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-1, -2) cause Alzheimer's disease (AD). Mice carrying both mutant genes (PS/APP) develop AD-like deposits composed of beta-amyloid (Abeta) at an early age. In this study, we have examined how Abeta deposition is associated with immune responses. Both fibrillar and nonfibrillar Abeta (diffuse) deposits were visible in the frontal cortex by 3 months, and the amyloid load increased dramatically with age. The number of fibrillar Abeta 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 Abeta, but was also up-regulated in some plaque-associated microglia. These results show: i) an increasing proportion of amyloid is composed of fibrillar Abeta in the aging PS/APP mouse brain; ii) microglia and astrocytes are activated by both fibrillar and diffuse Abeta; and iii) cyclooxygenase-2 and complement component 1q levels increase in response to the formation of fibrillar Abeta in PS/APP mice.
Matsuoka
Y
Y
Dementia Research Group, Nathan Kline Institute/New York University Medical Center, 14 Old Orangeburg Road, Orangeburg, NY 10462, USA.
Picciano
M
M
Malester
B
B
LaFrancois
J
J
Zehr
C
C
Daeschner
J M
JM
Olschowka
J A
JA
Fonseca
M I
MI
O'Banion
M K
MK
Tenner
A J
AJ
Lemere
C A
CA
Duff
K
K
D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000686:Amyloidosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D015922:Complement C1q / Q000378:metabolism; D051546:Cyclooxygenase 2; D018836:Inflammation Mediators / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D009457:Neuroglia / Q000502:physiology; D053764:Presenilin-1; D053766:Presenilin-2; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D014018:Tissue Distribution
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018836:Inflammation Mediators; D007527:Isoenzymes; D008565:Membrane Proteins; D053764:Presenilin-1; D053766:Presenilin-2; D015922:Complement C1q; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases