Synaptic proteasome is inhibited in Alzheimer’s disease models and is associated with memory impairment in mice
Felipe C. Ribeiro, Danielle Cozachenco Ferreira, Juliana Fortuna, Guilherme B. de Freitas, Jorge M Souza, Soniza Alves‐Leon, Renata Elaine Paraizo Leite, Claudia Kimie Suemoto, Lea T. Grinberg, Fernanda G. De Felice, Mychael V. Lourenco, Sergio T. Ferreira- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
The proteasome plays key roles in neuronal function by regulating protein turnover, quality control, and elimination of oxidized and misfolded proteins. Recent evidence indicates that proteasome activity is required for synaptic plasticity and memory, and may be altered in Alzheimer’s disease (AD).
Method
Here, we investigate proteasome function and localization at synapses in AD post‐mortem brain tissue and in experimental models of AD by using western blotting, immunocytochemistry and proteasome activity assay. We also evaluated core AD‐related features upon proteasome inhibition by using DCFDA measurement, phaloidin staining, SUnSET and mice memory tasks.
Result
We found a marked increase in ubiquitinylated proteins in post‐mortem AD hippocampi compared to controls. Using human ex vivo adult cortical tissue, primary neuronal cultures, isolated synaptosomes and in vivo experiments in mice, we show that amyloid‐b oligomers (AbOs) inhibit synaptic proteasome activity and trigger a reduction in synaptic proteasome content. We further show proteasome inhibition specifically in hippocampal synaptic fractions derived from APPswePS1DE9 mice. Treatment with the proteasome inhibitor, lactacystin, induces reactive oxygen species formation and loss of dendritic spines in hippocampal neurons, inhibits hippocampal mRNA translation, and causes memory impairment in mice.
Conclusion
These findings demonstrate that synaptic proteasome activity is inhibited in post‐mortem AD brain tissue and in experimental models of AD. Results further show that proteasome inhibition is associated with spine loss and memory impairment in mice, suggesting that proteasome inhibition may contribute to synaptic and memory deficits in AD.