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Complicated Cell Process May Be Cause of Damage Leading to Alzheimers

Alzheimer's disease, cell damage, beta-amyloid

Caspases are a family of intracellular pro-enzymes that are activated to play essential roles in the body. Although they are for development, they can “run amok” and cause damage instead. The processes of certain caspases are of interest in science as playing a role in certain disease states, including Alzheimer’s disease.

Alzheimer’s disease is a type of dementia that causes problems with memory, thinking, and behavior. One of the earliest events in Alzheimer’s is the disruption of the brain’s synapses – the small gaps across which nerve impulses are passed – leading to neuronal death. Two abnormal structures called plaques and tangles are the prime suspects in damaging and killing these nerve cells which ultimately leads to cognitive decline. However, scientists do not exactly know how these develop but may be coming closer to an answer.

Researchers at Columbia University Medical Center are focusing on a protein known as caspase-2 which appears to be a key regulator of a signaling pathway that leads to cognitive decline.

Michael Shelanski MD PhD, co-director of the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, discovered that in tissue culture studies of mouse neurons, caspace-2 may cause synaptic changes that leads to the death of neurons in the presence of amyloid beta, the protein that accumulates to cause plaques in the brains of patients with Alzheimer’s. However, the same protein is also necessary for the maintenance of normal synaptic functions.

So what happens?

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Dr. Shelanski tested a hypothesis using mice that have been genetically altered to have Alzheimer’s disease (called J20 transgenic mice). The team further altered the mice to be lacking in caspase-2. Using a water maze test, “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, PhD, associate research scientist at CUMC.

One reason for the lack of memory impairment may be found within a component known as dendritic spines. The more spines a neuron has, the more impulses it can transmit. The J20/catalase-2-null mice had a higher density of dendritic spines than the J20 mice.

Normally, caspase-2 interacts with RhoA in the form and structure of dendritic spines. However, when the complex of Caspase-2/RhoA is exposed to amyloid beta, it breaks apart – activating the previously inactive compound. Once activated, a process occurs that contributes to the demise of the spines and ultimately the neuron cell.

“This strongly suggests that caspase-2 is a critical regulator in the memory decline associated with beta-amyloid in Alzheimer's disease,” says co-lead author Julio Pozueta PhD. Inhibiting the protein in the early course of Alzheimer’s may help protect neurons and slow down the cognitive effects of the disease.

Caspase-2 isn’t the first caspase to be implicated in the process that leads to Alzheimer’s. Caspase-1 enzyme is thought to set off the production of beta cytokine IL-1 causing inflammation leading to cellular damage. Caspase-3 may also play a role in neuronal death.

Journal Reference:
Julio Pozueta, Roger Lefort, Elena M. Ribe, Carol M. Troy, Ottavio Arancio & Michael Shelanski. Caspase-2 is required for dendritic spine and behavioural alterations in J20 APP transgenic mice. Nature Communications 4,Article number: 1939 doi:10.1038/ncomms2927. Published 10 June 2013

Additional Resource:
Alzheimer’s Association