TOLL-LIKE RECEPTORS AND ALZHEIMER'S DISEASE: A THERAPEUTIC PERSPECTIVE

Microglia play opposing roles in Alzheimer's disease (AD) pathogenesis: in early stage they exert neuroprotection mediated through amyloid-beta (Ab) phagocytosis, while as the disease progresses, they fail in Ab clearance and induce neuroinflammation and neurodegeneration. Both Ab-clearance and inflammation are TLR-mediated: specific TLRs promote Ab clearance in the early stage, while the same TLRs chronically activated by accumulated Ab and tau proteins initiate a pro-inflammatory cascade leading to degenerative changes to neurons. These current knowledges allow to select specific immunomodulators, to treat the different stages of AD. Neutralizing antibodies to block TLR-mediated inflammation might be considered an interesting approach for TLRs expressed on the cell surface. Small-molecule antagonists such as eritoran against TLR4 might represent a better prospect, although these might also be amenable to inhibition by kinases present on the signaling pathways. Innovative antibody-derived molecules able to cross the blood brain barrier stimulating or inhibiting also TLRs expressed by microglia, then exerting their effects on CNS directly, are the nanobodies, that represent a promising approach, since they exhibit high affinity, have the potential to be given to patients as an inhaled drug, a skin patch or a pill. Recently, small interfering RNAselective compounds has become more straightforward because of the significant progress made in predictive modeling for new therapeutic approaches. Modulation of TLR expression with small molecules acting as TLR-agonists/antagonists might represent an alternative approach in AD therapy.Moreover, these TLR-targeting drugs have fewer side effects and lower or no toxicity compared to drugs commonly used in AD treatment.