Abstract |
Alzheimer's disease (AD) is the most common cause of dementia worldwide and mainly characterized by the aggregated β- amyloid (Aβ) and hyperphosphorylated tau. FLZ is a novel synthetic derivative of natural squamosamide and has been proved to improve memory deficits in dementia animal models. In this study, we aimed to investigate the mechanisms of FLZ's neuroprotective effect in APP/PS1 double transgenic mice and SH-SY5Y (APPwt/swe) cells. The results showed that treatment with FLZ significantly improved the memory deficits of APP/PS1 transgenic mice and decreased apoptosis of SH-SY5Y (APPwt/swe) cells. FLZ markedly attenuated Aβ accumulation and tau phosphorylation both in vivo and in vitro. Mechanistic study showed that FLZ interfered APP processing, i.e., FLZ decreased β- amyloid precursor protein (APP) phosphorylation, APP-carboxy-terminal fragment (APP-CTF) production and β- amyloid precursor protein cleaving enzyme 1 (BACE1) expression. These results indicated that FLZ reduced Aβ production through inhibiting amyloidogenic pathway. The mechanistic study about FLZ's inhibitory effect on tau phosphorylation revealed t the involvement of Akt/ glycogen synthase kinase 3β (GSK3β) pathway. FLZ treatment increased Akt activity and inhibited GSK3β activity both in vivo and in vitro. The inhibitory effect of FLZ on GSK3β activity and tau phosphorylation was suppressed by inhibiting Akt activity, indicating that Akt/GSK3β pathway might be the possible mechanism involved in the inhibitory effect of FLZ on tau hyperphosphorylation. These results suggested FLZ might be a potential anti-AD drug as it not only reduced Aβ production via inhibition amyloidogenic APP processing pathway, but also attenuated tau hyperphosphoylation mediated by Akt/GSK3β.
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Authors | Xiu-Qi Bao, Ning Li, Tao Wang, Xiang-Chen Kong, Wen-Jiao Tai, Hua Sun, Dan Zhang |
Journal | PloS one
(PLoS One)
Vol. 8
Issue 11
Pg. e78033
( 2013)
ISSN: 1932-6203 [Electronic] United States |
PMID | 24223757
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Amyloid beta-Peptides
- Benzeneacetamides
- Neuroprotective Agents
- Phenols
- tau Proteins
- squamosamide
- GSK3B protein, human
- Glycogen Synthase Kinase 3 beta
- Gsk3b protein, mouse
- Proto-Oncogene Proteins c-akt
- Glycogen Synthase Kinase 3
- Amyloid Precursor Protein Secretases
- Casp3 protein, mouse
- Caspase 3
- Aspartic Acid Endopeptidases
- BACE1 protein, human
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Topics |
- Alzheimer Disease
(drug therapy, metabolism)
- Amyloid Precursor Protein Secretases
(metabolism)
- Amyloid beta-Peptides
(metabolism)
- Animals
- Apoptosis
- Aspartic Acid Endopeptidases
(metabolism)
- Benzeneacetamides
(pharmacology)
- Caspase 3
(metabolism)
- Cell Line, Tumor
- Drug Evaluation, Preclinical
- Escape Reaction
- Glycogen Synthase Kinase 3
(metabolism)
- Glycogen Synthase Kinase 3 beta
- Hippocampus
(drug effects, metabolism)
- Humans
- Male
- Maze Learning
(drug effects)
- Memory Disorders
(drug therapy, metabolism)
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Neuroprotective Agents
(pharmacology)
- Phenols
(pharmacology)
- Phosphorylation
- Protein Processing, Post-Translational
(drug effects)
- Proto-Oncogene Proteins c-akt
(metabolism)
- Signal Transduction
- tau Proteins
(metabolism)
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