Alzheimer's: A Nasal Spray Protects Neurons and Memory

A nasal spray containing vesicles naturally released by cells may work against Alzheimer's. This is the promise of a study conducted by researchers at the Università Cattolica, Fondazione Policlinico Universitario A. Gemelli IRCCS, and the E. Menni Research Center of the Fondazione Poliambulanza. The spray is based on extracellular vesicles derived from the amniotic membrane. The study, published in Translational Neurodegeneration (Nature press), demonstrated its ability, in an experimental model of Alzheimer's: it reaches the brain, counteracts neuroinflammation, protects neuronal function, and preserves memory. The researchers also obtained positive results on human neurons in vitro.

Researchers have demonstrated that these nanovesicles, administered intranasally to an animal model that mimics the clinical picture of Alzheimer's disease, reach the hippocampus, a brain region crucial for memory and particularly vulnerable in Alzheimer's disease. There, they enter into both neurons and microglia, cells that play an important surveillance and defense role in the brain. The beneficial effects of this treatment affect various aspects of the disease, from modulating neuroinflammation to protecting neuronal function and, in particular, synapses, the connections that ensure information transmission in neural circuits, resulting in a significant improvement in cognitive abilities. The extracellular vesicles are able to both prevent the onset of memory deficits and counteract cognitive decline once it has already occurred.

This work stems from the synergy between two lines of research developed at the Università Cattolica del Sacro Cuore, the Fondazione Policlinico Universitario A. Gemelli IRCCS, and the E. Menni Research Center of Fondazione Poliambulanza.

On the one hand, the studies of the group led by Professor Ornella Parolini, Full Professor of Applied Biology and scientific director of IRCCS Ospedale “Casa Sollievo della sofferenza”, were crucial. Parolini has been studying the placenta for many years, particularly the cells of the amniotic membrane and the set of factors these cells release—the so-called secretome—studying their protective and regenerative effects in various experimental models. The E. Menni Research Center of Fondazione Poliambulanza led by professor Parolinicontributed to this line of research, offering its expertise in the isolation and characterization of cells and the identification of the set of molecules they produce (the secretome).

The consolidated experience of the role of neuroinflammation and altered brain plasticity in neurodegenerative diseases of the group led by Professor Claudio Grassi, Professor of Physiology and Director of the Department of Neuroscience at the Università Cattolica, was crucial. Professor Salvatore Fusco, Associate Professor of Physiology, coordinates studies on the cellular and molecular mechanisms underlying the effects of extracellular vesicles in the central nervous system.

The contribution of the Fondazione Policlinico Universitario A. Gemelli IRCCS was particularly important in giving the study a translational dimension. At the Policlinico's Memory Clinic, skin biopsies were collected from patients with Alzheimer's disease and healthy subjects, from which pluripotent stem cells and, subsequently, human neurons were generated. This allowed the protective effects of the vesicles to be verified in experimental human models as well.

The study's lead authors are Drs. Andrea Papait, researcher in Cellular and Applied Biology, and Francesca Natale, researcher in Physiology, who worked to integrate these two research fields, linking the biology and immunomodulatory properties of amniotic extracellular vesicles with their effects on neuroinflammation, neuronal function, and memory.

Administered via a nasal spray formulation, the vesicles reached the hippocampus and entered into both neurons and microglia. The treatment does not simply "switch off" the immune response. Rather, it remodels the inflammatory microenvironment, modifying the functional state and morphology of microglia and creating favorable conditions for maintaining neuronal integrity and function.

The treatment's effects particularly affect molecules involved in synapse function. In the hippocampus of mice and in treated human neurons levels of proteins closely linked to neuronal plasticity increased, as well as the efficiency of synaptic transmission, and memory processes.

These data therefore indicate a clear correlation between the modulation of brain inflammation and the restoration of molecular conditions favorable to the function of neuronal networks. Indeed, the effects observed at the cellular and molecular levels were associated with improved cognitive performance, assessed through tests of recognition memory, spatial memory, and working memory.

Professor Fusco explains: "The study suggests the need to direct research into Alzheimer's therapies by focusing not only on counteracting the accumulation of toxic compounds like beta-amyloid and tau, but also by paying close attention to the cellular environment in which neurons live (e.g., microglia and astrocytes) and the molecular signals (e.g., cytokines or microRNAs) exchanged by these cells, which can influence synapse function”.

Professor Grassi concludes: “These are preclinical results that require further validation in humans and do not yet represent an available therapy for Alzheimer's disease, but they point to a very promising direction: understanding whether some of the mechanisms through which the placenta naturally regulates inflammation and protects tissues could offer new tools for the treatment of neurodegenerative diseases and, more generally, whether the use of extracellular vesicles represents a new frontier for the treatment of neurological diseases”.

(Newswise/MF)