Search

Alzheimer’s disease (AD) is currently constrained by limited clinical treatment options. The initial pathophysiological event, which can be traced back to decades before the clinical symptoms become apparent, involves the excessive accumulation of amyloid-beta (Aβ), a peptide comprised of 40–42 amino acids, in extraneuronal plaques within the brain. Biochemical and histological studies have shown that overaccumulation of Aβ instigates an aberrant escalation in the phosphorylation and secretion of tau, a microtubule-binding axonal protein. The accumulation of hyperphosphorylated tau into intraneuronal neurofibrillary tangles is in turn correlated with microglial dysfunction and reactive astrocytosis, culminating in synaptic dysfunction and neurodegeneration. As neurodegeneration progresses, it gives rise to mild clinical symptoms of AD, which may eventually evolve into overt dementia. Synaptic loss in AD may develop even before tau alteration and in response to possible elevations in soluble oligomeric forms of Aβ associated with early AD. These findings largely rely on post-mortem autopsy examinations, which typically involve a limited number of patients. Over the past decade, a range of fluid biomarkers such as neurogranin, α-synuclein, visinin-like protein 1 (VILIP-1), neuronal pentraxin 2, and β-synuclein, along with positron emission tomography (PET) markers like synaptic vesicle glycoprotein 2A, have been developed. These advancements have facilitated the exploration of how synaptic markers in AD patients correlate with cognitive impairment. However, fluid biomarkers indicating synaptic loss have only been validated in cerebrospinal fluid (CSF), not in plasma, with the exception of VILIP-1. The most promising PET radiotracer, [11C]UCB-J, currently faces significant challenges hindering its widespread clinical use, primarily due to the necessity of a cyclotron. As such, additional research geared toward the exploration of synaptic pathology biomarkers is crucial. This will not only enable their extensive clinical application, but also refine the optimization process of AD pharmacological trials.

Brain drug delivery is hampered by the presence of the blood brain barrier and nanocarriers, administered by intranasal route, could represent an alternative and efficient strategy to improve drug localization in the Central Nervous System (CNS). The aim of this work is to design and characterize non-ionic surfactant vesicles (NSVs) and perfluorocarbon gas non-ionic surfactant based nanobubbles (VNBs) suitable for Nose to Brain Delivery (N2B). In particular, Pluronic F127, Span 85 and cholesterol have been employed to prepare NSVs and VNBs. Both systems have been characterized in terms of (a) hydrodynamic diameter, ζ-potential and morphology (b) vesicle bilayer feature (anisotropy), (c) physical-chemical stability and (d) fluorescent model probe release capability. VNBs have been also studied in terms of gas entrapment and acoustic efficiency. In addition, in order to understand optimal ultrasound (US) parameters to obtain in vitrostable cavitation, the acoustic pressure effect on VNBs fluorescent probes release kinetics was evaluated. The obtained results suggest that NSVs and VNBs show a hydrodynamic diameter suitable for N2B delivery. Moreover, in this study, we develop a new kind of protocol to evaluate an in vitroUS characterization of VNBs and our data suggest a stable and controlled probe release, encouraging the possibility to deliver VNBs in mixture with NSVs loaded neuroprotective drugs for brain delivery coupled to US obtaining stable cavitation. In this context, extracellular field recordings in specific area of hippocampus (CA1-CA3) have been carried out in order to assure that empty NSVs do not affect synaptic plasticity in the form of long-term potentiation, a molecular mechanism which underlies learning and memory.