title: Toll-like receptors in Alzheimer's disease: a therapeutic perspective.
abstract: Alzheimer's disease (AD) is a neurodegenerative disorder mainly characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, loss of synapses and neurons and chronic neuroinflammation. Emerging data highlight the involvement of innate immunity, that has been shown to play opposing roles during the AD progression. Activated microglia and reactive astrocytes exert neuroprotection mediated through Aβ phagocytosis in the early stage, whereas, as the disease progresses, they fail in Aβ clearance and exert detrimental effects, including neuroinflammation and neurodegeneration. Specific toll-like receptors (TLRs) and coreceptors can directly or indirectly be activated to induce Aβ uptake or inflammatory responses, depending on the disease stage. Fibrillar Aβ can directly interact with TLR2, TLR4, and CD14 to induce microglial Aβ phagocytosis in the beginning stages, and neuroinflammatory responses in the late stages. Early TLR3-mediated signal enhances neuronal Aβ autophagy, although it increases neuronal apoptosis in the late AD stage. Similarly, TLR7, TLR8 and TLR9 can enhance microglial Aβ uptake in the early stage, but over time they contribute to neuroinflammation. Therefore, TLRs, and in particular TLR2 and TLR4, represent a suitable target for therapeutic intervention within the disease progression and targeting them carefully could increase Aβ autophagy and phagocytosis or reduce inflammatory responses. Several modulators with selective TLR agonist or antagonist activity have been developed, and many of them could have a therapeutic benefit in AD patients. This paper outlines the role of specific TLRs in AD, also focusing on TLR-targeted compounds yet indicated for the treatment of other inflammatory diseases, that could be used to treat the different stages of the disease.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Gambuzza
authors.forename: Vincenza
authors.initials: V
authors.lastname: Sofo
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Salmeri
authors.forename: Luca
authors.initials: L
authors.lastname: Soraci
authors.forename: Silvia
authors.initials: S
authors.lastname: Marino
authors.affiliation: Ministry of Health, Territorial Office of Messina, Italy. gambuzza2002@yahoo.it.
authors.forename: Placido
authors.initials: P
authors.lastname: Bramanti
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D006801:Humans; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D014150:Antipsychotic Agents; D051193:Toll-Like Receptors