomatic APP/PS1 mice subsequently tested in the novel object recognition memory test (NORT). At the end mouse brains were collected and analyzed through histology and biochemistry for Ab deposition. Results. Administration of mApoE-PA-Lip decreased total insoluble brain Ab1-42, total plaque area and Ab oligomers. Plaque reduction was confirmed by PET imaging with [11C]-PIB. The reduction of brain Ab was associated with its increase in liver and spleen. Treatment also restored mouse impaired memory to normal at post-symptomatic ages and prevented its loss when administered at pre-symptomatic ages. Conclusions. These data suggest that bi-functionalized Lip destabilize brain Ab aggregates and promote peptide removal from the brain and its peripheral clearance. This innovative therapeutic approach can be considered as a new candidate for AD treatment.