Dynamin 1 regulates amyloid generation through modulation of BACE-1
Li Zhu1, Meng Su, Louise Lucast
1Department of Neurology and Alzheimer's Disease Research Center, Mount Sinai School of Medicine, New York, New York, United States of America.
Plos One
|October 2, 2012
Summary
Dynamin 1 (dyn1) regulates amyloid-beta (Aβ) generation in Alzheimer's disease by controlling the localization of beta-site APP-cleaving enzyme 1 (BACE-1). Inhibiting dyn1 reduces Aβ production by affecting BACE-1 activity and distribution.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Endocytosis plays a critical role in Alzheimer's disease (AD) pathogenesis.
- The precise regulation of beta-site APP-cleaving enzyme 1 (BACE-1) trafficking remains unclear.
- Dynamin, a key protein in endocytosis, has controversial links to AD, prompting investigation into its specific role.
Purpose of the Study:
- To investigate the role of dynamin 1 (dyn1) in the biogenesis of amyloid-beta (Aβ).
- To elucidate the mechanism by which dyn1 influences the subcellular localization of BACE-1.
- To determine the impact of dyn1 modulation on Aβ production and BACE-1 activity.
Main Methods:
- Genetic perturbation of dyn1 using knockdown (KD) in cell culture.
- Treatment with a selective dynamin inhibitor, Dynasore.
- Analysis of Aβ levels, BACE-1 cleavage products (sAPPβ, βCTF), and APP holomer levels.
- Assessment of nicastrin (NCT) and PS1 N-terminal fragment (NTF) at the cell surface.
- Studies in dyn1 knockout (KO) primary neurons and dyn1 haploinsufficient AD transgenic mice.
Main Results:
- Genetic disruption or inhibition of dyn1 significantly reduced both secreted and intracellular Aβ levels.
- dyn1 KD led to BACE-1 redistribution from the Golgi-TGN/endosome to the cell surface, increasing holoAPP at the cell surface.
- A reduction in BACE-1 cleavage products (sAPPβ and βCTF) was observed, alongside an increase in α-secretase products (sAPPα and αCTF).
- Dynasore treatment mimicked the effects of BACE-1 inhibition on βCTF and Aβ levels.
- Combined inhibition of BACE-1 and dyn1 did not yield further Aβ reduction, indicating dyn1's effect is primarily via BACE-1 internalization regulation.
- Reduced Aβ levels were confirmed in dyn1 KO neurons and dyn1 haploinsufficient AD mice.
Conclusions:
- Dynamin 1 (dyn1) plays a significant role in amyloid generation in Alzheimer's disease.
- Dyn1 regulates Aβ production by controlling the subcellular localization of BACE-1.
- These findings reveal a novel mechanism linking dyn1 function to BACE-1 enzymatic activity and AD pathogenesis.
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