New Player in Alzheimer’s Disease Pathogenesis Identified

Scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) have shown that a protein called membralin is critical for keeping Alzheimer’s disease pathology in check. The study, published in Nature Communications, shows that membralin regulates the cell’s machinery for producing beta-amyloid (or amyloid beta, Aβ), the protein that causes neurons to die in Alzheimer’s disease.

“Our results suggest a new path toward future treatments for Alzheimer’s disease,” says Huaxi Xu, Ph.D., the Jeanne and Gary Herberger Leadership Chair of SBP’s Neuroscience and Aging Research Center. “If we can find molecules that modulate membralin, or identify its role in the cellular protein disposal machinery known as the endoplasmic reticulum-associated degradation (ERAD) system, this may put the brakes on neurodegeneration.”

ERAD is the mechanism by which cells get rid of proteins that are folded incorrectly in the ER. It also controls the levels of certain mature, functional proteins. Xu’s team found that one of the fully formed, working proteins that ERAD regulates is a component of an enzyme called gamma secretase that generates Aβ.

This discovery helps fill in the picture of how Alzheimer’s disease, an incredibly complicated disorder influenced by many genetic and environmental factors. No therapies have yet been demonstrated to slow progression of the disease, which affects around 47 million people worldwide. Until such drugs are developed, patients face a steady, or sometimes rapid, decline in memory and reasoning.

Memory loss in Alzheimer’s results from the toxic effects of Aβ, which causes connections between neurons to break down. Aβ is created when gamma secretase cuts the amyloid precursor protein into smaller pieces. While Aβ is made in all human brains as they age, differences in the rate at which it is produced and eliminated from the brain and in how it affects neurons, means that not everyone develops dementia.

“We were interested in membralin because of its genetic association with Alzheimer’s, and in this study we established the connection between membralin and Alzheimer’s based on findings from the laboratory of a former colleague at SBP, Professor Dongxian Zhang,” Xu explains. “That investigation showed that eliminating the gene for membralin leads to rapid motor neuron degeneration, but its cellular function wasn’t clear.”

Using proteomics, microscopic analysis, and functional assays, the group provided definitive evidence that membralin functions as part of the ERAD system. Later, they found that membralin-dependent ERAD breaks down a protein that’s part of the gamma secretase enzyme complex, and that reducing the amount of membralin in a mouse model of Alzheimer’s exacerbates neurodegeneration and memory problems.

“Our findings explain why mutations that decrease membralin expression would increase the risk for Alzheimer’s,” Xu comments. “This would lead to an accumulation of gamma secretase because its degradation is disabled, and the gamma-secretase complex would then generate more Aβ. Those mutations are rare, but there may be other factors that cause neurons to make less membralin.”

Xu and colleagues also observed lower levels of membralin, on average, in the brains of patients with Alzheimer’s than in unaffected individuals, demonstrating the relevance of their findings to humans.

“Previous studies have suggested that ERAD contributes to many diseases where cells become overwhelmed by an irregular accumulation of proteins, including Alzheimer’s,” says Xu. “This study provides conclusive, mechanistic evidence that ERAD plays an important role in restraining Alzheimer’s disease pathology. We now plan to search for compounds that enhance production of membralin or the rate of ERAD to test whether they ameliorate pathology and cognitive decline in models of Alzheimer’s. That would further support the validity of this mechanism as a drug target.”

Pre-Clinical Study Suggests Parkinson’s Could Start in Gut Endocrine Cells

Recent research on Parkinson’s disease has focused on the gut-brain connection, examining patients’ gut bacteria, and even how severing the vagus nerve connecting the stomach and brain might protect some people from the debilitating disease.

But scientists understand little about what’s happening in the gut — the ingestion of environmental toxins or germs, perhaps — that leads to brain damage and the hallmarks of Parkinson’s such as tremors, stiffness and trouble walking.

Duke University researchers have identified a potential new mechanism in both mice and human endocrine cells that populate the small intestines. Inside these cells is a protein called alpha-synuclein, which is known to go awry and lead to damaging clumps in the brains of Parkinson’s patients, as well as those with Alzheimer’s disease.

According to findings published June 15 in the journal JCI Insight, Duke researchers and collaborators from the University of California, San Francisco, hypothesize that an agent in the gut might interfere with alpha-synuclein in gut endocrine cells, deforming the protein. The deformed or misfolded protein might then spread via the nervous system to the brain as a prion, or infectious protein, in similar fashion to mad cow disease.

“There is abundant evidence that misfolded alpha-synuclein is found in the nerves of the gut before it appears in the brain, but exactly where this misfolding occurs is unknown,” said gastroenterologist Rodger Liddle, M.D., senior author of the paper and professor of medicine at Duke. “This is another piece of evidence that supports the hypothesis that Parkinson’s arises in the gut.”

Alpha-synuclein is the subject of much ongoing research on Parkinson’s, as it’s the main component of Lewy bodies, or toxic protein deposits that take up residence in brain cells, killing them from the inside. The clumps form when alpha-synuclein develops a kink in its normally spiral structure, making it ‘sticky,’ and prone to aggregating, Liddle said.

But how would a protein go from traveling through the inner-most ‘tube’ of the intestine, where there are no nerve cells, into the nervous system? That’s a question Liddle and colleagues sought to answer in a 2015 manuscript published in the Journal of Clinical Investigation. Although the main function of gut endocrine cells is to regulate digestion, the Duke researchers found these cells also have nerve-like properties.

Rather than using hormones to communicate indirectly with the nervous system, these gut endocrine cells physically connect to nerves, providing a pathway to communicate with the brain, Liddle said. The researchers demonstrated this in a stunning time-lapse video (2015, Journal of Clinical Investigation) in which a gut endocrine cell is placed under the microscope near a neuron. In just a few hours, the endocrine cell moves toward the neuron and fibers appear between them as they establish communication.

Liddle and other scientists were astonished at the video, he said, because the endocrine cells — which are not nerves — were behaving like them. This suggests they are able to communicate directly with the nervous system and brain.

With the new finding of alpha-synuclein in endocrine cells, Liddle and colleagues now have a working explanation of how malformed proteins can spread from the inside of the intestines to the nervous system, using a non-nerve cell that acts like a nerve.

Liddle and colleagues plan to gather and examine the gut endocrine cells from people with Parkinson’s to see if they contain misfolded or otherwise abnormal alpha-synuclein. New clues about this protein could help scientists develop a biomarker that could diagnose Parkinson’s disease earlier, Liddle said.

New leads on alpha-synuclein could also aid the development of therapies targeting the protein. Scientists have been investigating treatments that could prevent alpha-synuclein from becoming malformed, but much of the research is still in its early stages, Liddle said.

“Unfortunately, there aren’t great treatments for Parkinson’s disease right now,” he said. “It’s conceivable down the road that there could be ways to prevent alpha-synuclein misfolding, if you can make the diagnosis early.”

In addition to Liddle, study authors include Rashmi Chandra of Duke, Annie Hiniker and Yien-Ming Kuo of the University of California, San Francisco (UCSF), and Robert L. Nussbaum of UCSF and the Invitae Corporation.

Diagnostic biomarkers in saliva show promise in recognizing early Alzheimer’s disease

Your spit may hold a clue to future brain health. Investigators at the Beaumont Research Institute, part of Beaumont Health in Michigan, are hopeful that their study involving small molecules in saliva will help identify those at risk of developing Alzheimer’s disease – a neurologic condition predicted to reach epidemic proportions worldwide by 2050.

Their study, “Diagnostic Biomarkers of Alzheimer’s Disease as Identified in Saliva using 1H NMR-Based Metabolomics” was published in the Journal of Alzheimer’s Disease 58(2) on May 16.

Investigators found salivary molecules hold promise as reliable diagnostic biomarkers. The study exemplifies the quest by scientists to combat Alzheimer’s disease, a degenerative brain disorder with no cure and few reliable diagnostic tests. In the United States, Alzheimer’s is a health epidemic affecting more than 5 million Americans. Investigators seek to develop valid and reliable biomarkers, diagnosing the disease in its earliest stages before brain damage occurs and dementia begins.

Researcher Stewart Graham, Ph.D., said, “We used metabolomics, a newer technique to study molecules involved in metabolism. Our goal was to find unique patterns of molecules in the saliva of our study participants that could be used to diagnose Alzheimer’s disease in the earliest stages, when treatment is considered most effective. Presently, therapies for Alzheimer’s are initiated only after a patient is diagnosed and treatments offer modest benefits.”

Metabolomics is used in medicine and biology for the study of living organisms. It measures large numbers of naturally occurring small molecules, called metabolites, present in the blood, saliva and tissues. The pattern or fingerprint of metabolites in the biological sample can be used to learn about the health of the organism.

“Our team’s study demonstrates the potential for using metabolomics and saliva for the early diagnosis of Alzheimer’s disease,” explained Dr. Graham. “Given the ease and convenience of collecting saliva, the development of accurate and sensitive biomarkers would be ideal for screening those at greatest risk of developing Alzheimer’s. In fact, unlike blood or cerebrospinal fluid, saliva is one of the most noninvasive means of getting cellular samples and it’s also inexpensive.”

The study participants included 29 adults in three groups: mild cognitive impairment, Alzheimer’s disease and a control group. After specimens were collected, the researchers positively identified and accurately quantified 57 metabolites. Some of the observed variances in the biomarkers were significant. From their data, they were able to make predictions as to those at most risk of developing Alzheimer’s. Said Dr. Graham, “Worldwide, the development of valid and reliable biomarkers for Alzheimer’s disease is considered the No. 1 priority for most national dementia strategies. It’s a necessary first step to design prevention and early-intervention research studies.”

As Americans age, the number of people affected by Alzheimer’s is rising dramatically. According to the Alzheimer’s Association, by 2050, it’s estimated the number of Americans living with Alzheimer’s disease will triple to about 15-16 million.

Alzheimer’s disease is a type of dementia affecting a person’s ability to think, communicate and function. It greatly impacts their relationships, their independence and lifestyle. The condition’s toll not only affects millions of Americans, but in 2017, it could cost the nation $259 billion.

Researchers Identify How Inflammation Spreads Through the Brain After Injury

Findings Could Transform How Understanding of Brain Injury and Disease

Researchers have identified a new mechanism by which inflammation can spread throughout the brain after injury. This mechanism may explain the widespread and long-lasting inflammation that occurs after traumatic brain injury, and may play a role in other neurodegenerative diseases.

The findings were published today in a study in the Journal of Neuroinflammation.

This new understanding has the potential to transform how brain inflammation is understood, and, ultimately, how it is treated. The researchers showed that microparticles derived from brain inflammatory cells are markedly increased in both the brain and the blood following experimental traumatic brain injury (TBI). These microparticles carry pro-inflammatory factors that can activate normal immune cells, making them potentially toxic to brain neurons. Injecting such microparticles into the brains of uninjured animals creates progressive inflammation at both the injection site and eventually in more distant sites.

Research has found that neuroinflammation often goes on for years after TBI, causing chronic brain damage. The researchers say that the microparticles may play a key role in this process.
Chronic inflammation has been increasingly implicated in the progressive cell loss and neurological changes that occur after TBI. These inflammatory microparticles may be a key mechanism for chronic, progressive brain inflammation and may represent a new target for treating brain injury.

The researchers on the paper include four University of Maryland School of Medicine researchers: Alan Faden, Stephen R. Thom, Bogdan A. Stoica, and David Loane.

“These results potentially provide a new conceptual framework for understanding brain inflammation and its relationship to brain cell loss and neurological deficits after head injury, and may be relevant for other neurodegenerative disorders such as Alzheimer disease in which neuroinflammation may also play a role,” said Dr. Faden. “The idea that brain inflammation can trigger more inflammation at a distance through the release of microparticles may offer novel treatment targets for a number of important brain diseases.”

The researchers studied mice, and found that in animals who had a traumatic brain injury, levels of microparticles in the blood were much higher. Because each kind of cell in the body has a distinct fingerprint, the researchers could track exactly where the microparticles came from. The microparticles they looked at in this study are released from cells known as microglia, immune cells that are common in the brain. After an injury, these cells often go into overdrive in an attempt to fix the injury. But this outsized response can change protective inflammatory responses to chronic destructive ones.

The findings have important potential clinical implications. The researchers say that microparticles in the blood have the potential to be used as a biomarker – a way to determine how serious a brain injury may be. This could help guide treatment of the injuries, whose severity is often difficult to gauge.

They also found that exposing the inflammatory microparticles to a compound called PEG-TB could neutralize them. This opens up the possibility of using that compound or others to treat TBI, and perhaps even other neurodegenerative diseases.

Estrogen Patch in Newly Postmenopausal Women May Reduce Alzheimer’s Risk

Can estrogen preserve brain function and decrease the risk of Alzheimer’s disease when given early in menopause? Newly postmenopausal women who received estrogen via a skin patch had reduced beta-amyloid deposits, the sticky plaques found in the brains of people with Alzheimer’s disease, a Mayo Clinic study published this month in the Journal of Alzheimer’s Disease found. Ultimately, these deposits harm neurons, leading to cognitive problems.

In the study, women with APOE e4 — one form of the most common gene associated with late-onset Alzheimer’s disease — had lower levels of amyloid deposits.

“This study showed, for the first time, that the brain amyloid deposition ─ a hallmark of Alzheimer’s disease ─ is reduced in newly postmenopausal women who received 17beta-Estradiol patch form of hormone therapy,” says lead author Kejal Kantarci, M.D., a Mayo Clinic radiologist. “Women with APOE e4, who have a greater genetic risk for Alzheimer’s disease, particularly benefited from this therapy.”

Menopause is defined as occurring 12 months after a woman’s last menstrual period and marks the end of menstrual cycles. In the U.S., the average age of menopause is 51. A rapid decline in estrogen with menopause may be associated with an increased risk of Alzheimer’s disease risk in women.

The Women’s Health Initiative study by the National Institutes of Health (NIH) reported that menopausal hormone therapy started in women 65 or older increased the risk of dementia. In contrast, the multicenter Kronos Early Estrogen Prevention Study tested the hypothesis that healthy and younger women would respond to menopausal hormone therapy more favorably.

The Mayo Clinic study used data from the Kronos study to determine the effects of menopausal hormone therapy shortly after menopause, during the critical window of rapid estrogen depletion — five to 36 months past menopause. Researchers investigated the brain amyloid deposition in 68 women ages 42 to 59 who participated in the Kronos trial during this critical window. The researchers used positron emission tomography, also known as a PET scan, to look for the brain amyloid deposits three years after the trial ended.

Of the 68 women, 21 received estrogen via a skin patch, 17 received estrogen orally and 30 received a placebo. Amyloid deposition was lower in women who received the patch, compared to the placebo, and the effect was most apparent in women with the APOE e4 genotype. The oral treatment was not associated with lower amyloid deposition.

The authors are seeking funding to perform amyloid PET imaging at eight more Kronos Early Estrogen Prevention study sites around the U.S.

“If our results are confirmed in the larger group of women, this finding has the potential to change the concepts for preventive interventions that drive the Alzheimer’s disease field today,” Dr. Kantarci says. “It also may have a significant impact on women making the decision to use hormone therapy in the early postmenopausal years.”

Penn Medicine Team and Collaborators Receive NIH Award to Launch Genomics Center on Alzheimer’s Disease

A five-year, projected $10.8 million award from the National Institute on Aging (NIA), part of the National Institutes of Health (NIH), will establish the Coordinating Center for Genetics and Genomics of Alzheimer’s Disease, a joint venture of researchers from the Perelman School of Medicine at the University of Pennsylvania and five other institutions. Penn will receive an estimated $4.5 million from the grant.

The Center is led by Gerard D. Schellenberg, PhD, a professor of Pathology and Laboratory Medicine and Li-San Wang, PhD, an associate professor of Pathology and Laboratory Medicine, in partnership with investigators from five other sites — Boston University, Case Western Reserve University, Columbia University, the University of Miami, and the University of Indiana.
“By coordinating the identification of Alzheimer’s-related genes, the Center’s team aims to find new therapeutic targets to reduce the economic and human burden caused by this disease,” Schellenberg said. “This is an exciting opportunity to apply new technologies to improve our understanding of the biological pathways underlying this devastating disease. The new center will stimulate collaborations between hundreds of U.S. and international Alzheimer’s genetics researchers by aggregating and analyzing very large data sets and sharing the results. This type of global interaction is needed if we are to make progress in solving this devastating illness.”

Alzheimer’s disease, a progressive neurodegenerative disorder, has become an epidemic that currently affects as many as five million people age 65 and older in the United States, with economic costs that are comparable to, if not greater than, caring for those of heart disease or cancer. Available drugs only marginally affect disease severity and progression. While there is no way to prevent this disease, the discovery of genetic risk factors for Alzheimer’s is bringing researchers closer to learning how the genes work together and may help identify the most effective interventions.
“The Genomics Center will be a state-of-the-art national clearinghouse for Alzheimer’s genomics information based at Penn,” Wang said. “We have an important mission to move the field of Alzheimer’s genetics forward by coordinating all NIA-funded activities for the Alzheimer’s Disease Sequencing Project.”

Center collaborators will collect and “harmonize” available AD genetics and associated physiological data into a common database to maximize statistical power to find therapeutic targets.

“Data-sharing and collaboration among cutting-edge research teams is key to advancing our understanding of complex genetic underpinnings of Alzheimer’s and related dementias,” said NIA director Richard Hodes, MD. “This new Center will play an important role in achieving our nation’s ultimate research goal, outlined under the National Plan to Address Alzheimer’s Disease to prevent and effectively treat Alzheimer’s disease by 2025.”

The Genomics Center will also bring in data from other non-NIA-funded studies, reprocess into a consistent format, and add to the common database housed at the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS), the national genetics data repository for Alzheimer’s disease developed and maintained by Wang’s team since 2012 and the Data Coordinating Center for the ADSP. The Genomic Center will amass genomic sequence data from subjects with Alzheimer’s disease and elderly cognitively normal subjects and use these data to identify genes that cause or protect against AD and other diseases.
“As the amount of data acquired increases, this will be a valuable resource for the study of other genetic disorders at Penn and other institutions,” Wang said.

The NIH Alzheimer’s Disease Sequencing Program (ADSP), a collaboration that also began in 2012 between NIA and the National Human Genome Research Institute (NHGRI), also part of NIH, has been analyzing data from 6,000 volunteers with Alzheimer’s disease and 5,000 older cognitively normal, unaffected individuals. In addition, the teams will study genomic data from 111 large families with multiple Alzheimer’s disease members, of Caucasian and Caribbean Hispanic descent to identify rare genetic variants. For the next phase of the project, the new Center will analyze new sequence data from an additional 3,000 AD cases.

The Lauder and Newhouse Families Announce New Initiative to Find Treatments for Frontotemporal Degeneration

As of 2016, we still don’t have a single approved drug to cure or even slow the progression of diseases caused by damage to the brain’s neurons. The Alzheimer’s Drug Discovery Foundation (ADDF) and The Association for Frontotemporal Degeneration (AFTD) are determined to change that. Today, they announce a $10 million investment to develop effective treatments for frontotemporal degeneration (FTD), a complex form of dementia that affects more than 50,000 people in the United States.

The Lauder Foundation, Leonard A. Lauder, President, and Ronald S. Lauder have jointly committed $5 million, which will be combined with $5 million from the Samuel I. Newhouse Foundation to create The Treat FTD Fund. The fund, a joint program of AFTD and the ADDF, will accelerate clinical trials for FTD over the next decade. And it has the potential to advance treatments for other neurodegenerative diseases, such as Alzheimer’s, ALS and Parkinson’s.

Leonard A. Lauder, ADDF Board Co-Chairman, said: “My brother and co-chairman, Ronald S. Lauder, and I founded the ADDF to find treatments for Alzheimer’s and other causes of dementia. Partnerships have always been an important part of that mission because they allow us to combine resources and to develop effective drugs faster.”

Donald Newhouse, President of Advance Publications, Inc., added: “My wife, Susan, suffered from primary progressive aphasia, a form of FTD. My brother, Si, suffers from the same dementia. Si’s wife, Victoria, and I and our families are committed to research to find treatments and a cure for FTD and Alzheimer’s. This partnership between the ADDF and AFTD is a significant step forward in carrying out our commitment.”

The partners are optimistic that this initiative will encourage more funders to invest in drug research for FTD and other devastating neurodegenerative diseases. Walter J. Koroshetz, MD, Director of the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health, remarked: “The challenge of developing effective treatments for persons with FTD calls for an ‘all hands on deck’ effort. Collaborations like this one will bring great scientists to work on FTD, and set a tone of hope for what NIH and the private sector can achieve together.”

The ADDF and AFTD plan to support new drugs in clinical trials, as well as “repurposed” drugs. Repurposing, in which drugs approved for one disease are used for others, is a growing area of research because it pares down the enormous costs and time of traditional drug development. The Treat FTD Fund will build on recent successes of both foundations in early-stage drug discovery and biomarker development that make clinical trials possible and increase their odds of success. A “Request for Proposals,” expected to be announced this summer, will be available at www.alzdiscovery.org and www.theaftd.org.