Studies in non-human primates (NHPs) by NYU Grossman School of Medicine researchers have shown how a new type of immunomodulatory therapy can stimulate the activity of immune defense cells and reduce the amount of misshapen proteins, amyloid beta plaques and tau tangles that are linked with the pathology of Alzheimer’s disease (AD).
The research found that elderly squirrel monkeys treated using CpG oligodeoxynucleotides (CpG ODN) had up to 59% fewer plaque deposits in their brains compared with untreated animals, and also lower levels of toxic tau, without evidence of excessive or sustained inflammation. Amyloid beta plaques are protein fragments that clump together and clog the junctions between nerve cells (neurons), while the nerve fiber protein tau can destroy neighboring tissue when disease-related changes to its chemical structure causes it to catch on other cells. The CpG ODN treatment also resulted in cognitive improvements in the animals.
The new investigation is the first to target the innate immune system with a potential therapy for AD in monkeys, according to Thomas Wisniewski, MD, the Gerald J. and Dorothy R. Friedman Professor in the Department of Neurology and director of the Center for Cognitive Neurology at NYU Langone. Wisniewski is co-senior and co-corresponding author of the team’s published paper in Brain.
“Our findings illustrate that this therapy is an effective way of manipulating the immune system to slow neurodegeneration,” added first author Akash Patel, MS, an assistant research scientist in the Center for Cognitive Neurology at NYU Langone Health. The team reports on the studies in a paper titled, “Innate Immunity Stimulation via CpG ODN Ameliorates Alzheimer’s Disease Pathology in Aged Squirrel Monkeys.”
Alzheimer’s disease is the sixth leading cause of death in the U.S. and has no known cure. “Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is characterized by amyloid ß (Aß) plaques within the brain parenchyma and Aß accumulation in blood vessels (cerebral amyloid angiopathy; CAA), as well as by the formation of neurofibrillary tangles and neurodegeneration,” the authors explained. Drug therapies designed to slow or manage the symptoms have failed, said Wisniewski, who is also director of the Alzheimer’s Disease Research Center at NYU Langone.
A growing body of evidence has implicated the immune system as a contributor to Alzheimer’s disease, the team noted. “It is becoming increasingly recognized that chronic neuroinflammation plays a significant role in AD progression,” they wrote. A subset of immune cells within the innate immune system engulf (phagocytose) and clear away debris and toxins from bodily tissues along with invading microbes. Studies have shown that these immune custodians become sluggish as a person ages and fail to clear toxins that cause neurodegeneration. “Large-scale genome wide association studies (GWAS) have identified several innate immunity-related genes that are associated with an elevated risk for the development of late onset AD (LOAD),” the authors continued. “Many of these genes are highly expressed among microglia as regulators of phagocytic activity and inflammatory activation state, suggesting that microglial functions play a key role in the pathogenesis of LOAD.”
Previous attempts at targeting the immune system have failed because the drugs overstimulated the system, causing dangerous levels of inflammation, which can kill brain cells. “How to harness innate immunity without stimulating potentially harmful inflammation has become a critical question in AD research,” the investigators stated. Toll-like receptors (TLRs) are a family of innate immune modulators, and while stimulating TLR signaling pathways has been associated with immune responses contributing to mitigation of AD pathology, “several studies have reported adverse effects from TLR manipulation in AD models.”
The team’s prior studies in transgenic (Tg) AD mouse models had indicated that stimulating innate immunity with TLR9 agonist, CpG ODN could effectively reduce AD-related pathology, without causing microhemorrhage or provoking sustained inflammation. “Our earlier extensive studies from multiple AD Tg mouse models clearly demonstrate that stimulation of innate immunity via TLR9 with CpG ODN can alleviate all pathological hallmarks of AD, including amyloid plaques, tau pathology, and CAA, in association with behavioral improvements and without any toxicity,” they wrote. However, it’s a big leap to go straight from mouse studies to human trials, and this is possibly why so many AD clinical trials fail, the investigators suggested. “… a premature jump from studies completed in Tg mice directly to human trials has been cited as one of the significant reasons for the failure of the vast majority of AD clinical trials.”
Their newly reported investigations, Wisniewski claims, are the first to target the innate immune system with the CpG ODN drugs as a potential therapy for AD in monkeys. “Previous studies established that NHPs are useful models for exploring the therapeutic potential of CpG ODN planned for human use,” the team continued. “The interventions described here represent the first study using elderly SQMs with established CAA pathology to assess the efficacy and long-term safety of a well-characterized TLR9 agonist Class B CpG ODN 2006.” CpG ODN 2006 has been well established in numerous human trials for a variety of diseases, the scientists further pointed out.
The research team’s investigations involved 15 female squirrel monkeys, aged between 17 and 19 years. As squirrel monkeys age, they almost all will naturally develop a form of neurodegeneration that mimics Alzheimer’s disease in humans, and this makes the primates ideal for studying the disease.
Eight animals received a single dose of the drug once a month for two years while the rest were instead given a saline solution. The researchers observed the behavior of the two groups and compared brain tissue and blood samples for plaque deposits, tau protein levels, and evidence of inflammation. The researchers say they are also the first to use the “pulsing” drug administration technique as an approach to avoiding excess inflammation. “Our new treatment avoids the pitfalls of earlier attempts because it is delivered in cycles, giving the immune system a chance to rest between doses,” Wisniewski said.”
Their results showed that as well as reducing characteristic AD pathology, the CpG ODN therapy led to cognitive benefits. When presented with a series of puzzles, elderly monkeys given the drug performed similarly to young adult animals and much better than those in their age group that had remained untreated. The treated monkeys also learned new puzzle-solving skills faster than their untreated peers. Importantly, there was no additional inflammation seen in the treated monkeys. “Overall, no signs of CpG ODN treatment associated sustained neuroinflammation were present in our elderly animals at the end of the chronic treatment period,” the team asserted.
“Present findings demonstrate that stimulation of innate immunity with TLR9 agonist CpG ODN is effective at inducing a suitable degree of immunostimulatory response that reduces the accumulation of Aß-related pathology, without producing excessive and sustained inflammatory environment,” the scientists stated. “The potential translatability to humans is enhanced by testing our promising therapeutic concept in non-human primates (NHPs), which more closely resemble AD-related pathology.”
The team concluded, “The present study represents the first in vivo evidence that stimulation of innate immunity with TLR9 agonist, CpG ODN, leads to behavioral improvements and a reduction of amyloid-related pathology, predominantly CAA, in the absence of microhemorrhages and encephalitis in elderly SQMs.
“The similarities in aging between the animals studied and our own species give us hope that this therapy will work in human patients as well,” said study co-senior author Henrieta Scholtzova, MD, PhD. Scholtzova, an associate professor in the Department of Neurology at NYU Langone, cautions that the researchers only evaluated elderly monkeys who were already showed significant signs of neurodegeneration. Further testing on younger animals would allow them to assess the effectiveness of the treatment in earlier stages of the disease. “Future studies will be aimed at determining the interplay between signaling pathways and cell types activated during an acute CpG ODN administration phase to further decipher the mechanism responsible for CpG ODN’s favorable immunomodulatory capabilities,” the team noted.
Scholtzova says the team next plans to begin testing CpG ODN therapy on human patients with mild cognitive impairments or in early stages of dementia. They also intend to study this treatment in related neurodegenerative illnesses. “Overall, the current research together with our earlier extensive preclinical evidence validates the beneficial therapeutic outcomes and safety of this innovative approach, enhancing the likelihood of CpG ODN’s therapeutic efficacy in clinical trials that are now being initiated,” the scientists wrote.
