P1‐157: Increased TLR8 and 9 Expression Correlates with Preserved Hyppocampal Volumes and Lack of Progression to Alzheimer's Disease in Individuals with A Diagnosis of Mild Cognitive Impairment

Mild cognitive impairment (MCI) is widely accepted as an intermediate state between the lack of pathologic cognitive impairment and Alzheimer’s disease (AD). Only a percentage of MCI individuals, nevertheless, progresses to AD. Amyloid theory, alterations of the blood-brain barrier and neuroinflammation seem to play an important role in AD neurodegeneration; pathogens infection, and in particular herpes simplex virus (HSV) infection, is also suggested to be involved in the pathogenesis of AD. The innate immune response to pathogens is triggered by the ligation of toll like receptors (TLR) on the surface of cells. We recently described that TLR expression is significantly upregulated in MCI compared to AD individuals, suggesting that the ability of MCI individual to mount stronger innate immune responses against pathogens is impaired in AD. We examined TLR expression and cytokine production in 46 individuals with a diagnosis of MCI who did (progressors) or did not (non progressors) progress to AD over a 24 months’ time period. TLRs expression (upon TLRs agonists-stimulation) and cytokine production (upon Ab1-42 stimulation) was measured at baseline in CD14+ immune cells of 46 MCI individuals who did (N=25) or did not (N=2) progress to AD using Flow Cytometry. ApoE4 status and hippocampus left and right volumes (using NMR tecniques) were analyzed as well in all individuals. Results of analysed performed at baseline, when all individuals were clinically classified as MCI, in non-progressors compared to progressors: 1) TLR8 and TLR9 expression on CD14+ cells was significantly upregulated (p= 0.0008 and 0.05 respectively); 2) Ab-stimulated production of the pro-inflammatory cytokines IL-6, TNFa, IL-1b by CD14+ cells was significantly reduced (p<0.05); and 3) left and right hyppocampal volumes were better preserved (p<0.05). No differences were detected in the ApoE4 status. The expression of TLR8 and TLR9, two receptors that activated by viral replication by-products, is significantly increased in MCI individuals who do not progress to AD. This correlates with better preserved hyppocampal volumes, suggesting that the ability to mount stronger antiviral responses is associated with protection against AD. The reduced production of proinflammatory cytokines is in apparent contrast with TLR results and needs to be further analyzed.