redOrbit Staff & Wire Reports – Your Universe Online
New research published Thursday in the journal Neuron sheds new light on the molecular causes of Alzheimer’s disease, while also revealing a potential new therapy which could help prevent cognitive decline and brain damage during the early stages of the neurodegenerative disorder.
The study focuses on a variant of a gene known as CD33, which typically contributes to Alzheimer’s disease by inhibiting the ability of a body’s immune cells to remove toxic molecules from the brain. Those toxins, which are known as beta-amyloid plaques, form between neurons in the brain. Past studies have linked those plaques to neuron death and cognitive deficits such as impaired memory, the researchers explained.
“Too much CD33 activity appears to promote late-onset Alzheimer’s by preventing support cells from clearing out toxic plaques, key risk factors for the disease,” explained senior author Dr. Rudolph Tanzi of Massachusetts General Hospital and Harvard University. “Future medications that impede CD33 activity in the brain might help prevent or treat the disorder.
“Before our study, nothing was known about the function of CD33 in the brain. Moreover, our findings suggest that pharmaceutical inactivation of CD33 represents a potentially powerful new therapy for the treatment and prevention of Alzheimer’s disease, and perhaps other neurodegenerative disorders,” he added. “Our findings raise the exciting possibility that the inability of microglia to degrade beta-amyloid in Alzheimer’s disease could be reversed therapeutically by inhibition of CD33 activity.”
Tanzi and his colleagues first became interested in CD33 variations during 2008 research into genes that contribute to late-onset Alzheimer’s disease. They knew the gene made a protein which regulated the immune system, but its function within the brain was unclear. In order to learn more about how it could contribute to the neurodegenerative condition, they looked at human genetics, biochemistry and human brain tissue, laboratory mice and cell-based experiments, the researchers explained.
They discovered the CD33 gene regulates the clearing of a toxic protein known as amyloid beta (A-beta) in the brains of Alzheimer’s patients. As part of the Neuron study, Tanzi and his co-authors describe a protective variant of CD33 which promotes clearance of the protein. They also illustrate how reducing the gene’s expression in immune cells known as microglia boosts their ability to clear-away A-beta, raising the hope the brain’s immune system could be aided with A-beta removal if CD33 activity is blocked.
“In the current study, the researchers first found that CD33 activity was significantly higher in microglia cells in brain samples from Alzheimer’s patients than in cells from non-demented controls,” Massachusetts General Hospital explained in a statement. “Moreover, they showed that the presence of a version of the gene that protected against Alzheimer’s disease reduced CD33 protein levels in the brain. Importantly, the same protective version of CD33 was found to reduce levels of A-beta 42 – the primary constituent of the amyloid plaques that characterize the disease.”
Increased numbers of CD33-containing microglia were also linked to higher a-beta levels and total beta-amyloid plaque levels. Their research was conducted using an Alzheimer’s mouse model, and according to Tanzi, their findings indicate inhibiting CD33 activity in a human patient’s brain could ultimately become a “powerful new approach to treating and possibly preventing Alzheimer’s disease.”
In related research, published online Thursday in the journal Cell , an international team of researchers report they located a network of genes involved in the inflammatory response in the brain which is a critical component in late-onset Alzheimer’s disease (LOAD).
The researchers analyzed the DNA of 376 deceased LOAD patients, as well as data tied to how those genes operate, to create a biological network model that demonstrates which genes are involved with LOAD and which biological pathways (or mechanisms) those genes are responsible for. This model would provide a more comprehensive understanding of the disease and identifies potential treatment targets.
“Creating a predictive model of Alzheimer’s disease is a landmark achievement, yielding valuable insights into the complex mechanism of the disease,” study author Dr. Eric Schadt, Chair of the Department of Genetics and Genomic Sciences at Mount Sinai Hospital, said in a statement.
Schadt and his colleagues discovered a pathway involving an inflammatory gene known as TYROBP. This pathway had not been previously linked to Alzheimer’s disease, but it is known to interact with another gene, TREM2, that also has recently been associated with the condition. Their newly published study claims that the TREM2-TYROBP pathway plays a vital role in LOAD and other common forms of the disorder.
“Defining the precise steps of the inflammatory response crucial to causing Alzheimer’s disease has been elusive. We are pleased to discover these novel insights into that process,” explained Bin Zhang, co-lead author of the study and an Associate Professor of Genetics and Genomic Sciences at Mount Sinai.
“As a next step, we will evaluate drugs that impact the TREM2-TYROBP pathway as potential therapies for the disease. This discovery enables us to design more specific compounds that target these key steps precisely, in contrast to existing anti-inflammatory drugs that may be less ideal for hitting this target,” he added.
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