Age-dependent increase in lysosome-associated membrane protein 1 and early-onset behavioral deficits in APPSL transgenic mouse model of Alzheimer's disease.
Amyloid precursor protein (APP) is strongly related to the onset of Alzheimer's disease. It possesses cleavage sites for beta- and gamma-secretases, and the resulting cleaved products (amyloid-beta peptides) are capable of causing neurotoxicity. Such cleavage is promoted by the Swedish and London mutations (APPSwe/Lon) inside the APP gene. Here, we characterized APPSL transgenic mice (APPSL-Tg) to determine the effects of this mutation. We observed that both the amount of insoluble amyloid-beta and the ratio of amyloid-beta 42/40 increased promptly in the brain during 6-16 months of age. Amyloid-beta plaques were observed in whole brain sections at 12 months. In contrast, the spatial memory assessed by the Morris water maze task was already impaired at 3 months, which suggested that the APPSL-Tg mice may represent an early-onset model of familial Alzheimer's disease. Furthermore, the levels of LAMP-1, a marker protein of lysosome, increased in the brain at 28 months. Such LAMP-1 protein was detected around the amyloid-beta plaques at the hippocampal regions of the APPSL-Tg mice. Our results suggested that the increase in LAMP-1 was enhanced by the accumulation of amyloid-beta occurring during aging. Our findings coincided with the pathological hallmarks of Alzheimer's disease.
Hashimoto
Tetsuya
T
Graduate School of Biosphere Science, Hiroshima University, 1-7-1 Kagamiyama, Higashi-hiroshima 739-8521, Japan.
Ogino
Koichi
K
Shin
Ryong-Woon
RW
Kitamoto
Tetsuyuki
T
Kikuchi
Tetsuro
T
Shimizu
Noriaki
N
D017668:Age of Onset; D000375:Aging / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism; D051907:Lysosomal Membrane Proteins / Q000378:metabolism*; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D008569:Memory Disorders / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D051907:Lysosomal Membrane Proteins; D010446:Peptide Fragments; D058255:Protease Nexins; D011956:Receptors, Cell Surface; C052255:Lamp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)