Deniz Ghaffari, Tanz Centre for Research in Neurodegenerative Diseases

Supervisor:
Peter St George-Hyslop, Professor

PhD Thesis:
“Investigation of the ABI3 protein in microglia and its association with Alzheimer’s disease in TgCRND8 mouse model”

Recent genome wide-association studies (GWAS) have identified several disease-related genetic variants among Alzheimer’s disease (AD) patients. A cluster of these genes, including TREM2, PLCG2 and ABI3, are highly expressed in microglia and their function in these cells is poorly understood. Since microglial dysfunction is thought to play an important role in AD pathogenesis, my PhD thesis was aimed at analysing the expression and cellular function of ABI3 in microglia within the context of AD pathology in the CRND8 transgenic mouse model.

Briefly, ABI3 cellular expression was analysed in vitro by immunofluorescence/ immunocytochemistry (IF/ICC) studies in murine microglial cell line and mouse primary microglial cells. The functional role of ABI3 in microglia was studied by performing migration and phagocytosis assays in C57 ABI3 WT and ABI3 knock-out (KO) mouse microglia in which, ABI3 was shown to significantly impact microglial migration. In addition, the AD-relevant consequences of ABI3 KO were studied by immunofluorescence/ immunohistochemistry (IF/IHC) in ABI3 WT and KO TgCRND8 mouse brain sections; and the consequences of AD-associated ABI3 S209F(S212F) mutation were investigated in vitro in ABI3 over-expressing cell lines and S212F ABI3 mouse models. ABI3 mutation was shown to significantly impact ABI3 cellular expression and post-translational modifications in microglia, thus providing an insight into underlying mechanisms in which, ABI3 mutation may increase the risk of developing LOAD by altering microglial functions.

Current Research:
In my current position as a postdoctoral researcher at Dr Hyslop’s lab in Tanz CRND, I’ve been continuing my PhD research project on investigating the alterations in TREM2, PLCG2 and ABI3 cellular pathways in microglia during AD pathology.

Awards and Publications:
Homerton College (University of Cambridge) research award (2017 & 2018)

Hepcidin Increases Cytokines in Alzheimer's Disease and Down's Syndrome Dementia: Implication of Impaired Iron Homeostasis in Neuroinflammation. Raha AA, Ghaffari SD, Henderson J, Chakraborty S, Allinson K, Friedland RP, Holland A, Zaman SH, Mukaetova-Ladinska EB, Raha-Chowdhury R. Front Aging Neurosci. 2021 Apr 30;13:653591. doi: 10.3389/fnagi.2021.653591. PMID: 33994996; PMCID: PMC8120149.

Impaired Iron Homeostasis and Haematopoiesis Impacts Inflammation in the Ageing Process in Down Syndrome Dementia. Raha-Chowdhury R., Raha AA, Henderson J, Ghaffari SD, Grigorova M, Beresford-Webb J, Allinson K, Chakraborty S, Holland A, Zaman SH. J Clin Med. 2021 Jun 29;10(13):2909. doi: 10.3390/jcm10132909. PMID: 34209847; PMCID: PMC8268765.