Immunomodulatory treatment stops the progression of Alzheimer’s disease and improves primate cognition

A study of non-human primates (NHP) by researchers at the NYU Grossman School of Medicine found that a new type of immunomodulatory therapy stimulates immune defense cell activity and associated malformed proteins, amyloid beta plaque, and tau tangles. The pathology of Alzheimer’s disease (AD) has shown how the amount of protein can be reduced.

Studies show that older squirrel monkeys treated with CpG oligodeoxynucleotides (CpG ODN) have up to 59% less plaque deposits in the brain and lower levels of toxic tau compared to untreated animals. There is no evidence of excessive or persistent inflammation. Amyloid beta plaque is a protein fragment that aggregates and clogs junctions between nerve cells (neurons), whereas nerve fiber protein tau is an adjacent tissue when it is trapped in other cells due to disease-related changes in its chemical structure. May destroy. CpG ODN treatment has also resulted in improved cognitive function in animals.

According to Thomas Wisniewski, MD, Gerald J., Professor of Neurology, Dorothy R. Friedman, and Director of the Center for Cognitive Neurology, this new study is the first to target the innate immune system with potential treatments for AD in monkeys. .. NYU Langone Neurology. Wisniewski is a co-senior and co-author of the papers published by the team. brain..

“Our findings show that this treatment is an effective way to manipulate the immune system to delay neurodegeneration,” said an assistant research scientist at the Center for Cognitive Neurology at NYU Langone Health. Leading authors Akash Patel and MS added. team is,”Innate immune stimulation via CpG ODN improves the pathology of Alzheimer’s disease in aging squirrel monkeys.. “

Alzheimer’s disease is the sixth leading cause of death in the United States and there is no known cure. “Alzheimer’s disease (AD), the most common cause of dementia in the elderly, causes amyloid β (Aβ) plaques in the brain parenchyma and Aβ accumulation in blood vessels (cerebral amyloid angiopathy; CAA) and their formation. It is characteristic. Causes of neurofibrillary tangles and dementia, “the authors explained. Wisnievsky, director of the Alzheimer’s Disease Research Center at NYU Langone, said medications designed to delay or control symptoms failed.

The team said increasing evidence suggests that the immune system is responsible for Alzheimer’s disease. “It is becoming increasingly recognized that chronic neuroinflammation plays an important role in the progression of AD,” they write. A subset of immune cells in the innate immune system swallow (phagocytosis) and remove debris and toxins from body tissues along with invading microorganisms. Studies show that these immunoadministrators become dull as people grow older and unable to get rid of the toxins that cause neurodegeneration. “A large genome-wide association study (GWAS) has identified several innate immunity-related genes associated with an increased risk of developing late-onset AD (LOAD),” the authors continued. “Many of these genes are highly expressed among microglia as regulators of phagocytic activity and inflammatory activation status, suggesting that microglial function plays an important role in the pathogenesis of LOAD. . “

Previous attempts to target the immune system have failed because the drug overstimulates the immune system and causes dangerous levels of inflammation that can kill brain cells. “How to utilize innate immunity without stimulating potentially harmful inflammation has become an important issue in AD research,” the researchers say. Toll-like receptors (TLRs) are a family of innate immune regulators, and stimulation of the TLR signaling pathway is associated with an immune response that contributes to alleviation of AD pathology. The negative effects of TLR operations have been reported in. “

A previous study by the team in a transgenic (Tg) AD mouse model was that stimulating innate immunity with the TLR9 agonist CpG ODN was associated with AD without causing microbleeding or persistent inflammation. It has been shown that the condition can be effectively alleviated. “Previous extensive studies from multiple ADTg mouse models include TLR9-mediated innate immune stimulation by CpG ODN, without toxicity, including amyloid plaques, tau pathology, and CAA, associated with improved behavior. It clearly shows that all pathological features of AD can be reduced, “they wrote. However, the direct shift from mouse studies to human studies is a major leap, and researchers have suggested that this is probably the reason why so many AD clinical trials fail. “… The premature jump from a completed study to a direct human trial in Tg mice is cited as one of the key reasons why the majority of AD clinical trials failed.”

Wisniewski argues that their newly reported study is the first study targeting the innate immune system with CpGODN drugs as a potential treatment for AD in monkeys. “Previous studies have established that NHP is a useful model for exploring the therapeutic potential of CpGODN, which is planned for human use,” the team continued. “The intervention described here used an elderly SQM with established CAA pathology to assess the efficacy and long-term safety of a well-characterized TLR9 agonist, Class B CpG ODN 2006. It represents the first study. ”CpG ODN 2006 has been established in numerous human trials in a variety of diseases, scientists further point out.

The research team’s study included 15 female squirrel monkeys between the ages of 17 and 19. As squirrel monkeys grow older, almost all spontaneously develop forms of neurodegeneration that mimic Alzheimer’s disease in humans. This makes primates ideal for studying illness.

Eight animals received a single dose of the drug once a month for two years and the rest were given saline instead. The researchers observed the behavior of the two groups and compared brain tissue and blood samples for evidence of plaque deposition, tau protein levels, and inflammation. Researchers also say they were the first to use “pulse” drug administration technology as an approach to avoiding excessive inflammation. “Our new treatment is given periodically, avoiding the pitfalls of previous attempts and giving the immune system the opportunity to rest between doses,” says Wisniewski.

Their results show that CpGODN therapy not only alleviates the characteristic AD pathology, but also provides cognitive benefits. When presented with a series of puzzles, the drugged older monkeys behaved like young adult animals and were far superior to those of their age group, which remained untreated. Treated monkeys also learned new puzzle-solving skills faster than their untreated peers. Importantly, the treated monkeys did not show any additional inflammation. “Overall, at the end of the chronic treatment period, there were no signs of CpGODN treatment associated with persistent neuroinflammation in our older animals,” the team claimed.

“Current findings indicate that innate immunity stimulation with the TLR9 agonist CpG ODN elicits an appropriate degree of immune stimulation response that reduces the accumulation of Aβ-related pathologies without creating an excessive and persistent inflammatory environment. It shows that it is effective, “said the scientist. “The potential translatability to humans is enhanced by testing our promising therapeutic concepts in non-human primates (NHPs), which are more similar to AD-related pathologies.”

The team concluded that: “This study presents the first in vivo evidence that innate immunity stimulation with the TLR9 agonist CpG ODN leads to improved behavior and amyloid-related conditions, primarily CAA, in the absence of microbleeding and encephalitis. SQM for the elderly.

“The similarity of aging between the animals studied and our own species gives us hope that this treatment will also work for human patients,” said the co-author of the study. Henrita Shorzowa, MD, said. Scholtzova, an associate professor of neurology at NYU Langone, warns that researchers have only evaluated older monkeys that have already shown significant signs of neurodegeneration. Further testing of young animals can assess the effectiveness of treatment in the early stages of the disease. “Future studies will determine the interaction between cell types and signaling pathways activated during the acute CpG ODN dosing phase to further decipher the mechanisms responsible for the preferred immunomodulatory capacity of CpG ODN. We are aiming for it, “said the team.

According to Scholtzova, the team will then begin testing CpGODN therapy in human patients with mild cognitive impairment or in the early stages of dementia. They will also study this treatment for related neurodegenerative diseases. “Overall, current studies, along with extensive previous preclinical evidence, validate the beneficial therapeutic outcomes and safety of this innovative approach and the potential therapeutic efficacy of CpGODN in ongoing clinical trials. Is increasing, “the scientists write.