New anti-AB vaccine could help halt Alzheimer's progression, preclinical
study finds

Date:
October 20, 2020
Source:
University of South Florida (USF Health)
Summary:
A preclinical study by neuroscientists indicates that an antigen-
presenting dendritic vaccine with a specific antibody response
to oligomeric A-beta may be safer and offer clinical benefit
in treating Alzheimer's disease. The vaccine uses immune cells
known as dendritic cells loaded with a modified A beta peptide as
the antigen.



FULL STORY ==========================================================================
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 Ab) 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 Ab 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 Ab 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 Ab 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 Ab 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 Ab (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 with
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 Ab
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 Ab-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.

The study included three groups of transgenic (APP/PS1) mice genetically engineered to develop high levels of Ab 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 Ab 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-Ab
antibodies in
both in their brains and in their blood than the transgenic control
mice administered dendritic cells containing no modified Ab peptide.

* Only Ab 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 Ab, 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.


========================================================================== Story Source: Materials provided by
University_of_South_Florida_(USF_Health). Original written by Anne
DeLotto Baier. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Ge Song, Haiqiang Yang, Ning Shen, Phillip Pham, Breanna Brown,
Xiaoyang
Lin, Yuzhu Hong, Paul Sinu, Jianfeng Cai, Xiaopeng Li, Michael
Leon, Marcia N. Gordon, David Morgan, Sai Zhang, Chuanhai Cao. An
Immunomodulatory Therapeutic Vaccine Targeting Oligomeric Amyloid-b.

Journal of Alzheimer's Disease, 2020; 77 (4): 1639 DOI: 10.3233/JAD-
200413 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201020135637.htm

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