Biology subjects

Maguire, E.

Publications and source records attributed to Maguire, E..

5 recordsLinked to original sources

bioRxiv2026

New Human IPSC Models of Late-onset Alzheimer's Disease Polygenic Risk Identify Multiple Impairments of Microglial Function

Genetic discoveries implicate microglia in late-onset Alzheimers disease (AD). We modelled AD in a powerful study of 51 human induced pluripotent stem cell (iPSC) microglia derived from high-polygenic risk AD or low-risk cognitively well individuals, sampled from a large cohort. We explored mitochondrial function, cytokine secretion, endocytosis, phagocytosis, lipid accumulation, calcium store release, and chemotaxis under basal conditions and immune challenge. High polygenic risk was independently associated with significant functional deficits in iPSC microglia under immune challenge, in mitochondrial ATP production (p=0.005, -13%), and inflammatory cytokine release (IL-6: p=0.018, -42%; TNF p=0.026, -38.5%). Furthermore, a selective deficit in amyloid-{beta} uptake was identified (p=0.00477, -5.9%). Deficits in inflammatory cytokine release were driven by APOE {varepsilon}4. These findings reflect primary changes in AD pathogenesis predating plaque formation and validate a human in vitro platform for late-onset AD to further understand disease mechanisms and screen drug or genetic therapies.

neuroscience↗

bioRxiv2023

Uncoupling of synaptic loss from amyloid burden by an Alzheimer's disease protective variant of PLCγ2.

A rare coding missense variant (rs72824905; P522R) in PLCG2 decreases the risk of late-onset Alzheimers disease, but how this protective effect is mediated is unclear. Here we demonstrate a mechanism for this protection, the R522 variant of PLC{gamma}2 alters microglial activity leading to a marked preservation of synaptic integrity and reduced peri-plaque microglial engulfment of synapses independently of amyloid burden. Our data advocate for a direct central role of PLC{gamma}2 in mediating synaptic loss as part of the pathological process of Alzheimers disease (AD), prioritising it as a therapeutic target and modulator of disease.

neuroscience↗

bioRxiv2020

The Alzheimer's disease protective P522R variant of PLCG2, consistently enhances stimulus-dependent PLCγ2 activation, depleting substrate and altering cell function.

Recent genome-wide association studies of Alzheimers disease (AD) have identified variants implicating immune pathways in disease development. A rare coding variant of PLCG2, which encodes PLC{gamma}2, shows a significant protective effect for AD (rs72824905, P522R, P=5.38x10-10, Odds Ratio = 0.68). Molecular dynamic modelling of the PLC{gamma}2-R522 variant, situated within the auto-inhibitory domain of PLC{gamma}2, suggests a structural change to the protein. Through CRISPR-engineering we have generated novel PLCG2-R522 harbouring human induced pluripotent cell lines (hiPSC) and a mouse knockin model, neither of which exhibits alterations in endogenous PLCG2 expression. Mouse microglia and macrophages and hiPSC-derived microglia-like cells with the R522 mutation, all demonstrate a consistent non-redundant hyperfunctionality in the context of normal expression of other PLC isoforms. This signalling alteration manifests as enhanced cellular Ca2+ store release ([~]20-40% increase) in response to physiologically-relevant stimuli (e.g. Fc receptor ligation and A{beta} oligomers). This hyperfunctionality resulted in increased PIP2 depletion in the cells with the PLC{gamma}2-R522 variant after exposure to stimuli and reduced basal detection of PIP2 levels in vivo. These PLC{gamma}2-R522 associated abnormalities resulted in impairments to phagocytosis (fungal and bacterial particles) and enhanced endocytosis (A{beta} oligomers and dextran). PLC{gamma}2 sits downstream of disease relevant pathways, such as TREM2 and CSF1R and alterations in its activity, direct impacts cell function, which in the context of the inherent drugability of enzymes such as PLC{gamma}2, raise the prospect of manipulation of PLC{gamma}2 as a therapeutic target in Alzheimers Disease.

neuroscience↗

bioRxiv2017

Mind-wandering in people with hippocampal amnesia

Subjective inner experiences, such as mind-wandering, represent the fundaments of human cognition. While the precise function of mind-wandering is still debated, it is increasingly acknowledged to have influence across cognition on processes such as future planning, creative thinking and problem-solving, and even on depressive rumination and other mental health disorders. Recently, there has been important progress in characterizing mind-wandering and identifying the neural networks associated with it. Two prominent features of mind-wandering are mental time travel and visuo-spatial imagery, which are often associated with the hippocampus. People with amnesia arising from selective bilateral hippocampal damage ( hippocampal amnesia) cannot vividly recall events from their past, envision their future or imagine fictitious scenes. This raises the question of whether the hippocampus plays a causal role in mind-wandering and if so, in what way. Leveraging a unique opportunity to shadow people with hippocampal amnesia for several days, we examined, for the first time, what they thought about spontaneously, without direct task demands. We found that they engaged in as much mind-wandering as control participants. However, whereas controls thought flexibly and creatively about the past, present and future, imagining vivid visual scenes, hippocampal amnesia resulted in thoughts primarily about the present comprising verbally-mediated semantic knowledge. These findings expose the hippocampus as a key pillar in the neural architecture of mind-wandering and also reveal its impact beyond memory, placing it at the heart of human mental life.\n\nSignificance statementHumans tend to mind-wander about 30-50% of their waking time. Two prominent features of this pervasive form of thought are mental time travel and visuo-spatial imagery, which are often associated with the hippocampus. To examine whether the hippocampus plays a causal role in mind-wandering, we examined the frequency and phenomenology of mind-wandering in patients with selective bilateral hippocampal damage. We found that they engaged in as much mind-wandering as controls. However, hippocampal damage changed the form and content of mind-wandering from flexible, episodic, and scene-based to abstract, semanticized, and verbal. These findings expose the hippocampus as a key pillar in the neural architecture of mind-wandering and reveal its impact beyond memory, placing it at the heart of our mental life.

neuroscience↗

bioRxiv2017

Effects Of Curcumin Nanoformulations On Cellular Function In Niemann-Pick Disease Type C Astrocytes

Niemann-Pick disease type C1 (NPC disease) is a neurodegenerative multi-lipid lysosomal storage disease caused by mutations in the NPC1 gene presenting with reduced lysosomal Ca2+ signalling and inhibited late endosome-lysosome transport. Elevating cytosolic Ca2+ levels in NPC cells has been shown to reduce lysosomal lipid storage. Treating Npc1-/- mice with the Ca2+ modulator curcumin led to reduced lipid storage, improved life expectancy and function. These studies led to reported utilisation of curcumin supplements by NPC disease families despite there being no clinical evidence of benefit and a report indicating no benefit of nanoformulated curcumin in Npc1-/- mice. The aim of this study was to determine whether various commercially available curcumin nanoformulations were capable of reproducing the findings obtained with unformulated pharmaceutical grade curcumin. We compared seven curcumin nanoformulations in Npc1-/- mouse astrocytes. All the nanoformulations elevate cytosolic Ca2+ levels but only two lowered lysosomal lipid storage. Importantly, some caused elevations in NPC lysosomal storage and/or decreased cellular viability. Although this is an in vitro study, our findings suggest that care should be taken when contemplating the use of curcumin supplements for NPC disease.

pharmacology and toxicology↗