Rita Cacace (Belgium)
VIB University of Antwerp
Center for Molecular Neurology
Rita Cacace is a postdoctoral researcher in the team of prof. Christine Van Broeckhoven at the Flanders Institute for Biotechnology, Center for Molecular Neurology, University of Antwerp, Belgium. Her work focuses on understanding the functional consequences of rare genetic variants to Alzheimer disease etiopathogenesis. After a master’s degree in Medical Biotechnology (2009, University of Naples “Federico II”, Naples Italy). Rita Cacace obtained her PhD in Biomedical Sciences in 2015 from the University of Antwerp. Her PhD thesis focused on exploring the missing genetics of Alzheimer’s disease. After her PhD, Dr. Cacace was awarded a 3-year personal postdoctoral fellowship from the Research Foundation Flanders. Starting from 2017 Dr. Cacace collaborated in a project from the Flanders Innovation and Entrepreneurship in partnership with Janssen Pharmaceuticals (Johnson & Johnson), Beerse, Belgium. In 2019 Dr. Cacace received an international mobility grant to join prof. Lennart Mucke’s lab, Gladstone Institute for Neurological Disease, University of California San Francisco, USA. Returned to Belgium, in 2020, Dr. Cacace was funded by the Alzheimer Research Foundation. In the same year she secured a fully funded postdoc from Autifony Therapeutics Limited, UK. Dr. Cacace is currently developing iPSC-derived disease models to identify novel therapeutic targets.

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 Conference Calendar

A FAMILY-BASED STUDY IN EARLY-ONSET ALZHEIMER’S SUPPORTS THE ROLE OF TOLL-LIKE RECEPTOR 9 DYSFUNCTION IN DISEASE PATHOGENESIS.

Session Name
0220 - GENETICS OF NEURODEGENERATION 1 (ID 7)
Session Type
SYMPOSIUM
Date
Wed, 16.03.2022
Session Time
08:30 AM - 10:30 AM
Room
ONSITE: 113
Lecture Time
08:45 AM - 09:00 AM
Presenter

Abstract

Aims

Family-based genetic studies in early-onset Alzheimer’s disease (EOAD) are powerful to identify novel genes in AD. In a long-lasting effort to collect clinicopathological data and biomaterials from EOAD patients for genetic studies, we identified a multigenerational Flanders-Belgian family with autosomal dominant AD, average onset age 57.8 years (range 58-64), negative for mutations in known causal and high-risk AD genes.

Methods

DNA, biomaterials and clinicopathological data in 2 consecutive generations: 5 AD patients, 2 with definite neuropathological diagnosis and 9 unaffected or at-risk individuals. Whole exome sequencing in 4 patients for gene identification. Functional modelling of mutation and pathway.

Results

WES analysis identified a novel mutation, p.E317D, in TLR9 co-segregating with AD. TLR9 is a DNA-sensing receptor expressed in immune cells and p.E317D falls in the DNA-sensing domain. The mutation caused >50% decrease in TLR9 signaling. Cytokine profiling of peripheral blood mononuclear cells (PBMC) upon TLR9 activation revealed a complex signaling with predominance of anti-inflammatory cytokines including IL-1RA and IFNβ. This cytokine pool reduced the levels of pro-inflammatory cytokines IL1β and TNFα and promoted phagocytosis of Aβ42 in human iPSC-derived microglia. We also demonstrated that phagocytosis was attributed to IFNs in the cytokine pool. Transcriptome analysis identified several genes including AXL and RUBICON as potential drivers for IFNs-induced phagocytosis.

Conclusions

We presented that PBMC mediated TLR9 signaling exerts a protective role in AD pathophysiology, promoting microglial anti-inflammation and phagocytic clearance of pathological proteins, functions that could be lost due to TLR9 genetic mutations.

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