TY - JOUR
T1 - Age-dependent increase in lysosome-associated membrane protein 1 and early-onset behavioral deficits in APPSL transgenic mouse model of Alzheimer's disease
AU - Hashimoto, Tetsuya
AU - Ogino, Koichi
AU - Shin, Ryong Woon
AU - Kitamoto, Tetsuyuki
AU - Kikuchi, Tetsuro
AU - Shimizu, Noriaki
PY - 2010/1/22
Y1 - 2010/1/22
N2 - Amyloid precursor protein (APP) is strongly related to the onset of Alzheimer's disease. It possesses cleavage sites for β- and γ-secretases, and the resulting cleaved products (amyloid-β 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-β and the ratio of amyloid-β 42/40 increased promptly in the brain during 6-16 months of age. Amyloid-β 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-β 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-β occurring during aging. Our findings coincided with the pathological hallmarks of Alzheimer's disease.
AB - Amyloid precursor protein (APP) is strongly related to the onset of Alzheimer's disease. It possesses cleavage sites for β- and γ-secretases, and the resulting cleaved products (amyloid-β 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-β and the ratio of amyloid-β 42/40 increased promptly in the brain during 6-16 months of age. Amyloid-β 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-β 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-β occurring during aging. Our findings coincided with the pathological hallmarks of Alzheimer's disease.
KW - Alzheimer's disease
KW - Amyloid precursor protein
KW - Amyloid-β
KW - LAMP-1
KW - Memory impairment
UR - http://www.scopus.com/inward/record.url?scp=72749120785&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=72749120785&partnerID=8YFLogxK
U2 - 10.1016/j.neulet.2009.12.015
DO - 10.1016/j.neulet.2009.12.015
M3 - Article
C2 - 20025930
AN - SCOPUS:72749120785
VL - 469
SP - 273
EP - 277
JO - Neuroscience Letters
JF - Neuroscience Letters
SN - 0304-3940
IS - 2
ER -