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From the Dementia Research Group,*
Nathan Kline
Institute/New York University Medical Center, Orangeburg, New York; the
Mayo Clinic,
Jacksonville, Florida; the
Department of Neurobiology and Anatomy,
University of Rochester Medical Center, Rochester, New York; the
Department of Molecular Biology and
Biochemistry,§
University of California,
Irvine, California; and the Center for Neurologic
Diseases,¶
Brigham and Women’s Hospital, Harvard
Institutes of Medicine, Boston, Massachusetts
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 ß-amyloid (Aß) at an early age. In this study, we have examined how Aß deposition is associated with immune responses. Both fibrillar and nonfibrillar Aß (diffuse) deposits were visible in the frontal cortex by 3 months, and the amyloid load increased dramatically with age. The number of fibrillar Aß 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 Aß, but was also up-regulated in some plaque-associated microglia. These results show: i) an increasing proportion of amyloid is composed of fibrillar Aß in the aging PS/APP mouse brain; ii) microglia and astrocytes are activated by both fibrillar and diffuse Aß; and iii) cyclooxygenase-2 and complement component 1q levels increase in response to the formation of fibrillar Aß in PS/APP mice.
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