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Intracerebroventricular Injection of Amyloid-β Peptides in Normal Mice to Acutely Induce Alzheimer-like Cognitive Deficits
Published on: March 16, 2016
A pharmacological chaperone improves memory by reducing Aβ and tau neuropathology in a mouse model with plaques and
Jian-Guo Li1, Jin Chiu1, Mercy Ramanjulu2
1Alzheimer's Center at Temple, Lewis Katz School of Medicine, Temple University, 3500 North Broad Street, MERB, suite 1160, Philadelphia, PA, 19140, USA.
Background:
The vacuolar protein sorting 35 (VPS35) is a major component of the retromer complex system, an ubiquitous multiprotein assembly responsible for sorting and trafficking protein cargos out of the endosomes. VPS35 can regulate APP metabolism and Aβ formation, and its levels are reduced in Alzheimer's disease (AD) brains. We and others demonstrated that VPS35 genetic manipulation modulates the phenotype of mouse models of AD. However, the translational value of this observation remains to be investigated.
Methods:
Triple transgenic mice were randomized to receive a pharmacological chaperone, which stabilizes the retromer complex, and the effect on their AD-like phenotype assessed.
Results:
Compared with controls, treated mice had a significant improvement in learning and memory, an elevation of VPS35 levels, and improved synaptic integrity. Additionally, the same animals had a significant decrease in Aβ levels and deposition, reduced tau phosphorylation and less astrocytes activation.
Conclusions:
Our study demonstrates that the enhancement of retromer function by pharmacological chaperones is a potentially novel and viable therapy against AD.
Insights
Pharmacological chaperones targeting vacuolar protein sorting 35 (VPS35) improved Alzheimer's disease (AD) mouse models. This retromer complex stabilization enhanced cognition and reduced AD pathology, suggesting a novel therapeutic approach.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Vacuolar protein sorting 35 (VPS35) is crucial for endosomal trafficking and linked to Alzheimer's disease (AD) pathology.
- Reduced VPS35 levels in AD brains suggest a role in disease progression.
- VPS35's modulation of AD phenotypes in mouse models warrants further investigation for therapeutic potential.
Purpose of the Study:
- To investigate the therapeutic potential of enhancing retromer complex function in a mouse model of Alzheimer's disease.
- To assess the effects of pharmacological chaperones on VPS35 levels and AD-related pathology.
Main Methods:
- Triple transgenic mice modeling Alzheimer's disease were treated with a pharmacological chaperone to stabilize the retromer complex.
- Cognitive function, VPS35 levels, synaptic integrity, amyloid-beta (Aβ) levels, tau phosphorylation, and astrocyte activation were assessed.
Main Results:
- Treatment significantly improved learning and memory in AD mice.
- Elevated VPS35 levels and enhanced synaptic integrity were observed post-treatment.
- Significant reductions in Aβ deposition, tau phosphorylation, and astrocyte activation were noted.
Conclusions:
- Enhancing retromer complex function via pharmacological chaperones offers a promising therapeutic strategy for Alzheimer's disease.
- This approach demonstrates potential for improving cognitive deficits and reducing key AD pathologies.
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