Large-scale analysis links glucose metabolism proteins to Alzheimer's disease biology

April 13, 2020
NIH/National Institute on Aging

In the largest study to date of proteins related to Alzheimer's disease, a team of researchers has identified disease-specific proteins and biological processes that could be developed into both new treatment targets and fluid biomarkers. The findings suggest that sets of proteins that regulate glucose metabolism, together with proteins related to a protective role of astrocytes and microglia -- the brain's support cells -- are strongly associated with Alzheimer's pathology and cognitive impairment.




https://www.sciencedaily.com/releases/2020/04/200413120031.htm








The study, part of the Accelerating Medicines Partnership for Alzheimer's Disease (AMP-AD), involved measuring the levels and analyzing the expression patterns of more than 3,000 proteins in a large number of brain and cerebrospinal fluid samples collected at multiple research centers across the United States. This research was funded by the National Institutes of Health's National Institute on Aging (NIA) and published April 13 in Nature Medicine.

"This is an example of how the collaborative, open science platform of AMP-AD is creating a pipeline of discovery for new approaches to diagnosis, treatment and prevention of Alzheimer's disease," said NIA Director Richard J. Hodes, M.D. "This study exemplifies how research can be accelerated when multiple research groups share their biological samples and data resources."

The research team, led by Erik C.B. Johnson, M.D., Ph.D, Nicholas T. Seyfried, Ph.D., and Allan Levey, M.D., Ph.D., all at the Emory School of Medicine, Atlanta, analyzed patterns of protein expression in more than 2,000 human brain and nearly 400 cerebrospinal fluid samples from both healthy people and those with Alzheimer's disease. The paper's authors, which included Madhav Thambisetty, M.D., Ph.D., investigator and chief of the Clinical and Translational Neuroscience Section in the NIA's Laboratory of Behavioral Neuroscience, identified groups (or modules) of proteins that reflect biological processes in the brain.

The researchers then analyzed how the protein modules relate to various pathologic and clinical features of Alzheimer's and other neurodegenerative disorders. They saw changes in proteins related to glucose metabolism and an anti-inflammatory response in glial cells in brain samples from both people with Alzheimer's as well as in samples from individuals with documented brain pathology who were cognitively normal. This suggests, the researchers noted, that the anti-inflammatory processes designed to protect nerve cells may have been activated in response to the disease.

The researchers also set out to reproduce the findings in cerebrospinal fluid. The team found that, just like with brain tissue, the proteins involved in the way cells extract energy from glucose are increased in the spinal fluid from people with Alzheimer's. Many of these proteins were also elevated in people with preclinical Alzheimer's, i.e., individuals with brain pathology but without symptoms of cognitive decline. Importantly, the glucose metabolism/glial protein module was populated with proteins known to be genetic risk factors for Alzheimer's, suggesting that the biological processes reflected by these protein families are involved in the actual disease process.

"We've been studying the possible links between abnormalities in the way the brain metabolizes glucose and Alzheimer's-related changes for a while now," Thambisetty said. "The latest analysis suggests that these proteins may also have potential as fluid biomarkers to detect the presence of early disease."

In a previous study, Thambisetty and colleagues, in collaboration with the Emory researchers, found a connection between abnormalities in how the brain breaks down glucose and the amount of the signature amyloid plaques and tangles in the brain, as well as the onset of symptoms such as problems with memory.

"This large, comparative proteomic study points to massive changes across many biological processes in Alzheimer's and offers new insights into the role of brain energy metabolism and neuroinflammation in the disease process," said Suzana Petanceska, Ph.D., program director at NIA overseeing the AMP-AD Target Discovery Program. "The data and analyses from this study has already been made available to the research community and can be used as a rich source of new targets for the treatment and prevention of Alzheimer's or serve as the foundation for developing fluid biomarkers."

Brain tissue samples came from autopsy of participants in Alzheimer's disease research centers and several epidemiologic studies across the country, including the Baltimore Longitudinal Study of Aging (BLSA), Religious Orders Study (ROS) and Memory and Aging Project (MAP), and Adult Changes in Thought (ACT) initiatives. The brain collections also contained samples from individuals with six other neurodegenerative disorders as well as samples representing normal aging, which enabled the discovery of molecular signatures specific for Alzheimer's. Cerebrospinal fluid samples were collected from study participants at the Emory Goizueta Alzheimer's Disease Research Center. These and other datasets are available to the research community through the AD Knowledge Portal, the data repository for the AMP-AD Target Discovery Program, and other NIA supported team-science projects operating under open science principles.



Story Source:

Materials provided by NIH/National Institute on Aging. Note: Content may be edited for style and length.


Journal Reference:
Erik C. B. Johnson, Eric B. Dammer, Duc M. Duong, Lingyan Ping, Maotian Zhou, Luming Yin, Lenora A. Higginbotham, Andrew Guajardo, Bartholomew White, Juan C. Troncoso, Madhav Thambisetty, Thomas J. Montine, Edward B. Lee, John Q. Trojanowski, Thomas G. Beach, Eric M. Reiman, Vahram Haroutunian, Minghui Wang, Eric Schadt, Bin Zhang, Dennis W. Dickson, Nilüfer Ertekin-Taner, Todd E. Golde, Vladislav A. Petyuk, Philip L. De Jager, David A. Bennett, Thomas S. Wingo, Srikant Rangaraju, Ihab Hajjar, Joshua M. Shulman, James J. Lah, Allan I. Levey, Nicholas T. Seyfried. Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation. Nature Medicine, 2020; DOI: 10.1038/s41591-020-0815-6

Virginia Governor Pushes State Further Left by Signing Series of Progressive Bills

Daniel Davis April 13, 2020




https://citizentruth.org/virginia-governor-pushes-state-further-left-by-signing-series-of-progressive-bills/







Democratic Gov. Ralph Northam signed a series of bills on Friday that will bring to fruition several progressive policy ideals when they go into effect July 1.

While much of life has been on hold due to the COVID-19 pandemic, the government of Virginia continues to enact new laws unrelated to the virus. Democratic Gov. Ralph Northam signed a series of bills on Friday that will bring to fruition several progressive policy ideals when they go into effect July 1.
Protecting the Right to Choose

Northam enacted a new law that removes several regulations on abortions, Caroline Kelly reported for CNN. Currently, patients must have an ultrasound 24 hours before an abortion in addition to counseling. The law will also empower nurse practitioners to perform the procedure in the first trimester of pregnancy, which was previously restricted to only physicians.

“No more will legislators in Richmond — most of whom are men — be telling women what they should and should not be doing with their bodies,” Northam said. The new law “will make women and families safer, and I’m proud to sign it into law,” he continued.

Although Democratic lawmakers praised the bill’s signing, anti-abortion activists were not as thrilled.

“What Gov. Northam did today was sign into law a measure that protections abortionists at the expense of women’s safety and the lives of more unborn children who will die because no information is given to their mothers,” said Olivia Gans Turner, president of the Virginia Society for Human Life.
Expanding Non-Discrimination to Include LGBTQ

The governor also signed the Virginia Values Act, the first law of its kind for a southern state, NBC 29 reported. The law prohibits employers, landlords, and credit institutions from discriminating on the basis of sexual orientation and gender identity.


“No longer will LGBTQ Virginians have to fear being fired, evicted, ordered need service in public places because of who they are,” Northam said. “This legislation sends a strong, clear message — Virginia is a place where all people are welcome to live, work, visit, and raise a family.”

The Supreme Court is currently deliberating on three cases related to LGBTQ rights. The central argument in those cases is that Title VII of the Civil Rights Act includes gender identity and sexual orientation under the label of “sex.” Since the law in question is a federal one and not an issue of whether states can provide stronger protections, Virginia’s law would be unaffected by the eventual Supreme Court rulings.
Taking Care of the Environment

A pair of laws signed by Northam are aimed at protecting the environment. The Virginia Clean Economy Act mandates energy companies within the state, Dominion Energy Virginia and Appalachian Power, be 100-percent carbon-free by 2045 and 2050, respectively. Furthermore, the law mandates the closure of all coal plants before 2025.

The Clean Energy and Community Flood Preparedness Act introduces a carbon dioxide cap-and-trade program. The Department of Environmental Quality will oversee the marketplace for exchanging allowances, WDBJ 7 reported.

Money raised with the cap-and-trade program will go toward the Virginia Community Flood Preparedness Fund. The low-interest program will be offered to communities prone to flooding to implement preventative measures.
Election Day Holiday

As debate rages about mail-in-voting initiatives and funding for the US Postal Service ahead of the Nov. 3 election, Northam signed a law making the day a holiday. The law also removes a photo ID requirement and allows for early voting up to 45 days before the election, CNN reported.

“Voting is a fundamental right, and these new laws strengthen our democracy by making it easier to cast a ballot, not harder,” the governor said. “No matter who you are or where you live in Virginia, your voice deserves to be heard. I’m proud to sign these bills into law.”

Alongside creating an Election Day holiday, the law repeals the Lee-Jackson Day holiday. The event commemorated Confederate civil war leaders Robert E. Lee and Thomas “Stonewall” Jackson. Northam said the holiday “commemorates a lost cause. It’s time to move on.”

Northam also signed a related bill that authorizes local governments to remove Confederate monuments, statues, and memorials. The previous state law had prohibited the action, NBC 29 reported. The governor also began the process of removing the statue of Lee at the US Capitol. Each state has two statues in the National Statuary Hall Collection and Virginia donated one of Lee during early 1900s.
Gun Control

Gov. Northam instituted several gun control measures including enhanced background checks, a red flag law, and restrictions for handgun purchases. Last year, a shooter killed 12 people at Virginia Beach.

“We lose too many Virginians to gun violence, and it is past time we took bold, meaningful action to make our communities safer,” Northam said. “I was proud to work with legislators and advocates on these measures, and I am proud to sign them into law. These common-sense laws will save lives.”

The law requires background checks for all gun sales while limiting handgun purchases to one per month. A red flag law will permit law enforcement to temporarily confiscate weapons if a gun owner is considered a danger to themself or others, according to USA Today.

President Donald Trump previously weighed in on the discussion of enacting gun laws in Virginia.


“Your 2nd Amendment is under very serious attack in the Great Commonwealth of Virginia. That’s what happens when you vote for Democrats, they will take your guns away,” Trump said.

The gun law did not include a ban on assault rifles, but Northam said it would come soon.

“We can’t stop here. We need to keep working on this issue. It will be year after year,” he said.

Our Post-Pandemic Future

Will human civilization simply resume course or will we recognize the need for numerous far-reaching reforms?




https://consortiumnews.com/2020/04/13/patrick-lawrence-our-post-pandemic-future/







Full restoration or fundamental change: As the Covid–19 infection and fatality curves at last begin to flatten, the entire world now asks which of these lies in our post–pandemic future. Will human civilization simply resume its course — its destructive, inequitable course, along which lies too much suffering — or will there be a sobering up, let us call it, a recognition that very far-reaching reforms are needed in too many spheres to count?

Another way to pose the question: Is humanity any longer capable of self-correction? Or has the dreadful prevalence of neoliberal thinking denuded us — we in Western, post-democracies, that is — of all will in the face of circumstances that require it, along with a determination to act imaginatively and bravely?

No one anywhere can credibly turn in an answer to this question — not yet. But several months into the Covid–19 crisis, it does not seem we Westerners are able to unmoor ourselves sufficiently from what can only be called the perverse security of our too-familiar insecurities. We do not appear to trust ourselves to depart from the the hellishly precarious life for so many in a neoliberal world.

Expressions of hope for a different kind of future are everywhere. In here-and-there fashion, there are signs it is justified. I am not much for monarchies, but one must say the Queen rose impressively to the occasion in her “We will meet again” speech to Britain last week. The grainy frames of all those wartime films depicting British gumption seemed to flicker by. It was the right thing to do at the right moment, especially given the prime minister (whatever one may think of him) was then on oxygen in an intensive-care ward. It has had the desired effect.

At about the same time, the British government asked for volunteers to assist the National Health Service to attend to the most vulnerable Britons. Whitehall expected 250,000 hands to go up — and got triple that number of applicants. “A stirring display of British national solidarity,” the ever–Anglophilic New York Times called it. It was, one has to say.



In this same line, the Financial Times published an editorial last week that has to be counted remarkable for what was said as well as who was saying it. “Virus lays bare the frailty of the social contract,” the headline announced. The paper of City of London stockbrokers then laid out a program worthy of left Labourites such as the late Michael Foote or the recently defeated Jeremy Corbyn. Here is the pithiest paragraph:


“Radical reforms — reversing the prevailing policy direction of the last four decades — will need to be put on the table. Governments will have to accept a more active role in the economy. They must see public services as investments rather than liabilities, and look for ways to make labour markets less insecure. Redistribution will again be on the agenda; the privileges of the elderly and wealthy in question. Policies until recently considered eccentric, such as basic income and wealth taxes, will have to be in the mix.”

Behind the FT’s editorial surprise lay another. The budget Prime Minister Boris Johnson made public in February turned British politics upside down. Here was a true-blue Tory committed to equalizing the UK’s economic geography — “leveling up” is Johnson’s phrase — to the benefit of disadvantaged regions that once were Britain’s industrial backbone. A high-speed rail line to the rust-belt North, worker-training programs, big new spending on the N.H.S. — Johnson’s plans amount to a kind of Tory populism, all-out Keynesianism from the party of big business.

It is tempting to read into these developments in the money center across the pond a harbinger of a fundamental shift — an imminent abandonment at last of the ruinous neoliberal economic model.

Were this so, it would stand as the single most positive outcome possible as the Covid–19 crisis recedes, whenever this proves to be. But any such interpretation would be incautious, especially in the American case. It is more likely these events will turn out exceptions proving the rule — the rule that nothing need change and nothing will.

Zero-Sum Nationalism

Rather than international unity in the face of a common challenge, the response to Coivd–19 among the industrialized post-democracies is zero-sum nationalism, every nation for itself and implicitly against all others. The virus’s savage spread has already left the European Union a shambles.

“Solidarity becomes a hollow mantra,” as Shada Islam, a prominent think-tank inhabitant, told The Guardian over the weekend. So have the Brussels technocrats punted the exceptional vision of the European project’s founders.

Prominent among the exceptions to this are those non–Western nations now coming selflessly to the aid of the afflicted in Europe as well as their allies in the non–West. This is another tragic irony in the making, a bitter one: The unenlightened responses to Covid–19 among the major Western powers are likely to leave the world more divided, not less, once the threat subsides — poor vs. wealthy, South vs. North.



America’s domestic response to the Covid–19 onslaught makes Europe’s look like a model case study in some business school curriculum. Bottlenecks are everywhere. The trillions the Federal Reserve and Treasury have committed are stuck in clotted bureaucracies and reluctant-to-lend banks such that small businesses are going under and families are going hungry while private-equity firms are pushing their way into loan programs not remotely intended for them. Talk about free-for-alls.

Management expertise used to be part of America’s claim to exceptionalism. “Can do,” a phrase from the first half of the last century, proved out as the U.S. mobilized for the second world war. By the early–1940s American shipyards were floating one new Liberty ship a day, believe it or not. The rest of the world noticed. In the postwar decades, the missionaries of American management theory were welcomed as demigods across both oceans.

And now? Who can imagine anyone taking an interest in American management methods? Let’s put it this way: Surrendering our chosen-people consciousness, whenever we are finally required to do so, will inevitably be bitter. Maybe America’s multiple failures since Covid–19 hit will set this process in motion. This would be salutary, and of no small consequence either at home or in global affairs.

Two other issues, resolved or unresolved as they may prove, will define how well or poorly America emerges from this crisis. If Americans cannot get a socialized health-care system on the back of the Covid–19 fight, it is difficult to imagine what it will take to achieve health-care justice. If Americans cannot at least begin taming the Pentagon beast, ditto.

In neither case does one find cause for optimism, difficult as this is to admit. There is hope and there is power, and we know how these face-offs almost always end.

A Psychological Crisis



There has been no stirring display of American national solidarity, if you have not noticed. We are all sitting around — more or less in silence, so far as one can make out — while corporate captains and a corrupt administration chart the course forward. Why is this? Do not look for any answer in politics, or in economic advantage or disadvantage. The problem transcends all such considerations.

Covid–19 is a health crisis, and very soon it will be an economic crisis few alive today will be able to fathom. But it is above all a psychological crisis. It is essential to understand this.

Americans are no longer the people who sent a Liberty ship a day to sea. “Can do” is now closer to “can’t do,” “rather not,” or “why should I?” The drug of material consumption separates us from that earlier, no-less-critical time. Hula hoops and Mustangs have left us very sadly atomized, a vast “lonely crowd,” somnambulant. And helpless to escape ourselves. Let us not be mistaken: This is the true American crisis Covid–19 bares.

A friend forwarded an extract from a commentary Linh Dinh, the wonderfully freewheeling Vietnamese–American poet, published in The Unz Review over the weekend. It is pertinent to our case:


“With our plastic, skyscraping project imploding, perhaps we can devolve into a breed that’s simpler, muddier and gnarlier, less distracted so much saner, and more honest to those around us, since we can’t escape them. Perhaps we’ll become men again.

Or maybe not. Cowed by fear, oozing despair and dependent on those who have clearly betrayed us at each turn, we’ll become even more catatonic in our cells. After lockdown, we’ll stumble like blind fools, into this farce, again.”

Later in the day this same friend sent along a line from Don De Lillo’s “White Noise” and I pass it on:

“Here we don’t die. We shop. But the difference is less marked than you think.”

The Coronavirus Crash

https://www.youtube.com/watch?v=hERGypOruqo&feature

Hero Captain may be reinstated, IMF predicts next Great Depression

https://www.youtube.com/watch?v=Zkqvmi2fg_0&feature=em-lsp

COVID-19 = Influenza? NO! It is not ‘just like the flu’…

https://www.youtube.com/watch?v=_gG9_EOtBJg

India's PM Modi extends lockdown till May 3

https://www.youtube.com/watch?v=iji_SV7H_rY