Affiliations: [a] Laboratório de Farmacologia e Terapêutica Experimental/IBILI, Faculdade de Medicina da Universidade de Coimbra, Portugal
| [b] CNC.IBILI – Universidade de Coimbra, Coimbra, Portugal
| [c]
Centro Hospitalar do Porto, Largo Prof. Abel Salazar, Porto, Portugal
| [d]
Instituto Politécnico de Coimbra, ESTESC-Coimbra Health School, Farmácia, Portugal
| [e] Instituto de Imunologia, Faculdade de Medicina da Universidade de Coimbra, Portugal
| [f] Laboratório de Imunologia e Oncologia, Centro de Neurociências e Biologia Celular, Universidade de Coimbra, Portugal
Correspondence:
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Correspondence to: Frederico C. Pereira, PhD, Laboratory of Pharmacology and Experimental Therapeutics, IBILI, Faculty of Medicine, University of Coimbra, Subunit 1- Polo 3, Azinhaga de Santa Comba, Celas, 3000-548 Coimbra, Portugal. Tel.: +351 239 480071; Fax: +351 239 480065; E-mail: [email protected].
Abstract: Neuroinflammation is a two-edged sword in Alzheimer’s disease (AD). A certain degree of neuroinflammation is instrumental in the clearance of amyloid-β (Aβ) peptides by activated microglia, although a sustained neuroinflammation might accelerate Aβ deposition, thus fostering the neurodegenerative process and functional decline in AD. There is an increasing body of evidence suggesting that the innate immune system via Toll-like receptor 4 (TLR4) finely orchestrates the highly regulated inflammatory cascade that takes place in AD pathology. Herein we critically review pre-clinical (in vitro and in vivo approaches) and clinical studies showing that monophosphoryl lipid A (MPL), a partial TLR4 agonist, may have beneficial effect on AD physiopathology. The in vivo data elegantly showed that MPL enhanced Aβ plaque phagocytosis thus decreasing the number and the size of Aβ deposits and soluble Aβ in brain from APPswe/PS1 mice. Furthermore, MPL also improved their cognition. The mechanism underlying this MPL effect was proposed to be microglial activation by recruiting TLR4. Additionally, it was demonstrated that MPL increased the Aβ antibody titer and showed a safe profile in mice and primates, when used as a vaccine adjuvant. Clinical studies using MPL as an adjuvant in Aβ immunotherapy are currently ongoing. Overall, we argue that the TLR4 partial agonist MPL is a potentially safe and effective new pharmacological tool in AD.
Keywords: Alzheimer’s disease, monophosphoryl lipid A, neuroinflammation, toll-like receptor
