Amyloid-β Inhibits Synaptic Proteasomal Function in Alzheimer’s Disease – Fight Aging!


Cells contain many proteasomes, one portion of a broad array of repair and quality control mechanisms. The proteasome is a hollow, capped cylindrical structure made of many component proteins. It admits entry only to proteins that have been decorated with the addition of a ubiquitin molecule. Once inside the proteasome’s central chamber, the ubiquinated protein is disassembled into short peptides suitable for reuse in the synthesis of other proteins. This ubiquitin-proteasome system is necessary to prevent the buildup of damaged, misfolded, unfolded, or otherwise unwanted proteins.

It has been noted that proteasomal function is impaired in Alzheimer’s disease patients, and that inhibition of proteasomal function, such as by downregulating expression of specific proteasomal component proteins, produces symptoms akin to those of neurodegenerative conditions. In today’s open access paper, researchers further explore this topic, showing that the amyloid-β associated with Alzheimer’s disease is capable of inhibiting proteasomal function in the synapses that link neurons in the brain. This points to the merits of both clearance of amyloid-β and also the development of ways to augment proteasomal function, such as by increased expression of some of its component proteins.

Synaptic proteasome is inhibited in Alzheimer’s disease models and associates with memory impairment in mice

The proteasome plays key roles in synaptic plasticity and memory by regulating protein turnover, quality control, and elimination of oxidized/misfolded proteins. Here, we investigate proteasome function and localization at synapses in Alzheimer’s disease (AD) post-mortem brain tissue and in experimental models.

We found a marked increase in ubiquitinylated proteins in post-mortem human AD hippocampi compared to controls. Using several experimental models, we show that amyloid-β oligomers (AβOs) inhibit synaptic proteasome activity and trigger a reduction in synaptic proteasome content. We further show proteasome inhibition specifically in hippocampal synaptic fractions derived from Alzheimer’s model mice.

Reduced synaptic proteasome activity instigated by AβOs is corrected by treatment with rolipram, a phosphodiesterase-4 inhibitor, in mice. Results further show that dynein inhibition blocks AβO-induced reduction in dendritic proteasome content in hippocampal neurons. Finally, proteasome inhibition induces AD-like pathological features, including reactive oxygen species and dendritic spine loss in hippocampal neurons, inhibition of hippocampal mRNA translation, and memory impairment in mice. Results suggest that proteasome inhibition may contribute to synaptic and memory deficits in AD.



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