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Role of Aβ Specific Regulatory T cells in harnessing cerebral Aβ clearance in Alzheimer’s Disease

Periodic Reporting for period 1 - TREGinAD (Role of Aβ Specific Regulatory T cells in harnessing cerebral Aβ clearance in Alzheimer’s Disease)

Reporting period: 2018-04-01 to 2020-03-31

With populations rapidly ageing, maintaining brain health has become a global priority. The number of people living with dementia is expected to rise to 152 million worldwide within the next 20 years, with an estimated cost upwards of US$1 trillion for dementia care.  Clinical trials for vaccination against Aβ, the pathogenic agent accumulating in the brain and triggering Alzheimer’s disease (AD), have failed or worst were accompanied by severe side effects due to an improper response of the immune system. In other neurodegenerative disorders, strategies based on strengthening a population of immune cells from the adaptive immunity named regulatory T cells (Treg) have proven successful. Indeed, Treg have the ability to prevent overly exuberant activation of other immune cells and at the same time direct them toward clearance of pathogens.
Using a mouse model of AD, which like patients present Aβ buildup in the brain, the goal of this project was to test a new type of vaccination in hopes that it will activate Treg specifically targeting the Aβ peptide. The objectives are: 1) to assess if Aβ specific Treg produced by the vaccination would prevent  improper brain inflammation and control partner immune cells to clear Aβ deposition; 2) To determine if the Treg infiltrate the brain to exert the predicted beneficial effects; 3) To identify other immune cell populations involved in the response to cerebral Aβ deposition.
APP/PS1 mice received different immunisation cocktails, 2 of which successfully amplified Aβ specific regulatory T cells. Importantly, an equal number of male and female mice were assessed to account for potential sex differences. Strikingly, amplification of Aβ specific Treg in response to vaccination protocols revealed an unexpected sexual dimorphism. The mechanism by which these T cells become polarised to a Treg lineage specifically in one sex remains unclear and needs further examination. Subsequent analyses revealed that T cells do enter the mice brain in all vaccination groups tested, although these populations were much less abundant than in the lymph nodes from the periphery. Successful vaccinal generation of Aβ specific Treg however did not have the expected impact on Aβ plaque load. These results have not been published yet, but the data produced during the Action have been used as anchoring evidence for grant applications to support future research avenues.
Additionally, the results have been disseminated in internal meetings in the host institution including: 1) in laboratory meetings of prof Marina Lynch group, 2) Glia Club (a monthly gathering of researchers and students from Physiology, Biochemistry and Immunology departments in Trinity College Dublin). The project was also presented externally during a seminar at the Institute of Cellular and Molecular Pharmacology in Sophia-Antipolis, France and discussed with researchers at international conferences in 2019 including Alzheimer's & Parkinson's Diseases Congress in Lisbon, Portugal and BNA2019 Festival of Neuroscience in Dublin, Ireland. In collaboration with another MSCA fellow, I have also founded a local network “NeuroInflammation Network Dublin” joined by researchers across all universities in Dublin with similar research interests. The project was also communicated to lay audiences as follow: 1) I designed and facilitated an outreach activity titled: “The immune system fights against Alzheimer’s disease” during the "Science is Wonder-ful!-European Researchers' Night event in Brussels in September 2018, 2) I coordinated and organised a total of 5 workshops for the association Native Scientist, showcasing my research to over French-speaking 120 pupils from 6 to 12 years old leaving in Dublin.
Our study has identify a valid immunisation strategy to produce Aβ specific regulatory T cells and highlights an important sexual dimorphisms in APP/PS1 mice response to vaccination.
Despite the apparent absence of effect on Aβ plaque load, further studies are needed to assess the exact impact of Aβ specific Treg populations generated by the vaccination protocols on cerebral amyloidosis and associated inflammation in APP/PS1 mice. Importantly, the striking sexual dimorphism revealed is of particular relevance since sex is a risk factor for AD which is more prevalent among women than men. Moreover sex differences in immune responses have been recently reported however sex-dependent variability of responses to Aβ immunotherapy have been overlooked so far.
The results obtained are strong evidence that elucidation of the sexual polymorphism in immune responses and in particular in the context of AD, is key to provide safer, innovative, personalized and patient-centered therapeutic tools. Although in early stages and having been significantly delayed by the COVID-19 pandemic, this project holds a strong impact on global human health and has a high translational potential in the pharmaceutical industry with prospective benefits of improving the outlook of AD.
Sex differential response to vaccinal strategies