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ORIGINAL RESEARCH article
Front. Cell. Neurosci.
Sec. Cellular Neuropathology
Volume 19 - 2025 | doi: 10.3389/fncel.2025.1571428
Chronic palmitoylethanolamide administration via slow-release subcutaneous pellets promotes neuroprotection and mitigates neuroinflammation in the Tg2576 mouse model of Alzheimer's disease
Provisionally accepted
DANIEL TORTOLANI 1
Davide Decandia 2
Giacomo Giacovazzo 1 Lucia Scipioni 3 Anna Panuccio 2 Francesca Ciaramellano 4 Fabiola Eugelio 1 Federico Fanti 1 Emanuele Claudio LaTagliata 4 Livia La Barbera 5
Debora Cutuli 2 Dario Compagnone 1
Marcello D'Amelio 5
Roberto Coccurello 6
Sergio Oddi 1
Laura Petrosini 4
Mauro Maccarrone 2*- 1 University of Teramo, Teramo, Italy
- 2 Sapienza University of Rome, Rome, Lazio, Italy
- 3 University of L'Aquila, L'Aquila, Abruzzo, Italy
- 4 Santa Lucia Foundation (IRCCS), Rome, Lazio, Italy
- 5 Campus Bio-Medico University, Rome, Lazio, Italy
- 6 National Research Council (CNR), Roma, Lazio, Italy
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive and non-cognitive decline associated with neuropathological hallmarks, including neuroinflammation. Palmitoylethanolamide (PEA), an endogenous lipid with anti-inflammatory and neuroprotective properties, has emerged as a promising therapeutic agent in managing AD. This study investigated the therapeutic effects of chronic (6-months) PEA administration via subcutaneous pellet in Tg2576 mice, a validated model of AD. The impact of PEA on amyloid precursor protein (APP) processing, astrocytic activation, microglial reactivity and neuroinflammation, nitrosative stress, dendritic spine density in hippocampal CA1 pyramidal neurons, and cognitive performance was assessed. Chronic PEA treatment of Tg2576 mice increased the expression of the α-secretase ADAM9 and reduced astrogliosis. Furthermore, PEA attenuated microglia reactivity, downregulated pro-inflammatory (CXCL13, MCP-1, GCSF) and upregulated anti-inflammatory (CXC3CL1 and IL-9) cytokine expression. Chronic PEA administration also decreased protein nitrosylation, downregulated calcineurin expression, restored dendritic spine density, and improved cognitive functions. Chronic PEA administration offers a promising therapeutic approach for AD by mitigating neuroinflammation, oxidative stress, and synaptic dysfunction, ultimately leading to cognitive function restoration.
Keywords: Alzheimer's disease, Ultramicronized palmitoylethanolamide, Oxidative Stress, Neuroinflammation, dendritic spine density, Memory
Received: 05 Feb 2025; Accepted: 07 Apr 2025.
Copyright: © 2025 TORTOLANI, Decandia, Giacovazzo, Scipioni, Panuccio, Ciaramellano, Eugelio, Fanti, LaTagliata, La Barbera, Cutuli, Compagnone, D'Amelio, Coccurello, Oddi, Petrosini and Maccarrone. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Mauro Maccarrone, Sapienza University of Rome, Rome, 00185, Lazio, Italy
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