O4-02-08: Chronic treatment with C5a antagonist decreases pathology in two mouse models of Alzheimer's disease

Inflammatory elements are prominent pathological markers of Alzheimer's Disease (AD). Complement activation has long been known to produce a local inflammatory reaction including recruitment of inflammatory phagocytes, and thus association of complement proteins and reactive glia with fibrillar amyloid plaques in later stages of development of AD is consistent with a role for this system in the acceleration or progression of inflammation in that disease. In vitro fibrillar amyloid activates both the classical and alternative complement cascades. In a mouse model of AD with a genetic deficiency of C1q we found a significantly reduced neuropathology in animals 12–18 months of age, suggesting complement dependent AD pathology in the intact animal. Since the downstream complement activation product, C5a, is known to be chemotactic for microglia and astrocytes, we chose to test whether a C5a receptor antagonist (PMX205: hydrocinnamate-[Orn-Pro-D-cyclohexylalanine-Trp-Arg]), which would not block the early complement component functions, would reduce inflammation and neuropathology. PMX 205 was administered to Tg2576 mice in the drinking water with or without biweekly subcutaneous injection. At end of treatment, animals were perfused and neuropathology was assessed by immunohistochemistry and image analysis. No signs of toxicity were detected. Immunohistochemistry and image analysis demonstrated a significant reduction in pathology in the treated animals as compared to untreated Tg2576. For example, in one set of animals treated from 12–15 months of age (n=12), fibrillar plaque (thioflavine positive) area was reduced by 53%, total amyloid (6E10) by 30% and activated microglia (CD45) by 47% compared to untreated Tg2567 (n=7). Similar decreases were seen in the triple transgenic mouse model (3xTg) after treatment with PMX205 from 17–20 months. In addition, in the 3xTg mice (that develop tangles as well as plaques), hyperphosphorylated tau (AT100) was also markedly reduced (69%, p<0.02). These data provide the first evidence that inhibition of a surface receptor mediated function of the complement cascade can have a neuroprotective effect in AD rodent models and suggests a potential novel therapy for slowing the progression of human AD.