In a model of human fetal brain development, Emory researchers can see perturbations of epigenetic markers in cells derived from people with familial early-onset Alzheimer’s disease, which takes decades to appear. This suggests that in people who inherit mutations linked to early-onset Alzheimer’s, it would be possible to detect molecular changes in their brains before birth.
The results were published in the journal Cell Reports.
“The beauty of using organoids is that they allow us to Read more
Why do people with cystic fibrosis (CF) have such trouble with lung infections? The conventional view is that people with CF are at greater risk for lung infections because thick, sticky mucus builds up in their lungs, allowing bacteria to thrive. CF is caused by a mutation that affects the composition of the mucus.
Rabindra Tirouvanziam, an immunologist at Emory, says a better question is: what type of cell is supposed to be fighting the Read more
Researchers interested in Alzheimer’s and other neurodegenerative diseases are focusing their attention on microglia, cells that are part of the immune system in the brain.
Author Donna Jackson Nakazawa titled her recent book on microglia “The Angel and the Assassin,” based on the cells’ dual nature; they can be benign or malevolent, either supporting neuronal health or driving harmful inflammation. Microglia resemble macrophages in their dual nature, but microglia are renewed within the brain, unlike macrophages, which are white blood cells that infiltrate into the brain from outside.
At Emory, neurologist Srikant Rangaraju’s lab recently published a paper in PNAS on a promising drug target on microglia: Kv1.3 potassium channels. Overall, the results strengthen the case for targeting Kv1.3 potassium channels as a therapeutic approach for Alzheimer’s.
Kv1.3 potassium channels have also been investigated as potential therapeutic targets in autoimmune disorders, since they are expressed on T cells as well as microglia. The peptide dalazatide, based on a toxin from the venom of the Caribbean sea anemone Stichodactyla helianthus, is being developed by the Ohio-based startup TEKv Therapeutics. The original venom peptide needed to be modified to make it more selective toward the right potassium channels – more about that here.
It appears that Kv1.3 levels on microglia increase in response to exposure to amyloid-beta, the toxic protein fragment that accumulates in the brain in Alzheimer’s, and Kv1.3 may be an indicator that microglia are turning to the malevolent side.
In the Emory paper, researchers showed that Kv1.3 potassium channels are present on a subset of microglia isolated from Alzheimer’s patients’ brains. They also used bone marrow transplant experiments to show that the immune cells in mouse brain that express Kv1.3 channels are microglia (internal brain origin), not macrophages (transplantable w/ bone marrow).
Investigators at Emory Brain Health Center have developed a platform for evaluating visual memory, while someone views photos for a few minutes on an iPad.
Emory researchers, led by Goizuieta Alzheimer’s Disease Research Center director Allan Levey and biomedical informatics chair Gari Clifford, are working with the company Linus Health to develop the VisMET (Visuospatial Memory Eye-Tracking Test) technology further. Results from the most recent version were published in the journal IEEE Transaction on Biomedical Engineering, and the Emory/Linus team continues to refine the technology.
The goal is to screen people for memory issues, identifying those with mild cognitive impairment (MCI) or Alzheimer’s disease. The task — difficult to call it a test — was designed to be more efficient, easier to administer, and more enjoyable than tests currently used.
“We think this could be a sensitive and specific method for detecting visual memory impairment, and it’s convenient enough for use on a wider scale,” Levey says.
The VisMET technology is based on this observation. When someone with MCI or Alzheimer’s views a photo twice, and the photo has been changed the second time (example: an object in the scene has been removed), their eyes spend less time checking the new or missing element in the photo, compared with healthy people. This is because the regions of the brain that drive visual memory formation, such as the entorhinal cortex and hippocampus, are some of the earliest to deteriorate in MCI or Alzheimer’s.
“The current way memory tests are implemented can be stressful,” says software engineer Alvince Pongos, who is co-first author of the IEEE TBME paper, now at MIT’s McGovern Institute for Brain Research. “The difficulty of standard memory tests can lead to test-givers repeating task instructions many times, and to test-takers being confused and frustrated. If we design simpler tasks and make our tools available in the comfort of one’s home, then we remove barriers allowing more people to engage with their health information.”
Emory Brain Health researchers have developed a computer program that passively assesses visual memory. An infrared eye tracker monitors eye movements, while the person being tested views a series of photos.
This approach, relatively unstrenuous for those whose memory is being assessed, is an alternative for the diagnosis of mild cognitive impairment or Alzheimer’s disease. It detects degeneration of the regions of the brain that govern visual memory (entorhinal cortex/hippocampus), which are some of the earliest to deteriorate.
The approach was published in Learning and Memory last year, but bioinformatics chair Gari Clifford discussed the project at a recent talk, and we felt it deserved more attention. First author Rafi Haque is a MD/PhD student in the Neuroscience program, with neurology chair/Goizueta ADRC director Allan Levey as senior author.
Eye tracking of people with MCI and Alzheimer’s shows they spend less time checking the new or missing element in the critical region of the photo, compared with healthy controls. Adapted from Haque et al 2019.
The entire test takes around 4 minutes on a standard 24 inch monitor (a follow-up publication on an iPad version is in the pipeline). Photos are presented twice a few minutes apart, and the second time, part of the photo is missing or new – see diagram above. Read more
Neuroscientist and geneticist David Weinshenker makes a case that the locus coeruleus (LC), a small region of the brainstem and part of the pons, is among the earliest regions to show signs of degeneration in both Alzheimer’s and Parkinson’s disease. You can check it out in Trends in Neurosciences.
The LC is the main source of the neurotransmitter norepinephrine in the brain, and gets its name (Latin for “blue spot”) from the pigment neuromelanin, which is formed as a byproduct of the synthesis of norepinephrine and its related neurotransmitter dopamine. The LC has connections all over the brain, and is thought to be involved in arousal and attention, stress responses, learning and memory, and the sleep-wake cycle.
Cells in the locus coeruleus are lost in mild cognitive impairment and Alzheimer’s. From Kelly et al Acta Neuropath. Comm. (2017) via Creative Commons
The protein tau is one of the toxic proteins tied to Alzheimer’s, and it forms intracellular tangles. Pathologists have observed that precursors to tau tangles can be found in the LC in apparently healthy people before anywhere else in the brain, sometimes during the first few decades of life, Weinshenker writes. A similar bad actor in Parkinson’s, alpha-synuclein, can also be detected in the LC before other parts of the brain that are well known for damage in Parkinson’s, such as the dopamine neurons in the substantia nigra.
“The LC is the earliest site to show tau pathology in AD and one of the earliest (but not the earliest) site to show alpha-synuclein pathology in PD,” Weinshenker tells Lab Land. “The degeneration of the cells in both these diseases is more gradual. It probably starts in the terminals/fibers and eventually the cell bodies die.” Read more
In recent news stories about Alzheimer’s disease research, we noticed a word popping up: unbiased. Allan Levey, chair of Emory’s neurology department and head of Emory’s Alzheimer’s Disease Research Center, likes to use that word too. It’s key to a “back to the drawing board” shift taking place in the Alzheimer’s field.
Last week’s announcement of a link between herpes viruses and Alzheimer’s, which Emory researchers contributed to, was part of this shift. Keep in mind: the idea that viral infection contributes to Alzheimer’s has been around a long time, and the Neuron paper doesn’t nail down causality.
Still, here’s an example quote from National Institute on Aging director Richard Hodes: “This is the first study to provide strong evidence based on unbiased approaches and large data sets that lends support to this line of inquiry.”
What is the bias that needs to be wrung out of the science? The “amyloid hypothesis” has dominated drug development for the last several years. Amyloid is a main constituent of the plaques that appear in the brains of people with Alzheimer’s, so treatments that counteract amyloid’s accumulation should help, right? Unfortunately, antibodies against amyloid or inhibitors of enzymes that process it generally haven’t worked out in big clinical trials, although the possibility remains that they weren’t introduced early enough to have a decent effect. Read more
Removal of a regulatory gene called LSD1 in adult mice induces changes in gene activity that look unexpectedly like Alzheimer’s disease, scientists have discovered.
Researchers also discovered that LSD1 protein is perturbed in brain samples from humans with Alzheimer’s disease and frontotemporal dementia (FTD). Based on their findings in human patients and mice, the research team is proposing LSD1 as a central player in these neurodegenerative diseases and a drug target.
In the brain, LSD1 (lysine specific histone demethylase 1) maintains silence among genes that are supposed to be turned off. When the researchers engineered mice that have the LSD1 gene snipped out in adulthood, the mice became cognitively impaired and paralyzed. Plenty of neurons were dying in the brains of LSD1-deleted mice, although other organs seemed fine. However, they lacked aggregated proteins in their brains, like those thought to drive Alzheimer’s disease and FTD.
“In these mice, we are skipping the aggregated proteins, which are usually thought of as the triggers of dementia, and going straight to the downstream effects,” says David Katz, PhD, assistant professor of cell biology at Emory University School of Medicine. 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.
The title of Keqiang Ye’s recent Nature Communications paper contains a provocative name for an enzyme: delta-secretase.
Just from its name, one can tell that a secretase is involved in secreting something. In this case, that something is beta-amyloid, the toxic protein fragment that tends to accumulate in the brains of people with Alzheimer’s disease.
Many Alzheimer’s researchers have studied gamma- and beta-secretases, but a review of the literature reveals that so far, only Ye and his colleagues have used the term delta-secretase.
This enzyme previously was called AEP, for asparagine endopeptidase. AEP appears to increase activity in the brain with aging and cleaves APP (amyloid precursor protein) in a way that makes it easier for the real bad guy, beta-secretase, to produce bad beta-amyloid.*At Alzforum, Jessica Shugart describes the enzyme this way:
Like a doting mother, AEP cuts APP into bite-sized portions for toddler BACE1 [beta-secretase] to chew on, facilitating an increase in beta-amyloid production.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.