University of South Florida Health neuroscientist suggests the therapeutic immunomodulatory vaccine may be safer for those with age-associated decline in immunity

In the Alzheimer’s disease brain, the amyloid beta peptide clumps together to form hardened plaques between nerve cells.

TAMPA, Fla (Oct. 20, 2020) — Our immune system’s capacity to mount a well-regulated defense against foreign substances, including toxins, weakens with age and makes vaccines less effective in people over age 65. At the same time, research has shown that immunotherapy targeting neurotoxic forms of the peptide amyloid beta (oligomeric Aβ) may halt the progression of Alzheimer’s disease, the most common age-related neurodegenerative disease.

A team led by Chuanhai Cao, PhD, of the University of South Florida Health (USF Health), has focused on overcoming, in those with impaired immunity, excess inflammation and other complications that interfere with development of a therapeutic Alzheimer’s vaccine.

Now, a preclinical study by Dr. Cao and colleagues indicates that an antigen-presenting dendritic vaccine with a specific antibody response to oligomeric Aβ may be safer and offer clinical benefit in treating Alzheimer’s disease. The vaccine, called E22W42 DC, uses immune cells known as dendritic cells (DC) loaded with a modified Aβ peptide as the antigen.

The  Alzheimer’s mouse model study of this new investigational vaccine was published early online Oct. 13 in the Journal of Alzheimer’s Disease.

One of the two hallmark pathologies of Alzheimer’s disease is hardened deposits of Aβ that clump together between nerve cells (amyloid protein plaques) in the brain; the other is neurofibrillary tangles of tau protein inside brain cells. Both lead to damaged neurological cell signaling, ultimately causing the onset of Alzheimer’s disease and symptoms.

“This therapeutic vaccine uses the body’s own immune cells to target the toxic Aβ molecules that accumulate harmfully in the brain,” said principal investigator Dr. Cao, a neuroscientist at the USF Health Taneja College of Pharmacy, USF Health Morsani College of Medicine and the university’s Byrd Alzheimer’s Center. “And, importantly, it provides strong immunomodulatory effects without inducing an unwanted, vaccine-associated autoimmune reaction in the aging mice.”

Unfortunately, clinical trials of all anti-amyloid treatments for Alzheimer’s disease so far have failed – including the initial vaccine trial targeting Aβ (AN-1792), which was suspended in 2002 after several immunized patients developed central nervous system inflammation.  “Inflammation is a primary symptom of Alzheimer’s disease, so any possible treatment which has neural inflammation as a side effect essentially pours gas on the fire,” Dr. Cao said.

A next-generation anti-amyloid vaccine for Alzheimer’s would ideally produce long-lasting, moderate antibody levels needed to prevent Aβ oligomers from further aggregating into destructive Alzheimer’s plaques, without over-stimulating the immune systems of elderly people, Dr. Cao added.

In this study, the researchers tested the vaccine they formulated using modified Aβ-sensitized dendritic cells derived from mouse bone marrow. Dendritic cells interact with other immune cells (T-cells and B-cells) to help regulate immunity, including suppressing harmful responses against healthy tissues.  “Because we use dendritic cells to generate antibodies, this vaccine can coordinate both innate and acquired immunity to potentially overcome age-related impairments of the immune system,” Dr. Cao said.

USF Health neuroscientist Chuanhai Cao, PhD, led the preclinical study testing a novel therapeutic Alzheimer’s vaccine.

The study included three groups of transgenic (APP/PS1) mice genetically engineered to develop high levels of Aβ and behavioral/cognitive abnormalities that mimic human Alzheimer’s disease.  One group was vaccinated with the investigational E22W42 DC vaccine, another received an endogenous amyloid beta peptide to stimulate dendritic cells (wild-type vaccine group), and the third was injected with dendritic cells only, containing no Aβ peptide (DC control group).  A fourth group was comprised of untreated healthy, older mice (nontransgenic control group).

Among the study findings:

– The vaccine slowed memory impairment in the Alzheimer’s transgenic mice, with mice in the E22W42 DC vaccinated group demonstrating memory performance similar to that of the nontransgenic, untreated mice. In a cognitive test called a radial arm water maze, the E22W42 DC-vaccinated mice also showed significantly less errors in working memory than the mice injected with non-sensitized dendritic cells only (DC controls). Loss of working memory makes it difficult to learn and retain new information, a characteristic of Alzheimer’s disease.

– No significant differences were found in the quantities of inflammatory cytokines measured in the plasma of the vaccinated mice, versus amounts in the control mice. The researchers concluded that the E22W42 DC vaccine has “little potential for over priming the immune system.”

– E22W42 DC-vaccinated mice showed higher levels of anti-Aβ antibodies in both in their brain and in their blood than the transgenic control mice administered dendritic cells containing no modified Aβ peptide.

– Only Aβ peptides with mutations introduced in the T-cell epitope (the distinct surface region of the antigen where complementary antibodies bind) can sensitize the dendritic cells to target toxic oligomeric forms of Aβ, the researchers reported.  A major advantage of E22W42 is that the antigen can stimulate a specific T-cell response that activates the immune system and silence some T-cell epitopes associated with an autoimmune response, they added.

“Though the E22W42-sensitized DC vaccine is being developed for patients with Alzheimer’s disease, it can potentially help strengthen the immune system of elderly patients (with other age-related disorders) as well,” the study authors concluded.

Dr. Cao conducted the study with collaborators from Tianjin University of Traditional Chinese Medicine and Michigan State University. The team’s research was supported by grants from the National Institutes of Health, Florida High Tech Corridor matching funds, and MegaNano Biotech Inc. The University of South Florida holds a patent related to E22W42 DC vaccine technology.

Tampa, FL (Aug. 27, 2014) — Extremely low levels of the compound in marijuana known as delta-9-tetrahydrocannabinol, or THC, may slow or halt the progression of Alzheimer’s disease, a recent study from neuroscientists at the University of South Florida shows.

Findings from the experiments, using a cellular model of Alzheimer’s disease, were reported online in the Journal of Alzheimer’s Disease.

Researchers from the USF Health Byrd Alzheimer’s Institute showed that extremely low doses of THC reduce the production of amyloid beta, found in a soluble form in most aging brains, and prevent abnormal accumulation of this protein — a process considered one of the pathological hallmarks evident early in the memory-robbing disease. These low concentrations of THC also selectively enhanced mitochondrial function, which is needed to help supply energy, transmit signals, and maintain a healthy brain.

“THC is known to be a potent antioxidant with neuroprotective properties, but this is the first report that the compound directly affects Alzheimer’s pathology by decreasing amyloid beta levels, inhibiting its aggregation, and enhancing mitochondrial function,” said study lead author Chuanhai Cao, PhD and a neuroscientist at the Byrd Alzheimer’s Institute and the USF College of Pharmacy.

“Decreased levels of amyloid beta means less aggregation, which may protect against the progression of Alzheimer’s disease. Since THC is a natural and relatively safe amyloid inhibitor, THC or its analogs may help us develop an effective treatment in the future.”

USF Health neuroscientist Chuanhai Cao, PhD, was the lead author of a study testing the effects of the marijuana compound THC on an Alzheimer’s disease cell model.

The researchers point out that at the low doses studied, the therapeutic benefits of THC appear to prevail over the associated risks of THC toxicity and memory impairment.

Neel Nabar, a study co-author and MD/PhD candidate, recognized the rapidly changing political climate surrounding the debate over medical marijuana.

“While we are still far from a consensus, this study indicates that THC and THC-related compounds may be of therapeutic value in Alzheimer’s disease,” Nabar said. “Are we advocating that people use illicit drugs to prevent the disease? No. It’s important to keep in mind that just because a drug may be effective doesn’t mean it can be safely used by anyone. However, these findings may lead to the development of related compounds that are safe, legal, and useful in the treatment of Alzheimer’s disease.”

The body’s own system of cannabinoid receptors interacts with naturally-occurring cannabinoid molecules, and these molecules function similarly to the THC isolated from the cannabis (marijuana) plant.

Dr. Cao’s laboratory at the Byrd Alzheimer’s Institute is currently investigating the effects of a drug cocktail that includes THC, caffeine as well as other natural compounds in a cellular model of Alzheimer’s disease, and will advance to a genetically-engineered mouse model of Alzheimer’s shortly.

“The dose and target population are critically important for any drug, so careful monitoring and control of drug levels in the blood and system are very important for therapeutic use, especially for a compound such as THC,” Dr. Cao said.

Article citation:  Chuanhai Cao, Yaqiong Li, Hui Liu, Ge Bai, Jonathan May, Xiaoyang Lin, Kyle Sutherland,  Neel Nabar and Jianfeng Cai; “The Potential Therapeutic Effects of THC on Alzheimer’s Disease,” Journal of Alzheimer’s Disease, DOI: 10.3233/JAD-140093.

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USF Health’s mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the College of Pharmacy, the School of Biomedical Sciences and the School of Physical Therapy and Rehabilitation Sciences; and the USF Physician’s Group. The University of South Florida is a Top 50 research university in total research expenditures among both public and private institutions nationwide, according to the National Science Foundation. For more information, visit www.health.usf.edu

Researchers from the University of South Florida and the University of Miami say the case control study provides the first direct evidence that caffeine/coffee intake is associated with a reduced risk of dementia or delayed onset.  Their findings appear in the online version of an article  published June 5 in the Journal of Alzheimer’s Disease. The collaborative study involved 124 people, ages 65 to 88, in Tampa and Miami.

“These intriguing results suggest that older adults with mild memory impairment who drink moderate levels of coffee — about 3 cups a day — will not convert to Alzheimer’s disease — or at least will experience a substantial delay before converting to Alzheimer’s,” said study lead author Dr. Chuanhai Cao, a neuroscientist at the USF College of Pharmacy and the USF Health Byrd Alzheimer’s Institute. “The results from this study, along with our earlier studies in Alzheimer’s mice, are very consistent in indicating that moderate daily caffeine/coffee intake throughout adulthood should appreciably protect against Alzheimer’s disease later in life.”

The study shows this protection probably occurs even in older people with early signs of the disease, called mild cognitive impairment, or MCI.  Patients with MCI already experience some short-term memory loss and initial Alzheimer’s pathology in their brains.  Each year, about 15 percent of MCI patients progress to full-blown Alzheimer’s disease.  The researchers focused on study participants with MCI, because many were destined to develop Alzheimer’s within a few years.

Blood caffeine levels at the study’s onset were substantially lower (51 percent less) in participants diagnosed with MCI who progressed to dementia during the two-to-four year follow-up than in those whose mild cognitive impairment remained stable over the same period.

No one with MCI who later developed Alzheimer’s had initial blood caffeine levels above a critical level of 1200 ng/ml – equivalent to drinking several cups of coffee a few hours before the blood sample was drawn.  In contrast, many with stable MCI had blood caffeine levels higher than this critical level.

“We found that 100 percent of the MCI patients with plasma caffeine levels above the critical level experienced no conversion to Alzheimer’s disease during the two-to-four year follow-up period,” said study co-author Dr. Gary Arendash.

The researchers believe higher blood caffeine levels indicate habitually higher caffeine intake, most probably through coffee.  Caffeinated coffee appeared to be the main, if not exclusive, source of caffeine in the memory-protected MCI patients, because they had the same profile of blood immune markers as Alzheimer’s mice given caffeinated coffee. Alzheimer’s mice given caffeine alone or decaffeinated coffee had a very different immune marker profile.

Since 2006, USF’s Dr. Cao and Dr. Arendash have published several studies investigating the effects of caffeine/coffee administered to Alzheimer’s mice.   Most recently, they reported that caffeine interacts with a yet unidentified component of coffee to boost blood levels of a critical growth factor that seems to fight off the Alzheimer’s disease process.

USF Health's Dr. Chuanhai Cao, study lead author

“We are not saying that moderate coffee consumption will completely protect people from Alzheimer’s disease,” Dr. Cao cautioned.  “However, we firmly believe that moderate coffee consumption can appreciably reduce your risk of Alzheimer’s or delay its onset.”

Alzheimer’s pathology is a process in which plaques and tangles accumulate in the brain, killing nerve cells, destroying neural connections, and ultimately leading to progressive and irreversible memory loss.  Since the neurodegenerative disease starts one or two decades before cognitive decline becomes apparent, the study authors point out, any intervention to cut the risk of Alzheimer’s should ideally begin that far in advance of symptoms.

“Moderate daily consumption of caffeinated coffee appears to be the best dietary option for long-term protection against Alzheimer’s memory loss,” Dr. Arendash said.  “Coffee is inexpensive, readily available, easily gets into the brain, and has few side-effects for most of us. Moreover, our studies show that caffeine and coffee appear to directly attack the Alzheimer’s disease process.”

In addition to Alzheimer’s disease, moderate caffeine/coffee intake appears to reduce the risk of several other diseases of aging, including Parkinson’s disease, stroke, Type II diabetes, and breast cancer.  However, supporting studies for these benefits have all been observational (uncontrolled), and controlled clinical trials are needed to definitively demonstrate therapeutic value.

A study tracking the health and coffee consumption of more than 400,000 older adults for 13 years, and published earlier this year in the New England Journal of Medicine, found that coffee drinkers reduced their risk of dying from heart disease, lung disease, pneumonia, stroke, diabetes, infections, and even injuries and accidents.

With new Alzheimer’s diagnostic guidelines encompassing the full continuum of the disease, approximately 10 million Americans now fall within one of three developmental stages of Alzheimer’s disease — Alzheimer’s disease brain pathology only, MCI, or diagnosed Alzheimer’s disease.  That number is expected to climb even higher as the baby-boomer generation continues to enter older age, unless an effective and proven preventive measure is identified.

“If we could conduct a large cohort study to look into the mechanisms of how and why coffee and caffeine can delay or prevent Alzheimer’s disease, it might result in billions of dollars in savings each year in addition to improved quality of life,” Dr. Cao said.

The USF-UM study was funded by the NIH-designated Florida Alzheimer’s Disease Research Center and the State of Florida.

Article citation:
“High Blood Caffeine Levels in MCI Linked to Lack of Progression to Dementia;”  Chuanhai Cao, David A. Lowenstein, Xiaoyang Lin, Chi Zang, Li Wang, Ranjan Duara, Yougui Wu, Alessandra Giannini, Ge Bai, Jianfeng Cai, Maria Greig, Elizabeth Schofield, Raj Ashok, Brent Small, Huntington Potter and Gary W. Arendash;  Journal of Alzheimer’s Disease, 29 (2012) 1-14,  DOI 10.3233/JAD-2012-111781.

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USF Health’s mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the College of Pharmacy, the School of Biomedical Sciences and the School of Physical Therapy and Rehabilitation Sciences; and the USF Physician’s Group. The University of South Florida is a global research university ranked 50^th in the nation by the National Science Foundation for both federal and total research expenditures among all U.S. universities.

Media contacts:
Shani Jefferson, USF Health Byrd Alzheimer’s Institute, 813-396-0675 or  sjeffer1@health.usf.edu
Anne DeLotto Baier, USF Health Communications, (813) 974-3303 or abaier@health.usf.edu