Multifunctional Liposomes Increase Synaptic Transmission Strength in Mouse Cortical Neurons

Alzheimer’s disease (AD) is characterized by the accumulation of plaques of β-amyloid (Aβ) peptide in the brain. Given its pivotal role, new nanotechnological therapeutic tools targeting Aβ are in demand. For this purpose, we synthesized bifunctional liposomes (mApoE-PA-LIP) with a peptide derived from the apolipoprotein-E receptor-binding domain (mApoE) for blood–brain barrier (BBB) targeting and with phosphatidic acid (PA) for Aβ binding. Our previous results indicate that mApoE-PA-LIP can destabilize brain Aβ aggregates and promote peptide removal across the BBB and its peripheral clearance both in vitro and in vivo models with memory improvement. We firstly evaluated the impact of mApoE-PA-LIP on intracellular Ca2+ dynamics in hCMEC/D3, as an in vitro human BBB model, and in cultured astrocytes, that are both among the main components of the neurovascular unit. Our results show that the mApoE-PA-LIP pre-treatment increases the ATP-evoked intracellular Ca2+ waves, both in the presence and absence of extracellular Ca2+, indicating that this effect is mainly due to endogenous Ca2+ release from endoplasmic reticulum (ER). Indeed, blocking Sarco-ER Ca2+ ATPase (SERCA) activity with cyclopiazonic acid, ATP failed to trigger any intracellular Ca2+ waves, indicating that metabotropic purinergic receptors (P2Y) are mainly involved. So, we assessed whether mApoE-PA-LIP can modulate the neuronal synaptic transmission in the cortical area. For this purpose, we performed electrophysiological recordings, using the whole-cell patch-clamp technique, on mouse brain slices. We evaluated inward and outward total currents, firing pattern, spontaneous excitatory post-synaptic currents (sEPSCs) frequency, and amplitude before and after the perfusion with mApoE-PA-LIP. Our preliminary data suggest that mApoE-PA-LIP trigger an increase of sEPSCs frequency. The results here outlined could give additional support to promote mApoE-PA-LIP as a putative therapeutic tool for AD treatment.