ORCID Profile
0000-0003-0342-5197
Current Organisations
McGill University
,
Western University
,
University of Oxford
,
Mayo Clinic Minnesota
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Publisher: Wiley
Date: 11-05-2023
DOI: 10.1111/NAN.12904
Abstract: Selective neuronal vulnerability of hippoc al Cornu Ammonis (CA)‐1 neurons is a pathological hallmark of Alzheimer's disease (AD) with an unknown underlying mechanism. We interrogated the expression of tuberous sclerosis complex‐1 (TSC1 hamartin) and mTOR‐related proteins in hippoc al CA1 and CA3 subfields. A human post‐mortem cohort of mild ( n = 7) and severe ( n = 10) AD and non‐neurological controls ( n = 9) was used for quantitative and semi‐quantitative analyses. We also developed an in vitro TSC1 knockdown model in rat hippoc al neurons, and transcriptomic analyses of TSC1 knockdown neuronal cultures were performed. We found a selective increase of TSC1 cytoplasmic inclusions in human AD CA1 neurons with hyperactivation of one of TSC1's downstream targets, the mammalian target of rapamycin complex‐1 (mTORC1), suggesting that TSC1 is no longer active in AD. TSC1 knockdown experiments showed accelerated cell death independent of amyloid‐beta toxicity. Transcriptomic analyses of TSC1 knockdown neuronal cultures revealed signatures that were significantly enriched for AD‐related pathways. Our combined data point to TSC1 dysregulation as a key driver of selective neuronal vulnerability in the AD hippoc us. Future work aimed at identifying targets amenable to therapeutic manipulation is urgently needed to halt selective neurodegeneration, and by extension, debilitating cognitive impairment characteristic of AD.
Publisher: Public Library of Science (PLoS)
Date: 06-02-2009
Publisher: Wiley
Date: 11-06-2023
DOI: 10.1002/GLIA.24208
Publisher: Oxford University Press (OUP)
Date: 29-06-2011
DOI: 10.1093/QJMED/HCR101
Publisher: SAGE Publications
Date: 18-10-2019
Abstract: The significant morbidity that accompanies stroke makes it one of the world's most devastating neurological disorders. Currently, proven effective therapies have been limited to thrombolysis and thrombectomy. The window for the administration of these therapies is narrow, h ered by the necessity of rapidly imaging patients. A therapy that could extend this window by protecting neurons may improve outcome. Endogenous neuroprotection has been shown to be, in part, due to changes in mTOR signalling pathways and the instigation of productive autophagy. Inducing this effect pharmacologically could improve clinical outcomes. One such therapy already in use in transplant medicine is the mTOR inhibitor rapamycin. Recent evidence suggests that rapamycin is neuroprotective, not only via neuronal autophagy but also through its broader effects on other cells of the neurovascular unit. This review highlights the potential use of rapamycin as a multimodal therapy, acting on the blood–brain barrier, cerebral blood flow and inflammation, as well as directly on neurons. There is significant potential in applying this old drug in new ways to improve functional outcomes for patients after stroke.
Publisher: SAGE Publications
Date: 04-08-2018
Abstract: Cornu ammonis 3 (CA3) hippoc al neurons are resistant to global ischemia, whereas cornu ammonis (CA1) 1 neurons are vulnerable. Hamartin expression in CA3 neurons mediates this endogenous resistance via productive autophagy. Neurons lacking hamartin demonstrate exacerbated endoplasmic reticulum stress and increased cell death. We investigated endoplasmic reticulum stress responses in CA1 and CA3 regions following global cerebral ischemia, and whether pharmacological modulation of endoplasmic reticulum stress or autophagy altered neuronal viability . In vivo: male Wistar rats underwent sham or 10 min of transient global cerebral ischemia. CA1 and CA3 areas were microdissected and endoplasmic reticulum stress protein expression quantified at 3 h and 12 h of reperfusion. In vitro: primary neuronal cultures (E18 Wistar rat embryos) were exposed to 2 h of oxygen and glucose deprivation or normoxia in the presence of an endoplasmic reticulum stress inducer (thapsigargin or tunicamycin), an endoplasmic reticulum stress inhibitor (salubrinal or 4-phenylbutyric acid), an autophagy inducer ([4′-(N-diethylamino) butyl]-2-chlorophenoxazine (10-NCP)) or autophagy inhibitor (3-methyladenine). In vivo, decreased endoplasmic reticulum stress protein expression (phospho-eIF2α and ATF4) was observed at 3 h of reperfusion in CA3 neurons following ischemia, and increased in CA1 neurons at 12 h of reperfusion. In vitro, endoplasmic reticulum stress inducers and high doses of the endoplasmic reticulum stress inhibitors also increased cell death. Both induction and inhibition of autophagy also increased cell death. Endoplasmic reticulum stress is associated with neuronal cell death following ischemia. Neither reduction of endoplasmic reticulum stress nor induction of autophagy demonstrated neuroprotection in vitro, highlighting their complex role in neuronal biology following ischemia.
Publisher: Wiley
Date: 04-09-2015
DOI: 10.1002/GLIA.22906
Publisher: SAGE Publications
Date: 02-10-2016
Abstract: The clinical relevance of the transient intraluminal filament model of middle cerebral artery occlusion (tMCAO) has been questioned due to distinct cerebral blood flow profiles upon reperfusion between tMCAO (abrupt reperfusion) and alteplase treatment (gradual reperfusion), resulting in differing pathophysiologies. Positive results from recent endovascular thrombectomy trials, where the occluding clot is mechanically removed, could revolutionize stroke treatment. The rapid cerebral blood flow restoration in both tMCAO and endovascular thrombectomy provides clinical relevance for this pre-clinical model. Any future clinical trials of neuroprotective agents as adjuncts to endovascular thrombectomy should consider tMCAO as the model of choice to determine pre-clinical efficacy.
Publisher: Oxford University Press (OUP)
Date: 10-2012
DOI: 10.1093/BRAIN/AWS242
Publisher: Wiley
Date: 30-03-2023
DOI: 10.1002/GLIA.24371
Abstract: Cerebral blood flow (CBF) is important for the maintenance of brain function and its dysregulation has been implicated in Alzheimer's disease (AD). Microglia associations with capillaries suggest they may play a role in the regulation of CBF or the blood–brain‐barrier (BBB). We explored the relationship between microglia and pericytes, a vessel‐resident cell type that has a major role in the control of CBF and maintenance of the BBB, discovering a spatially distinct subset of microglia that closely associate with pericytes. We termed these pericyte‐associated microglia (PEM). PEM are present throughout the brain and spinal cord in NG2DsRed × CX 3 CR1 +/GFP mice, and in the human frontal cortex. Using in vivo two‐photon microscopy, we found microglia residing adjacent to pericytes at all levels of the capillary tree and found they can maintain their position for at least 28 days. PEM can associate with pericytes lacking astroglial endfeet coverage and capillary vessel width is increased beneath pericytes with or without an associated PEM, but capillary width decreases if a pericyte loses a PEM. Deletion of the microglia fractalkine receptor (CX 3 CR1) did not disrupt the association between pericytes and PEM. Finally, we found the proportion of microglia that are PEM declines in the superior frontal gyrus in AD. In summary, we identify microglia that specifically associate with pericytes and find these are reduced in number in AD, which may be a novel mechanism contributing to vascular dysfunction in neurodegenerative diseases.
Publisher: SAGE Publications
Date: 26-08-2015
DOI: 10.1111/IJS.12618
Abstract: Acute ischemic strokes involving occlusion of large vessels usually recanalize poorly following treatment with intravenous thrombolysis. Recent studies have shown higher recanalization and higher good outcome rates with endovascular therapy compared with best medical management alone. A systematic review and meta-analysis investigating the benefits of all randomized controlled trials of endovascular thrombectomy where at least 25% of patients were treated with a thrombectomy device for the treatment of acute ischemic stroke compared with best medical treatment have yet to be performed. To perform a systematic review and a meta-analysis evaluating the effectiveness of endovascular thrombectomy compared with best medical care for treatment of acute ischemic stroke. Our search identified 437 publications, from which eight studies (totaling 2423 patients) matched the inclusion criteria. Overall, endovascular thrombectomy was associated with improved functional outcomes (modified Rankin Scale 0–2) [odds ratio 1·56 (1·32–1·85), P 0·00001]. There was a tendency toward decreased mortality [odds ratio 0·84 (0·67–1·05), P = 0·12], and symptomatic intracerebral hemorrhage was not increased [odds ratio 1·03 (0·71–1·49), P = 0·88] compared with best medical management alone. The odds ratio for a favorable functional outcome increased to 2·23 (1·77–2·81, P 0·00001) when newer generation thrombectomy devices were used in greater than 50% of the cases in each trial. There is clear evidence for improvement in functional independence with endovascular thrombectomy compared with standard medical care, suggesting that endovascular thrombectomy should be considered the standard effective treatment alongside thombolysis in eligible patients.
Publisher: Oxford University Press (OUP)
Date: 13-05-2022
Abstract: To match the metabolic demands of the brain, mechanisms have evolved to couple neuronal activity to vasodilation, thus increasing local cerebral blood flow and delivery of oxygen and glucose to active neurons. Rather than relying on metabolic feedback signals such as the consumption of oxygen or glucose, the main signalling pathways rely on the release of vasoactive molecules by neurons and astrocytes, which act on contractile cells. Vascular smooth muscle cells and pericytes are the contractile cells associated with arterioles and capillaries, respectively, which relax and induce vasodilation. Much progress has been made in understanding the complex signalling pathways of neurovascular coupling, but issues such as the contributions of capillary pericytes and astrocyte calcium signal remain contentious. Study of neurovascular coupling mechanisms is especially important as cerebral blood flow dysregulation is a prominent feature of Alzheimer’s disease. In this article we will discuss developments and controversies in the understanding of neurovascular coupling and finish by discussing current knowledge concerning neurovascular uncoupling in Alzheimer’s disease.
Publisher: Cold Spring Harbor Laboratory
Date: 11-08-2022
DOI: 10.1101/2022.08.08.503250
Abstract: Cerebral blood flow is important for the maintenance of brain function and its dysregulation has been implicated in Alzheimer’s disease (AD). Subpopulations of microglia have well-characterised associations with the vasculature in the central nervous system but the precise relationship between microglia and cells which exist on the vasculature is not yet clear. In this study we explored the relationship between microglia and pericytes, a vessel-resident cell type that has a major role in the regulation of cerebral blood flow and maintenance of the blood brain barrier. Using fixed tissue sections and in vivo live imaging, we discovered a subset of microglia that closely associated with pericytes, termed PE ricyte-associated M icroglia (PEM). PEM are present throughout all regions of the brain and spinal cord in NG2DsRed x CX 3 CR1 +/GFP mice, and in the human frontal cortex. They reside adjacent to pericytes at all levels of the capillary tree and can maintain their position for at least 28 days. PEM associate with pericytes lacking astroglial endfeet coverage but are segregated from pericytes by capillary basement membranes and capillary vessel width is similarly increased beneath pericytes with or without an associated PEM. Deletion of the microglia fractalkine receptor (CX 3 CR1) did not disrupt the association between pericytes and PEM, suggesting the association is not reliant on fractalkine signalling. Finally, we found that the proportion of microglia that are capillary-associated and PEM declines in the superior frontal gyrus (SFG) in AD, which is exacerbated by the APOE ε3/ε4 genotype. In summary, we identify and characterise a subpopulation of microglia that specifically associate with pericytes and find this population is reduced in the SFG in AD. This reduction may be a novel mechanism contributing to vascular dysfunction in diseases such as AD.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Gabriele De Luca.