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Abstract
Alzheimer's disease (AD) is pathologically characterized by deposition of β-amyloid
(Aβ) peptides, which closely correlates with the balance of nerve growth factor (NGF)-related
TrkA/p75
NTR signaling. (−)-Epigallocatechin-3-gallate (EGCG) is used for prevention and treatment
of many neurodegenerative diseases, including AD. However, whether the neuroprotective
effects of EGCG treatment were via modulating the balance of TrkA/p75
NTR signaling was still unknown. In this study, we found that EGCG treatment (2 mg ·
kg
–1 · day
–1) dramatically ameliorated the cognitive impairments, reduced the overexpressions
of Aβ(1–40) and amyloid precursor protein (APP), and inhibited the neuronal apoptosis
in the
APP/PS1 mice. Interestingly, the EGCG treatment enhanced the relative expression level of
NGF by increasing the NGF/proNGF ratio in the
APP/PS1 mice. Moreover, after EGCG treatment, TrkA signaling was activated by increasing
the phosphorylation of TrkA following the increased phosphorylation of c-Raf, ERK1/2,
and cAMP response element-binding protein (CREB), simultaneously the p75
NTR signaling was significantly inhibited by decreasing the p75
ICD expression, JNK2 phosphorylation, and cleaved-caspase 3 expression, so that the Aβ
deposits and neuronal apoptosis in the hippocampus were inhibited.
Memory function often declines with age, and is believed to deteriorate initially because of changes in synaptic function rather than loss of neurons. Some individuals then go on to develop Alzheimer's disease with neurodegeneration. Here we use Tg2576 mice, which express a human amyloid-beta precursor protein (APP) variant linked to Alzheimer's disease, to investigate the cause of memory decline in the absence of neurodegeneration or amyloid-beta protein amyloidosis. Young Tg2576 mice ( 14 months old) form abundant neuritic plaques containing amyloid-beta (refs 3-6). We found that memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a 56-kDa soluble amyloid-beta assembly, which we term Abeta*56 (Abeta star 56). Abeta*56 purified from the brains of impaired Tg2576 mice disrupts memory when administered to young rats. We propose that Abeta*56 impairs memory independently of plaques or neuronal loss, and may contribute to cognitive deficits associated with Alzheimer's disease.
Transgenic mice overexpressing the 695-amino acid isoform of human Alzheimer beta-amyloid (Abeta) precursor protein containing a Lys670 --> Asn, Met671 --> Leu mutation had normal learning and memory in spatial reference and alternation tasks at 3 months of age but showed impairment by 9 to 10 months of age. A fivefold increase in Abeta(1-40) and a 14-fold increase in Abeta(1-42/43) accompanied the appearance of these behavioral deficits. Numerous Abeta plaques that stained with Congo red dye were present in cortical and limbic structures of mice with elevated amounts of Abeta. The correlative appearance of behavioral, biochemical, and pathological abnormalities reminiscent of Alzheimer's disease in these transgenic mice suggests new opportunities for exploring the pathophysiology and neurobiology of this disease.
[]Department of Pharmacology, School of Pharmaceutical Sciences, China Medical University,
No.92 Bei’er Road, Heping District, Shenyang, 110001 Liaoning Province People’s Republic
of China
[]Laboratory Animal Center, China Medical University, Shenyang, People’s Republic of
China
[]Department of Biomedical Engineering, College of Basic Medical Science, China Medical
University, Shenyang, People’s Republic of China
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