P‐168: Implication of neuroinflammatory reaction in the development of Alzheimer's disease

Background: Alzheimer’s disease (AD) is characterized by the extracellular deposition of beta-amyloid peptide (A ) fibrils and is accompanied by extensive loss of neurons in the brain of affected individuals. Inflammation has been argued to play a role in the pathogenesis of AD. The evidence supporting this view came from studies reporting the presence of inflammatory mediators in AD lesions and the effect of Non-Steroidal AntiInflammatory Drugs (NSAIDS) on AD. There were also epidemiological and genentic evidences which show that an inflammatory process contributes to AD pathology. Objective(s): We studied to establish a convincing theoretical link between neuroinflammatory process and amyloidogenesis, vital process in AD development. Methods: Memory impairment was determined by passive avoidance and water maze tests after mice were injected intraperitoneally and intracerebroventricularly with lipopolysaccharide (LPS). Activities of and -secretase were assessed by using commercially available assay kit, and expression of amyloidogenic proteins (APP, BACE, C99) was detected by Western blotting using specific antibodies. Accumulation and level of A 1-42 were assessed by immunohistochemistry and specific A 1-42 ELISA kit, respectively. Moreover, astrocytes and neuronal cells were isolated from rat brain for in vitro study. Results: Injection of LPS induced memory impairment determined by passive avoidance (Figure 1A) and water maze tests (Figure 1B) in mice. Consistent with memory impairment, LPS increased and -secretase activities as well as the expression of amyloid precursor protein (APP), 99-residue carboxy-terminal fragment of APP (C99) and A 1-42, critical components in the development of AD, in cortex and hippocampus. Moreover, repeated dosing of LPS resulted in an accumulation of A 1-42 in the mice brain (Figure 2). The expression of amyloidogenic proteins was increased by increased inflammatory reactions in astrocytes and neuronal cells. Furthermore, anti-inflammatory agents suppressed the LPS-induced amyloidogenesis and improved LPS-induced memory impairment. It was also found that expression of inflammatory marker proteins was co-elevated with A accumulation in the brain of AD animal model. Conclusions: This study suggests that neuroinflammatory reaction could contribute to AD pathology, and anti-inflammatory agent could be useful for prevention of AD. P-169 ASSOCIATION BETWEEN STATINS AND RISK OF AD IS AGE DEPENDENT