Clinical Decline in Alzheimer’s Requires Plaque and Proteins
Without p-tau protein present, impact of amyloid is “not significantly different from zero”
According to a new study, the neuron-killing pathology of Alzheimer’s disease (AD), which begins before clinical symptoms appear, requires the presence of both amyloid-beta (a-beta) plaque deposits and elevated levels of an altered protein called p-tau.
Without both, progressive clinical decline associated with AD in cognitively healthy older individuals is “not significantly different from zero,” reports a team of scientists at the University of California, San Diego School of Medicine in the April 23 online issue of the Archives of Neurology.
“I think this is the biggest contribution of our work,” said Rahul S. Desikan, MD, PhD, research fellow and resident radiologist in the UC San Diego Department of Radiology and first author of the study. “A number of planned clinical trials – and the majority of Alzheimer’s studies – focus predominantly on a-beta. Our results highlight the importance of also looking at p-tau, particularly in trials investigating therapies to remove a-beta. Older, non-demented individuals who have elevated a-beta levels, but normal p-tau levels, may not progress to Alzheimer’s, while older individuals with elevated levels of both will likely develop the disease.”
The findings also underscore the importance of p-tau as a target for new approaches to treating patients with conditions ranging from mild cognitive impairment (MCI) to full-blown AD. An estimated 5.4 million Americans have AD. It’s believed that 10 to 20 percent of Americans age 65 and older have MCI, a risk factor for AD. Some current therapies appear to delay clinical AD onset, but the disease remains irreversible and incurable.
“It may be that a-beta initiates the Alzheimer’s cascade,” said Desikan. “But once started, the neurodegenerative mechanism may become independent of a-beta, with p-tau and other proteins playing a bigger role in the downstream degenerative cascade. If that’s the case, prevention with anti-a-beta compounds may prove efficacious against AD for older, non-demented individuals who have not yet developed tau pathology. But novel, tau-targeting therapies may help the millions of individuals who already suffer from mild cognitive impairment or Alzheimer’s disease.”
The new study involved evaluations of healthy, non-demented elderly individuals participating in the ongoing, multi-site Alzheimer’s Disease Neuroimaging Initiative, or ADNI. Launched in 2003, ADNI is a longitudinal effort to measure the progression of mild cognitive impairment and early-stage AD.
The researchers studied samples of cerebrospinal fluid (CSF) taken from ADNI participants.
How Genes Organize the Surface of the Brain
The first atlas of the surface of the human brain based upon genetic information has been produced by a national team of scientists, led by researchers at the University of California, San Diego School of Medicine and the VA San Diego Healthcare System. The work is published in the March 30 issue of the journal Science.
The atlas reveals that the cerebral cortex – the sheet of neural tissue enveloping the brain – is roughly divided into genetic divisions that differ from other brain maps based on physiology or function. The genetic atlas provides scientists with a new tool for studying and explaining how the brain works, particularly the involvement of genes.
“Genetics are important to understanding all kinds of biological phenomena,” said William S. Kremen, PhD, professor of psychiatry at the UC San Diego School of Medicine and co-senior author with Anders M. Dale, PhD, professor of radiology, neurosciences, and psychiatry, also at the UC San Diego School of Medicine.
According to Chi-Hua Chen, PhD, first author and a postdoctoral fellow in the UC San Diego Department of Psychiatry, “If we can understand the genetic underpinnings of the brain, we can get a better idea of how it develops and works, information we can then use to ultimately improve treatments for diseases and disorders.”
The human cerebral cortex, characterized by distinctive twisting folds and fissures called sulci, is just 0.08 to 0.16 inches thick, but contains multiple layers of interconnected neurons with key roles in memory, attention, language, cognition and consciousness.
Other atlases have mapped the brain by cytoarchitecture – differences in tissues or function. The new map is based entirely upon genetic information derived from magnetic resonance imaging (MRI) of 406 adult twins participating in the Vietnam Era Twin Registry (VETSA), an ongoing longitudinal study of cognitive aging supported in part by grants from the National Institutes of Health (NIH). It follows a related study published last year by Kremen, Dale and colleagues that affirmed the human cortical regionalization is similar to and consistent with patterns found in other mammals, evidence of a common conservation mechanism in evolution.
New Drug Target Improves Memory in Mouse Model of Alzheimer’s Disease
Researchers at the University of California, San Diego, the Medical University of South Carolina, the University of Cincinnati, and American Life Science Pharmaceuticals of San Diego have validated the protease cathepsin B (CatB) as a target for improving memory deficits and reducing the pathology of Alzheimer’s disease (AD) in an animal model representative of most AD patients. The study has been published in the online edition of the Journal of Alzheimer’s Disease.
According to investigator Vivian Y. H. Hook, PhD, professor of the UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences and professor of neurosciences, pharmacology and medicine at the UCSD School of Medicine, the study is important because it could lead to new therapeutics that improve the memory deficits of AD.
Abnormal accumulation of brain amyloid-β peptides (Aβ) is thought to cause the memory loss and amyloid plaque pathology of AD. Aβ peptides are “cut” out from a larger protein called the amyloid precursor protein (APP) by an enzymatic “scissor” called β-secretase, and aggregate to form plaques in the brain regions responsible for memory. Inhibiting the β-secretase “scissors” from “cutting” the APP with a drug would reduce brain Aβ levels and thereby improve memory deficits and reduce amyloid plaque pathology. The vast majority of AD patients have wild-type (WT) β-secretase activity and thus the WT β-secretase has been a target of great interest for a long time.
Another protease, BACE1, has long been thought to be the β-secretase involved in AD pathology, because deleting that gene from animal models reduces brain Aβ and plaque pathology. However, deleting the BACE1 gene was reported to make memory deficits worse in a transgenic model having WT β-secretase activity.
Hook and colleagues set off to find a WT β-secretase target, which improves memory deficits while reducing amyloid plaque pathology. In the current paper, the researchers show that CatB is such a target because deleting that gene in a transgenic mouse model having WT β-secretase activity improves memory deficits and reduces amyloid plaque, which develop in this model, mimicking that found in AD. In contrast, deleting the BACE1 gene in that transgenic model had no effect on memory deficits or pathology.
Stem-cell-derived neurons, made from patients with Alzheimer’s disease, provide a new tool for unraveling the mechanisms underlying the neurodegenerative disease. In this image, DNA is shown in blue, dendrites and cell bodies in red and endosomal markers Rab5 and EEA1 in green and orange, respectively.
Researchers Induce Alzheimer’s Neurons From Pluripotent Stem Cells
First-ever feat provides new method to understand cause of disease, develop drugs
Led by researchers at the University of California, San Diego School of Medicine, scientists have, for the first time, created stem cell-derived, in vitro models of sporadic and hereditary Alzheimer’s disease (AD), using induced pluripotent stem cells from patients with the much-dreaded neurodegenerative disorder.
“Creating highly purified and functional human Alzheimer’s neurons in a dish – this has never been done before,” said senior study author Lawrence Goldstein, PhD, professor in the Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute Investigator and director of the UC San Diego Stem Cell Program. “It’s a first step. These aren’t perfect models. They’re proof of concept. But now we know how to make them. It requires extraordinary care and diligence, really rigorous quality controls to induce consistent behavior, but we can do it.”
The feat, published in the January 25 online edition of the journal Nature, represents a new and much-needed method for studying the causes of AD, a progressive dementia that afflicts approximately 5.4 million Americans. More importantly, the living cells provide an unprecedented tool for developing and testing drugs to treat the disorder.
“We’re dealing with the human brain. You can’t just do a biopsy on living patients,” said Goldstein. “Instead, researchers have had to work around, mimicking some aspects of the disease in non-neuronal human cells or using limited animal models. Neither approach is really satisfactory.”
National Academy of Sciences Honors UC San Diego Professor
The National Academy of Sciences (NAS) will honor 17 individuals with awards in recognition of their extraordinary scientific achievements in a wide range of fields spanning the physical, biological, and social sciences. Among them is Larry R. Squire, PhD, Distinguished Professor of Psychiatry, Neurosciences, and Psychology at the University of California, San Diego School of Medicine, and research career scientist at VA Medical Center, San Diego.
Squire is the recipient of the National Academy of Sciences Award for Scientific Reviewing. A leader in the field of memory and foremost expert in the anatomical and functional basis of mammalian memory, Squire is honored for “his prolific and comprehensive reviews on memory research, for his seminal books that are standards in the field, and critical reviews of books on neuroscience.”
The prize of $10,000, presented this year in the field of neuroscience, recognizes excellence in scientific reviewing. The award is supported by Annual Reviews, the Institute for Scientific Information, and The Scientist in honor of J. Murray Luck.
UC San Diego's William C. Mobley Recognized for Contributions to Down Syndrome
Jérôme Lejeune Foundation U.S. Scientific Committee Chair acknowledged by U.S. Congress, honored with international prize in Paris
William C. Mobley, MD, PhD, chair of the Department of Neurosciences at the University of California, San Diego School of Medicine and Chairman of the U.S. Scientific Advisory Committee of the Jérôme Lejeune Foundation, was recognized by U.S. Congressman Pete Sessions from the floor of the House of Representatives in December. Sessions said of Mobley – who received the International Sisley-Jérôme Lejeune Prize in a ceremony at the Museum of Medical History in Paris on December 8 – “Dr. Mobley’s many contributions in the field of Down syndrome have been truly valued in the special needs community. His research to identify causes of neurodegenerative disorders has brought new optimism to those afflicted with diseases, from Alzheimer’s to Down syndrome.”
The International Sisley-Jérôme Lejeune award was given to Mobley in recognition of his ambitious and innovative research into treatments for neurological disabilities, in particular Down syndrome. In his acceptance speech, Mobley commented that “Today, we have not yet developed an effective treatment, but our work shows that it will soon be possible.”
Rare Genetic Mutations Linked To Bipolar Disorder
An international team of scientists, led by researchers at the University of California, San Diego School of Medicine, reports that abnormal sequences of DNA known as rare copy number variants, or CNVs, appear to play a significant role in the risk for early onset bipolar disorder.
CNVs are genomic alterations in which there are too few or too many copies of sections of DNA. Researchers have known that spontaneously occurring (de novo) CNVs – genetic mutations not inherited from parents – significantly increase the risk for some neuropsychiatric conditions, such as schizophrenia or the autism spectrum disorders. But their role was unclear in bipolar disorder, previously known as manic depression.
Principal investigator Jonathan Sebat, PhD, assistant professor of psychiatry and cellular and molecular medicine at UC San Diego’s Institute of Genomic Medicine, and colleagues, found that de novo CNVs contribute significant genetic risk in about 5 percent of early onset bipolar disorder, which appears in childhood or early adulthood.
Cognitive consilience
More than a century ago, a Spanish pathologist named Santiago Ramon y Cajal produced a series of highly detailed drawings of the microscopic structures of the human brain. It marked the beginning of modern neuroanatomy and ultimately helped earn Cajal a share of the 1906 Nobel Prize for medicine (with Italian anatomist Camillo Golgi.
Cajal’s drawings remain a marvel and are still widely used, but advances in neuroscience demand new ways to look at – and understand – how the human brain is structured and how it functions.
A recent PhD graduate and a post-doc at the University of California San Diego – Soren Solari in the Department of Mechanical and Aerospace Engineering and Rich Stoner in the Department of Neurosciences - have created a modern take on Cajal’s pioneering work.
Publishing in the journal Frontiers in Neuroanatomy, Solari and Stoner have created a detailed review of cortical circuitry, along with a first-of-a-kind interactive website and an iPhone/iPad application that allows scientists to navigate aspects of the human brain.
“We wanted to create an interactive Figure 1,” said Stoner, who currently conducts research at the UC San Diego Autism Center of Excellence. “Readers of the review are able to click on a circuit and quickly find an accompanying reference.”
To build the tool, Solari and Stoner synthesized seven hypothetical circuits of the brain from scores of published neuroanatomy papers into a single interactive map that depicts consolidated long-term declarative memory, short-term declarative memory, working memory/information processing, behavioral memory selection, behavioral memory output, cognitive control and cortical information flow regulation. The map is built on data derived from multiple mammalian models.
“It’s the first coherent view of cortical circuits across different scales from different sources,” said Stoner. “We use the term ‘cognitive consilience’ because it’s about bringing together a lot of different information to form a coherent picture. It’s the unity of knowledge.”
By clicking on different links within each depicted circuit, users can read brief descriptions of the visualized cells and structures. The information is not definitive, of course. Solari and Stoner say they have erected this first iteration as a model for future researchers to add new information. “We’d like to see this become a viable tool for scientists to describe their work,” said Stoner.
An MRI depicts a glioblastoma (center white mass) before treatment with the drug erlotinib (A) and after (B).
Old Drugs Find New Target For Treating Brain Tumor
Scientists at the University of California, San Diego School of Medicine and UC San Diego Moores Cancer Center, in collaboration with colleagues in Boston and South Korea, say they have identified a novel gene mutation that causes at least one form of glioblastoma (GBM), the most common type of malignant brain tumor.
Past studies have identified epidermal growth factor receptor (EGFR) as a common genetically altered gene in GBM, though the cause or causes of the alteration is not known. The research team, led by scientists at the Dana-Farber Cancer Institute in Boston, analyzed the GBM genomic database, ultimately identifying and characterizing an exon 27 deletion mutation within the EGFR carboxyl-terminus domain (CTD). An exon is a segment of a DNA or RNA molecule containing information coding for a protein or peptide sequence.
“The deletion mutant seems to possess a novel mechanism for inducing cellular transformation,” said Frank Furnari, PhD, associate professor of medicine at the UC San Diego School of Medicine and an associate investigator at the San Diego branch of the Ludwig Institute for Cancer Research.
The study researchers determined that cellular transformation was induced by the previously unknown EGFR CTD deletion mutant, both in vitro and in vivo, and resulted in GBM in the animals. The researchers then turned to testing a pair of approved drugs that target EGFR: a monoclonal antibody called cetuximab and a small molecule inhibitor called erlotinib.
Non-Coding RNA Relocates Genes When It’s Time To Go To Work
Cells develop and thrive by turning genes on and off as needed in a precise pattern, a process known as regulated gene transcription. In a paper published in the November 9 issue of The Journal of Neuroscience, researchers at the University of California, San Diego School of Medicine say this process is even more complex than previously thought, with regulated genes actually relocated to other, more conducive places in the cell nucleus.
“When regulated gene transcription goes awry, many human diseases result, such as diabetes, atherosclerosis, cancer and growth defects in children,” said Michael G. Rosenfeld, MD, a professor in the UC San Diego Department of Medicine, Howard Hughes Medical Institute investigator and senior author of the study. “We’ve shown that rather than being activated at certain, random locations within the cell nucleus, regulated genes can dynamically relocate. The discovery provides a more comprehensive picture of the interaction between regulated genes and human disease.”
Specifically, Rosenfeld and colleagues found that genes regulating cell proliferation responded to growth signals by moving targeted genes from a “silencing environment” in the nucleus called Polycomb bodies to another nuclear compartment called interchromatin granules, which is enriched with activating transcription factors. The movement was precisely guided by two non-coding RNA (ncRNA) molecules called TUG1 and NEAT2.
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