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• Identifying links between fetal Down syndrome and maternal Alzheimer's disease. Down Syndrome (DS), is the most common cause of intellectual disability (ID), affecting 1 in 750 live births worldwide. Alzheimer’s disease (AD) is linked to DS, as the amyloid precursor protein (APP) gene, present on the triplicated chromosome 21, is over-expressed in individuals with DS. The accumulation of neurotoxic APP-derived extracellular amyloid-β (Aβ) deposits, together with intraneuronal accumulation of tau tangles characterize late-onset AD (LOAD). Pregnancy at a young age (≤35y) with a DS-affected fetus is associated with an almost 5-fold increased risk of developing LOAD later in life, however, the mechanisms responsible are unknown. The increase in maternal age worldwide, which is a known risk factor for a DS pregnancy, stresses the need to elucidate any potential mechanistic link between pregnancy with a DS-affected fetus and maternal LOAD, and ultimately develop a therapeutic approach to reduce the risk of maternal LOAD. 

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• Microglial phagocytosis in Alzheimer's disease. Microglia, the primary brain-resident immune cells, protect the brain from various harmful pathogens and insults and maintain its homeostasis by phagocytosing extracellular particles. How microglia are metabolically regulated by their microenvironment remains largely elusive. Here we investigated how extracellular lactate, which is abundant in the brain and dynamically changing in pathological states, affects microglial phagocytotic ability. We show that L-lactate reduces microglia phagocytic capacity in a Hydroxycarboxylic Acid Receptor 1 (HCAR1)- but not Monocarboxylate transporter 1 (MCT1)-dependent manner. Our findings point to a potential role for extracellular lactate in suppressing the phagocytic activity of microglial cells in homeostasis and inflammatory conditions.

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• The role of immune B cells in Alzheimer's disease. The role of adaptive immunity in Alzheimer’s disease (AD) remains poorly understood. Unlike T cells, which both exacerbate and ameliorate AD, B cells were shown to produce beneficial amyloidosis-reducing antibodies. Despite playing adverse roles in aging and multiple sclerosis, B cells have not been linked to the etiology of AD. Our preliminary data indicate that AD symptoms are delayed in several AD mouse models when B cells are transiently or permanently depleted, suggesting that AD manifestation requires B cells. In this project we follow this paradigm-shifting study, and study the mechanisms by which B cells promote AD.