Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer's disease

Mutations in the amyloid precursor protein (APP) and presenilin-1 and -2 genes (PS-I, -2) cause Alzheimer's disease (AD), Mice carrying both mutant genes (PS/APP) develop AD-like deposits composed of beta -amyloid (A beta) at an early age. In this study, we have examined how A beta deposition is associated with immune responses. Both fibrillar and nonfibrillar A beta (diffuse) deposits were visible in the frontal cortex by 3 months, and the amyloid load increased dramatically with age. The number of fibrillar A beta deposits increased up to the oldest age studied (2.5 years old), whereas there were less marked changes in the number of diffuse deposits in mice over 1 year old. Activated microglia and astrocytes increased synchronously with amyloid burden and were, in general, closely associated with deposits. Cyclooxygenase-2, an inflammatory response molecule involved in the prostaglandin pathway, was up-regulated in astrocytes associated with some fibrillar deposits. Complement component Iq, an immune response component, strongly colocalized with fibrillar A beta, but was also up-regulated in some plaque-associated microglia These results show: i) an increasing proportion of amyloid is composed of frbrillar A beta in the aging PS/APP mouse brain; ii) microglia and astrocytes are activated by both fibrillar and diffuse A beta; and iii) cyclooxygenase-a and complement component 1q levels increase in response to the formation of fibrillar A beta in PS/APP mice.