| Brain inflammation is a hallmark of Alzheimer's Disease (AD) neuropathology. This involves microglial activation which has been well characterized around fibrillar plaques in humans and in transgenic mouse models. Plaques are initiated by the accumulation of Aβ1-42 (beta-amyloid) which is a highly aggregating, neurotoxic protein derived from alternative processing of APP (amyloid precursor protein). Genetic factors involved in influencing the intensity of an inflammatory response have been shown clearly in other pathologies but not in AD. Therefore, an in vitro model of microglial activation by Aβ1-42, was developed using mouse strains having a low (A/J) or high (C57BL/6) inflammatory response. Interferon-γ-primed C57BL/6 microglia underwent morphological changes from resting (ramified) morphology to activated (ameboid) morphology, increases in nitric oxide (NO) production, and very high levels of tumor necrosis factor α (TNF-α) when stimulated with Aβ1-42. On the other hand, A/J microglia underwent few morphological changes, had increased levels of NO and had minimal increases in TNF-α levels when submitted to the same treatment. Thus, microglial activation to Aβ1-42 was influenced by the magnitude in inflammatory response which may be determined by genetic factors. The timing of an inflammatory response in the process of Aβ deposition is still under debate. Therefore, to define the kinetics of the inflammatory response in brain amyloidogenesis, TgCRND8 mice which overexpress hAPP and aggressively develop amyloidosis, were used to characterize the evolution of diffuse and fibrillar plaque formation and gliosis. Histopathological analysis revealed diffuse plaques as early as 12 weeks of age. Fibrillar (senile) plaques and microgliosis were seen at 13 weeks of age whereas astrocytic clustering began at 14–15 weeks of age. Microglial activation was found to be correlated strongly to Aβ deposition and fibrillar plaque formation. Therefore, the early appearance of the inflammatory response to Aβ deposition in brain amyloidosis suggests that microglia contribute to Aβ deposition or clearance. To determine whether the variations in inflammatory response to Aβ occur in vivo, TgCRND8 mice were backcrossed onto mice with low (A/J) or high (C57BL/6) inflammatory responses. These mice did not differ in their hAPP mRNA expression, Aβ load, and ratio of Aβ 1-42/Aβ1-40. However, immunohistochemical analysis showed more Aβ deposition, plaque burden, and lower survival in CRND8.B6 mice compared to CRND8.AJ mice. Hence, genetic factors, possibly related to inflammatory response, can influence the rate of brain amyloidosis. This delineates the need for individual therapy to regulate the inflammatory response in AD patients. |
