If you’re wondering where Alzheimer’s research might be headed after the latest large-scale failure of a clinical trial based on the “amyloid hypothesis,” check this out.
Plaques. Tangles. Clumps. These are all pathological signs of neurodegenerative diseases that scientists can see under the microscope. But they don’t explain most of the broader trends of cognitive resilience or decline in aging individuals. What’s missing?
A recent proteomics analysis in Nature Communications from Emory researchers identifies key proteins connected with cognitive trajectory – meaning the rate at which someone starts to decline and develop mild cognitive impairment or dementia.
This paper fits in with the multi-year push for “unbiased” Alzheimer’s/aging research at Emory. The lead and senior authors are Aliza and Thomas Wingo, with proteomics from biochemist Nick Seyfried and company.
The proteins the Emory team spotlights are not the usual suspects that scientists have been grinding on for years in the Alzheimer’s field, such as beta-amyloid and tau. They’re proteins connected with cellular energy factories (mitochondria) or with synapses, the connections between brain cells.
“Our most notable finding is that proteins involving mitochondrial activities or synaptic functions had increased abundance among individuals with cognitive stability regardless of the burden of β-amyloid plaques or neurofibrillary tangles,” the authors write. “Taken together, our findings and others highlight that mitochondrial activities would be a fruitful research target for early prevention of cognitive decline and enhancement of cognitive stability.” Read more
Just a shoutout regarding Emory folks in Alzforum, the research news site focusing on Alzheimer’s and other neurodegenerative disorders.
Alzforum recently highlighted proteomics wizard Nick Seyfried’s presentation at a June meeting in Germany (Alzheimer’s Proteomics Treasure Trove). This includes work from the Emory ADRC and Baltimore Longitudinal Study of Aging that was published in Cell Systems in December: the first large-scale systems biology analysis of post-mortem brain proteins in Alzheimer’s. The idea is to have a fresh “unbiased” look at proteins involved in Alzheimer’s.
Also, neuroscientists Malu Tansey and Tom Kukar have been teaming up to provide detailed comments on papers being reported in Alzforum. Here’s one on inflammation related to gene alterations in frontotemporal dementia, and another on auto-immune responses in Parkinson’s.
Much of basic biomedical research concerns proteins. The enzymes that keep cells running, the regulators and receptors that control what our cells do, the antibodies that defend us against invaders — all of these are proteins.
That means every day, scientists are asking questions like:
What’s happening to my favorite protein? Is there more or less of it in this sample? What other proteins work with it or stick to it?
That’s where a proteomics core facility comes in. Given a mixture of hundreds or even thousands of proteins, proteomics specialists can separate, identify and quantify them.
Researchers in the areas of Alzheimer’s disease, cancer metabolism, schizophrenia and vaccines all make use of Emory’s proteomics core facility. It was key to the Alzheimer’s Disease Research Center’s 2013 discovery of a new form of Alzheimer’s disease protein pathology.
Director Nick Seyfried reports that the core has acquired close to $3 million in sophisticated mass spectrometry equipment in the last few years. The Emory Integrated Proteomics Core, one of the Emory Integrated Core Facilities, is supported in part by the Winship Cancer Institute, the Atlanta Clinical and Translational Science Institute, and a recently renewed grant for ENNCF (Emory Neurosciences NINDS Core Facilities).
Protein mass spectrometry is like Wonkavision
There’s a scene in both the 1971 and 2005 film adaptations of Roald Dahl’s Charlie and the Chocolate Factory, in which a chocolate bar is separated into millions of tiny pieces and sent flying across a clean room. Protein mass spectrometry resembles the first part of this process. Read more
If youâ€™ve been paying attention to Alzheimerâ€™s disease research, youâ€™ve probably read a lot about beta-amyloid. Itâ€™s a toxic protein fragment that dominates the plaques that appear in the brains of people with Alzheimerâ€™s. Many experimental therapies for Alzheimerâ€™s target beta-amyloid, but so far, they’ve not proven effective.
That could be for several reasons. Maybe those treatments started too late to make a difference. But an increasing number of Alzheimerâ€™s researchers are starting to reconsider the field’s emphasis on amyloid. Nature News has a feature this week explaining how the spotlight is shifting to the protein ApoE, encoded by the gene whose variation is responsible for the top genetic risk factor for Alzheimerâ€™s.
In line with this trend, Emoryâ€™s Alzheimer’s Disease Research Center recently received a five-year, $7.2 million grant to go beyond the usual suspects like beta-amyloid. Emory will lead several universities in a project to comprehensively examine proteins altered in Alzheimerâ€™s. Youâ€™ve heard of the Cancer Genome Atlas? Think of this as the Alzheimerâ€™s Proteome Atlas, potentially addressing the same kind of questions about which changes are the drivers and which are the passengers.
Emoryâ€™s back-to-basics proteomics approach has already yielded some scientific fruit, uncovering changes in proteins involved in RNA splicing and processing. Also, the Nature feature also has some background on a clinical trial called TOMMORROW, which Emoryâ€™s ADRC is participating in.