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Inflammatory Responses to Amyloidosis in a Transgenic Mouse Model of Alzheimer’s Disease

https://doi.org/10.1016/S0002-9440(10)64085-0Get rights and content

Mutations in the amyloid precursor protein (APP) and presenilin-1 and -2 genes (PS-1, -2) cause Alzheimer’s disease (AD). Mice carrying both mutant genes (PS/APP) develop AD-like deposits composed of β-amyloid (Aβ) at an early age. In this study, we have examined how Aβ deposition is associated with immune responses. Both fibrillar and nonfibrillar Aβ (diffuse) deposits were visible in the frontal cortex by 3 months, and the amyloid load increased dramatically with age. The number of fibrillar Aβ 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 1q, an immune response component, strongly colocalized with fibrillar Aβ, but was also up-regulated in some plaque-associated microglia. These results show: i) an increasing proportion of amyloid is composed of fibrillar Aβ in the aging PS/APP mouse brain; ii) microglia and astrocytes are activated by both fibrillar and diffuse Aβ; and iii) cyclooxygenase-2 and complement component 1q levels increase in response to the formation of fibrillar Aβ in PS/APP mice.

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Supported by National Institutes of Health grants NIH AG-16573 (to A. J. T.), NIH AG-172116 (to K. D.), and NS 33553 (to M. K. O.).

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