Fight Aging!

Alzheimer's disease is one of the few areas of research into age-related conditions that needs comparatively little assistance at this time: public awareness of the issue of dementia is growing and so is support for greater funding. The research community is already large and energetic, and at least some well-funded groups are working on technologies - such as immune therapies aimed at removal of amyloid deposits - that will probably be of use to other efforts to reverse the causes of aging. This avalanche is well underway.

All that said, it is still a very complex problem as yet comparatively poorly understood, for all that tangible progress is taking place year after year. Much like cancer research, I expect to see Alzheimer's research - already large in comparison to much of the rest of the field of aging research - grow further to consume a great deal of funding, spur the accelerating development of biotechnology, and generate much new knowledge of the intricate relationship between metabolism and aging, as well as the fine details of the operation of the human brain. Below you'll find two fairly representative samples of recent research from the Alzheimer's research community.

Loss of Memory in Alzheimer's Mice Models Reversed through Gene Therapy

[Researchers] have discovered the cellular mechanism involved in memory consolidation and were able to develop a gene therapy which reverses the loss of memory in mice models with initial stages of Alzheimer's disease. The therapy consists in injecting into the hippocampus - a region of the brain essential to memory processing - a gene which causes the production of a protein blocked in patients with Alzheimer's, the "Crtc1" (CREB regulated transcription coactivator-1). The protein restored through gene therapy gives way to the signals needed to activate the genes involved in long-term memory consolidation.

In persons with the disease, the formation of amyloid plaque aggregates, a process known to cause the onset of Alzheimer's disease, prevents the Crtc1 protein from functioning correctly. "When the Crtc1 protein is altered, the genes responsible for the synapses or connections between neurons in the hippocampus cannot be activated and the individual cannot perform memory tasks correctly this study opens up new perspectives on therapeutic prevention and treatment of Alzheimer's disease, given that we have demonstrated that a gene therapy which activates the Crtc1 protein is effective in preventing the loss of memory in lab mice".

A new approach to treating Alzheimer's disease

Cellular processes are not perfect. They, like us, make mistakes. Sometimes, the by-products of those mistakes are harmless. Other times, they can lead to disease or even death. With Alzheimer's disease, the mistake occurs when a protein called neuron's membrane is cut in the wrong place, leading to a buildup of abnormal fragments called amyloid-beta. These fragments clump together to form a plaque around neurons, eventually interfering with brain function.

But the cell has systems to deal with mistakes. A protein complex called retromer acts like a cellular garbage truck, collecting faulty gene products and trafficking them to be destroyed or recycled. For years, Alzheimer's research has focused on preventing the formation of amyloid-beta with little success. But instead of trying to stop mistakes, what if researchers improved the system for dealing with them? A team of researchers [did] just that. They have devised a novel approach to the treatment of Alzheimer's disease that significantly increases retromer levels while decreasing amyloid-beta levels in neurons, without harming the cell.

Pharmacological chaperones stabilize retromer to limit APP processing

Retromer is a multiprotein complex that trafficks cargo out of endosomes. The neuronal retromer traffics the amyloid-precursor protein (APP) away from endosomes, a site where APP is cleaved into pathogenic fragments in Alzheimer's disease. Here we determined whether pharmacological chaperones can enhance retromer stability and function.

First, we relied on the crystal structures of retromer proteins to help identify the 'weak link' of the complex and to complete an in silico screen of small molecules predicted to enhance retromer stability. Among the hits, an in vitro assay identified one molecule that stabilized retromer against thermal denaturation. Second, we turned to cultured hippocampal neurons, showing that this small molecule increases the levels of retromer proteins, shifts APP away from the endosome, and decreases the pathogenic processing of APP.

These findings show that pharmacological chaperones can enhance the function of a multiprotein complex and may have potential therapeutic implications for neurodegenerative diseases.