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
Posted on July 3, 2018
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.
David Katz, PhD
The results were published Oct. 9 in Nature Communications.
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.
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.
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.
Aficionados of Alzheimer’s research may be familiar with other secretases. Gamma-secretase was the target of some once-promising drugs that failed in clinical trials, partly because they also inhibit Notch signaling, important for development and differentiation in several tissues. Now beta-secretase inhibitors are entering Alzheimer’s clinical trials, with similar concerns about side effects.
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
The importance of the SorLA or LR11 receptor in braking Alzheimer’s was originally defined here at Emory by Jim Lah and Allan Levey’s labs. Japanese researchers recently determined the structure of SorLA and published the results in Nature Structural and Molecular Biology. Their findings point toward a direct role for SorLA in binding toxic circulating beta-amyloid and transporting it to the lysosome for degradation. Hat tip to Alzforum.
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.
Posted on June 4, 2014
Scans can show beta amyloid, a protein associated with Alzheimer’s disease (right)
For the first time in 25 years, medical experts are proposing new diagnostic criteria aimed at better and earlier detection of Alzheimer’s disease (AD).
The guidelines, proposed by the National Institute on Aging (NIA) and the Alzheimer’s Association, update and revise the current Alzheimer’s criteria with modern technologies and the latest research advances.
According to the Alzheimerâ€™s Association, an estimated 5.3 million Americans have AD, most of them 65 and older. The disease is thought to begin years, possibly even decades, before symptoms are noticeable. But there is no single, generally accepted way to identify the disease in its earliest stages before symptoms are evident.
The new diagnostic guidelines focus on advances in detecting biomarkers for the disease, such as substances found in spinal fluid or appearing on cutting-edge brain imaging scans conducted with PET or MRI.
Emphasis will be on diagnosing early stages of the disease as soon as possible so that patients can take measures to slow the progression or prevent further damage.