Researchers have discovered a key protein linked to Alzheimer's, inhibition of which could prevent the neuronal damage and subsequent cognitive decline associated with the disease.
Researchers at Columbia University Medical Center (CUMC) have demonstrated that a protein called caspase-2 is a key regulator of a signaling pathway that leads to cognitive decline in Alzheimer's disease.
The findings, made in a mouse model of Alzheimer's, suggest that inhibiting this protein could prevent the neuronal damage and subsequent cognitive decline associated with the disease.
One of the earliest events in Alzheimer's is disruption of the brain's synapses (the small gaps across which nerve impulses are passed), which can lead to neuronal death.
Although what drives this process has not been clear, studies have indicated that caspace-2 might be involved, according to senior author Michael Shelanski.
Several years ago, in tissue culture studies of mouse neurons, Shelanski found that caspace-2 plays a critical role in the death of neurons in the presence of amyloid beta, the protein that accumulates in the neurons of people with Alzheimer's. Other researchers have shown that caspase-2 also contributes to the maintenance of normal synaptic functions.
Shelanski and his team hypothesised that aberrant activation of caspase-2 may cause synaptic changes in Alzheimer's disease. They crossed J20 transgenic mice with caspase-2 null mice (mice that lack caspase-2).
They compared the animals' ability to negotiate a radial-arm water maze, a standard test of cognitive ability, with that of regular J20 mice and of normal mice at 4, 9, and 14 months of age. The results for the three groups of mice were similar at the first two intervals.
At 14 months, however, the J20/caspase-2 null mice did significantly better in the water maze test than the J20 mice and similarly to the normal mice.
"We showed that removing caspase-2 from J20 mice prevented memory impairment - without significant changes in the level of soluble amyloid beta," said co-lead author Roger Lefort.
Analysis of the neurons showed that the J20/caspase-2 null mice had a higher density of dendritic spines than the J20 mice. The more spines a neuron has, the more impulses it can transmit.
"The J20/caspase-2 null mice showed the same dendritic spine density and morphology as the normal mice as opposed to the deficits in the J20 mice," said co-lead author Julio Pozueta.
"This strongly suggests that caspase-2 is a critical regulator in the memory decline associated with beta-amyloid in Alzheimer's disease," said Pozueta.
The study was published in the journal Nature Communications.
