Alzheimer's mice show improved memory when innoculated with an enzyme involved in protein degradation.
The memory of mice with Alzheimer’s-like symptoms is improved by inoculating the mice with an enzyme involved in protein degradation, report US researchers. The work could lead to new therapies for patients with Alzheimer’s disease (AD).
The accumulation of a protein called amyloid-beta in the brain is thought to play a key role in the progression of AD. But the molecular mechanism for how the protein affects memory remains unclear.
In a new study, Ottavio Arancio, a neuroscientist at Columbia University Medical Center in New York, found that the accumulation of amyloid-beta in mice was linked to a deficit in an enzyme called Uch-L1. This is associated with a protein degradation system - the proteasome system - that cells use to eliminate excess or abnormal proteins.
Unwanted proteins are tagged with a protein called ubiquitin, and a sufficient number of ubiquitin tags then interacts with a structure called the proteasome. Proteasomes digest proteins into their constituent peptides and amino acids.
’We have found that in a mouse model of AD, an increase in amyloid-beta reduces Uch-L1, which is an enzyme that is important in the proteasome system,’ Arancio told Chemistry World.
By inhibiting the ubiquitin-proteasome, amyloid-beta effectively blocks a cascade of enzymatic reactions that activates a protein critical for memory formation called Creb (Cyclic adenosine monophosphateresponse element-binding), explained Arancio.
Arancio’s team showed that adding Uch-L1 to brain slices treated with amyloid-beta or to mice with increased levels of amyloid-beta, restores long-term potentiation (LTP). LTP is thought to be how memories are stored and how things are learned. It is measured by attaching electrodes to the brain cells on either side of a synapse, the junction between two neurons. When the synapse is bombarded with a series of nerve impulses or action potentials, the synapse undergoes a functional change. This change is LTP.
’What’s exciting is that this is a new direction in Alzheimer’s research,’ said Gunnar Gouras, a neuroscientist at Weill Medical College of Cornell University in New York, US. ’This work builds on synaptic biology, which we know is important in Alzheimer’s but is not well understood.’
The researchers found that in addition to improvements in synaptic function, the ability of ’Alzheimer’s mice’ to make new memories was rescued by inoculation with Uch-L1. To show this, Arancio and colleagues placed the mice in a cage where they received a mild shock when they moved across the floor. The mice were taken out of the cage and reintroduced twenty-four hours later. Normal animals and AD mice treated with Uch-L1 remembered what happened when they moved around so they froze in place. Mice with high levels of amyloid-beta in their brains did not stop moving.
Almost all current AD therapies target amyloid-beta. Arancio’s approach is different. ’The most exciting thing to me,’ he said, ’is that there is hope for improving memory by using the proteasome as a target.’
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B Gong et alCell126, 775