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The treatment of diseases that affect the central nervous system (CNS) represents a great research challenge due to the restriction imposed by the blood&ndash, brain barrier (BBB) to allow the passage of drugs into the brain. However, the use of modified nanomedicines engineered with different ligands that can be recognized by receptors expressed in the BBB offers a favorable alternative for this purpose. In this work, a BBB-penetrating peptide, angiopep-2 (Ang&ndash, 2), was conjugated to poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles through pre- and post-formulation strategies. Then, their ability to cross the BBB was qualitatively assessed on an animal model. Proof-of-concept studies with fluorescent and confocal microscopy studies highlighted that the brain-targeted PLGA nanoparticles were able to cross the BBB and accumulated in neuronal cells, thus showing a promising brain drug delivery system.

The accumulation of amyloid &beta, (A&beta, ) triggers a cascade of toxic events in Alzheimer&rsquo, s disease (AD). The KLVFF peptide can interfere with A&beta, aggregation. However, the peptide suffers from poor bioavailability and the inability to cross the blood&ndash, brain barrier. In this work, we study the possibility of adopting nanomedicine to overcome KLVFF limits in biodistribution. We produced new engineered polymeric nanoparticles (NPs), and we evaluated the cellular toxicity of these NPs and validated that KVLFF peptides released by NPs show the same promising effects on AD pathology. Our results revealed the successful generation of KVLFF loaded NPs that, without significant effects on cell heath, are even more potent in reversing A&beta, induced pathologies compared to the free peptide. Therefore, NPs will significantly advance KVLFF treatment as a therapeutic option for AD.

Intracellular Aβ (iAβ) expression, extracellular Aβ (eAβ) plaque formation and microglial reactivity are characteristic neuropathological events of Alzheimer's disease (AD) and have been detected in several transgenic mouse models of this disease. In this work we decided to investigate the early (2-7 months of age) development of these phenomena at both regional and cellular levels in 5XFAD mice, a severe transgenic mouse model of AD. We demonstrated that 1) Aβ pathology develops in many but not all brain regions, 2) iAβ is transient and almost always followed by eAβ in grey matter regions, and the respective levels are roughly proportional, and 3) in about 1/3 of the grey matter regions with Aβ pathology and in several white matter regions, eAβ plaques can appear where no iAβ-positive structures were detected. We also showed that male and female mice share a similar regional and cellular pattern of Aβ pathology development that is more prominent in females. Early iAβ is associated to the activation of microglia, while subsequent formation of eAβ plaques is associated with markedly increased density of microglial cells that acquire a characteristic clustered phenotype. Present analysis is relevant to set a reference for pathophysiological studies and to define specific targets for the test of therapeutic interventions in this widely used AD transgenic model.