Overexpression of the neuritotrophic cytokine S100beta precedes the appearance of neuritic beta-amyloid plaques in APPV717F mice.
Homozygous APPV717F transgenic mice overexpress a human beta-amyloid precursor protein (betaAPP) minigene encoding a familial Alzheimer's disease mutation. These mice develop Alzheimer-type neuritic beta-amyloid plaques surrounded by astrocytes. S100beta is an astrocyte-derived cytokine that promotes neurite growth and promotes excessive expression of betaAPP. S100beta overexpression in Alzheimer's disease correlates with the proliferation of betaAPP-immunoreactive neurites in beta-amyloid plaques. We found age-related increases in tissue levels of both betaAPP and S100beta mRNA in transgenic mice. Neuronal betaAPP overexpression was found in cell somas in young mice, whereas older mice showed betaAPP overexpression in dystrophic neurites in plaques. These age-related changes were accompanied by progressive increases in S100beta expression, as determined by S100beta load (percent immunoreactive area). These increases were evident as early as 1 and 2 months of age, months before the appearance of beta-amyloid deposits in these mice. Such precocious astrocyte activation and S100beta overexpression are similar to our earlier findings in Down's syndrome. Accelerated age-related overexpression of S100beta may interact with age-associated overexpression of mutant betaAPP in transgenic mice to promote development of Alzheimer-like neuropathological changes.
Sheng
J G
JG
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, USA.
Mrak
R E
RE
Bales
K R
KR
Cordell
B
B
Paul
S M
SM
Jones
R A
RA
Woodward
S
S
Zhou
X Q
XQ
McGinness
J M
JM
Griffin
W S
WS
D000375:Aging / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000502:physiology; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D016501:Neurites / Q000502:physiology*; D058225:Plaque, Amyloid / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D005904:Glial Fibrillary Acidic Protein; D012333:RNA, Messenger; D009418:S100 Proteins; C110294:S100A1 protein