AmyP53, a Therapeutic Peptide Candidate for the Treatment of Alzheimer’s and Parkinson’s Disease: Safety, Stability, Pharmacokinetics Parameters and Nose-to Brain Delivery

Coralie Di Scala (1) , Nicholas Armstrong (2, 3) , Henri Chahinian (4) , Eric Chabrière (2, 3) , Jacques Fantini (5) , Nouara Yahi (4)

1 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
2 MEPHI - Microbes évolution phylogénie et infections
3 IHU Marseille - Institut Hospitalier Universitaire Méditerranée Infection
4 UNIS - Inserm U1072 - Unité de Neurobiologie des canaux Ioniques et de la Synapse
5 UNIS - Unité de Neurobiologie des canaux Ioniques et de la Synapse

Neurodegenerative disorders are a major public health issue. Despite decades of research efforts, we are still seeking an efficient cure for these pathologies. The initial paradigm of large aggregates of amyloid proteins (amyloid plaques, Lewis bodies) as the root cause of Alzheimer’s and Parkinson’s diseases has been mostly dismissed. Instead, membrane-bound oligomers forming Ca2+-permeable amyloid pores are now considered appropriate targets for these diseases. Over the last 20 years, our group deciphered the molecular mechanisms of amyloid pore formation, which appeared to involve a common pathway for all amyloid proteins, including Aβ (Alzheimer) and α-synuclein (Parkinson). We then designed a short peptide (AmyP53), which prevents amyloid pore formation by targeting gangliosides, the plasma membrane receptors of amyloid proteins. Herein, we show that aqueous solutions of AmyP53 are remarkably stable upon storage at temperatures up to 45 °C for several months. AmyP53 appeared to be more stable in whole blood than in plasma. Pharmacokinetics studies in rats demonstrated that the peptide can rapidly and safely reach the brain after intranasal administration. The data suggest both the direct transport of AmyP53 via the olfactory bulb (and/or the trigeminal nerve) and an indirect transport via the circulation and the blood–brain barrier. In vitro experiments confirmed that AmyP53 is as active as cargo peptides in crossing the blood–brain barrier, consistent with its amino acid sequence specificities and physicochemical properties. Overall, these data open a route for the use of a nasal spray formulation of AmyP53 for the prevention and/or treatment of Alzheimer’s and Parkinson’s diseases in future clinical trials in humans.

Mots clés: Alzheimer’s; Parkinson’s; therapy; peptide; ganglioside; amyloid pore

Domaines: Sciences du Vivant [q-bio]

Coralie Di Scala, Nicholas Armstrong, Henri Chahinian, Eric Chabrière, Jacques Fantini, et al.. AmyP53, a Therapeutic Peptide Candidate for the Treatment of Alzheimer’s and Parkinson’s Disease: Safety, Stability, Pharmacokinetics Parameters and Nose-to Brain Delivery. International Journal of Molecular Sciences, 2022, 23 (21), pp.13383. ⟨10.3390/ijms232113383⟩. ⟨hal-03951655⟩