Publications by authors named "Amira Latif-Hernandez"

8 Publications

  • Page 1 of 1

Restoring metabolism of myeloid cells reverses cognitive decline in ageing.

Nature 2021 Feb 20;590(7844):122-128. Epub 2021 Jan 20.

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.

Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty. The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer's disease. Systemically, circulating pro-inflammatory factors can promote cognitive decline, and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration. However, the underlying mechanisms that initiate and sustain maladaptive inflammation with ageing are not well defined. Here we show that in ageing mice myeloid cell bioenergetics are suppressed in response to increased signalling by the lipid messenger prostaglandin E (PGE), a major modulator of inflammation. In ageing macrophages and microglia, PGE signalling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flux and mitochondrial respiration. This energy-deficient state, which drives maladaptive pro-inflammatory responses, is further augmented by a dependence of aged myeloid cells on glucose as a principal fuel source. In aged mice, inhibition of myeloid EP2 signalling rejuvenates cellular bioenergetics, systemic and brain inflammatory states, hippocampal synaptic plasticity and spatial memory. Moreover, blockade of peripheral myeloid EP2 signalling is sufficient to restore cognition in aged mice. Our study suggests that cognitive ageing is not a static or irrevocable condition but can be reversed by reprogramming myeloid glucose metabolism to restore youthful immune functions.
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http://dx.doi.org/10.1038/s41586-020-03160-0DOI Listing
February 2021

The two faces of synaptic failure in App knock-in mice.

Alzheimers Res Ther 2020 08 24;12(1):100. Epub 2020 Aug 24.

Brain and Cognition, KU Leuven, Tiensestraat 102, Box 3714, 3000, Leuven, Belgium.

Background: Intensive basic and preclinical research into Alzheimer's disease (AD) has yielded important new findings, but they could not yet been translated into effective therapies. One of the reasons is the lack of animal models that sufficiently reproduce the complexity of human AD and the response of human brain circuits to novel treatment approaches. As a step in overcoming these limitations, new App knock-in models have been developed that avoid transgenic APP overexpression and its associated side effects. These mice are proposed to serve as valuable models to examine Aß-related pathology in "preclinical AD."

Methods: Since AD as the most common form of dementia progresses into synaptic failure as a major cause of cognitive deficits, the detailed characterization of synaptic dysfunction in these new models is essential. Here, we addressed this by extracellular and whole-cell patch-clamp recordings in App mice compared to App animals which served as controls.

Results: We found a beginning synaptic impairment (LTP deficit) at 3-4 months in the prefrontal cortex of App mice that is further aggravated and extended to the hippocampus at 6-8 months. Measurements of miniature EPSCs and IPSCs point to a marked increase in excitatory and inhibitory presynaptic activity, the latter accompanied by a moderate increase in postsynaptic inhibitory function.

Conclusions: Our data reveal a marked impairment of primarily postsynaptic processes at the level of synaptic plasticity but the dominance of a presumably compensatory presynaptic upregulation at the level of elementary miniature synaptic function.
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http://dx.doi.org/10.1186/s13195-020-00667-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445922PMC
August 2020

Commentary: APP as a Mediator of the Synapse Pathology in Alzheimer's Disease.

Front Cell Neurosci 2018 31;12:150. Epub 2018 May 31.

Department of Bioscience, Durham University, Durham, United Kingdom.

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http://dx.doi.org/10.3389/fncel.2018.00150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5990595PMC
May 2018

Spatial reversal learning defect coincides with hypersynchronous telencephalic BOLD functional connectivity in APP knock-in mice.

Sci Rep 2018 04 19;8(1):6264. Epub 2018 Apr 19.

Bio-Imaging Lab, University of Antwerp, Antwerpen, Belgium.

Amyloid pathology occurs early in Alzheimer's disease (AD), and has therefore been the focus of numerous studies. Transgenic mouse models have been instrumental to study amyloidosis, but observations might have been confounded by APP-overexpression artifacts. The current study investigated early functional defects in an APP knock-in mouse model, which allows assessing the effects of pathological amyloid-beta (Aβ) without interference of APP-artifacts. Female APP knock-in mice of 3 and 7 months old were compared to age-matched APP mice with increased Aβ42/40 ratio and initial Aβ-plaque deposition around 6 months of age. Spatial learning was examined using a Morris water maze protocol consisting of acquisition and reversal trials interleaved with reference memory tests. Functional connectivity (FC) of brain networks was assessed using resting-state functional MRI (rsfMRI). The Morris water maze data revealed that 3 months old APP mice were unable to reach the same reference memory proficiency as APP mice after reversal training. This cognitive defect in 3-month-old APP mice coincided with hypersynchronous FC of the hippocampal, cingulate, caudate-putamen, and default-mode-like networks. The occurrence of these defects in APP mice demonstrates that cognitive flexibility and synchronicity of telencephalic activity are specifically altered by early Aβ pathology without changes in APP neurochemistry.
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http://dx.doi.org/10.1038/s41598-018-24657-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908850PMC
April 2018

Subtle behavioral changes and increased prefrontal-hippocampal network synchronicity in APP mice before prominent plaque deposition.

Behav Brain Res 2019 05 20;364:431-441. Epub 2017 Nov 20.

Laboratory of Biological Psychology, University of Leuven, KU Leuven, Belgium. Electronic address:

Amyloid-β (Aβ) peptides occur in the brains of patients with Alzheimer's disease (AD), but their role in functional impairment is still debated. High levels of APP and APP fragments in mice that overexpress APP might confound their use in preclinical research. We examined the occurrence of behavioral, cognitive and neuroimaging changes in APP knock-in mice that display Aβ42 amyloidosis in the absence of APP overexpression. Female APP mice (carrying Swedish, Iberian and Arctic APP mutations) were compared to APP mice (APP Swedish) at 3, 7 and 10 months. Mice were subjected to a test battery that referred to clinical AD symptoms, comprising cage activity, open field, elevated plus maze, social preference and novelty test, and spatial learning, reversal learning and spatial reference memory performance. Our assessment confirmed that behavior at these early ages was largely unaffected in these mice in accordance with previous reports, with some subtle behavioral changes, mainly in social and anxiety-related test performance. Resting-state functional MRI (rsfMRI) assessed connectivity between hippocampal and prefrontal regions with an established role in flexibility, learning and memory. Increased prefrontal-hippocampal network synchronicity was found in 3-month-old APP mice. These functional changes occurred before prominent amyloid plaque deposition.
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http://dx.doi.org/10.1016/j.bbr.2017.11.017DOI Listing
May 2019

Separate Ionotropic and Metabotropic Glutamate Receptor Functions in Depotentiation vs. LTP: A Distinct Role for Group1 mGluR Subtypes and NMDARs.

Front Cell Neurosci 2016 7;10:252. Epub 2016 Nov 7.

Laboratory of Biological Psychology, KU Leuven Leuven, Belgium.

Depotentiation (DP) is a mechanism by which synapses that have recently undergone long-term potentiation (LTP) can reverse their synaptic strengthening within a short time-window after LTP induction. Group 1 metabotropic glutamate receptors (mGluRs) were shown to be involved in different forms of LTP and long-term depression (LTD), but little is known about their roles in DP. Here, we generated DP by applying low-frequency stimulation (LFS) at 5 Hz after LTP had been induced by a single train of theta-burst-stimulation (TBS). While application of LFS for 2 min (DP2') generated only a short-lasting DP that was independent of the activation of -methyl-D-aspartate receptors (NMDARs) and group 1 mGluRs, LFS given for 8 min (DP8') induced a robust DP that was maintained for at least 2 h. This strong form of DP was contingent on NMDAR activation. Interestingly, DP8' appears to include a metabotropic NMDAR function because it was blocked by the competitive NMDAR antagonist D-AP5 but not by the use-dependent inhibitor MK-801 or high Mg. Furthermore, DP8' was enhanced by application of the mGluR1 antagonist (YM 298198, 1 μM). The mGluR5 antagonist 2-Methyl-6(phenylethynyl) pyridine (MPEP, 40 μM), in contrast, failed to affect it. The induction of LTP, in turn, was NMDAR dependent (as tested with D-AP5), and blocked by MPEP but not by YM 298198. These results indicate a functional dissociation of mGluR1 and mGluR5 in two related and consecutively induced types of NMDAR-dependent synaptic plasticity (LTP → DP) with far-reaching consequences for their role in plasticity and learning under normal and pathological conditions.
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http://dx.doi.org/10.3389/fncel.2016.00252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5098392PMC
November 2016

Quinolinic acid injection in mouse medial prefrontal cortex affects reversal learning abilities, cortical connectivity and hippocampal synaptic plasticity.

Sci Rep 2016 11 7;6:36489. Epub 2016 Nov 7.

Laboratory of Biological Psychology, Brain and Cognition, KU Leuven, Tiensestraat 102, 3000 Leuven, Belgium.

Intracerebral injection of the excitotoxic, endogenous tryptophan metabolite, quinolinic acid (QA), constitutes a chemical model of neurodegenerative brain disease. Complementary techniques were combined to examine the consequences of QA injection into medial prefrontal cortex (mPFC) of C57BL6 mice. In accordance with the NMDAR-mediated synapto- and neurotoxic action of QA, we found an initial increase in excitability and an augmentation of hippocampal long-term potentiation, converting within two weeks into a reduction and impairment, respectively, of these processes. QA-induced mPFC excitotoxicity impaired behavioral flexibility in a reversal variant of the hidden-platform Morris water maze (MWM), whereas regular, extended MWM training was unaffected. QA-induced mPFC damage specifically affected the spatial-cognitive strategies that mice use to locate the platform during reversal learning. These behavioral and cognitive defects coincided with changes in cortical functional connectivity (FC) and hippocampal neuroplasticity. FC between various cortical regions was assessed by resting-state fMRI (rsfMRI) methodology, and mice that had received QA injection into mPFC showed increased FC between various cortical regions. mPFC and hippocampus (HC) are anatomically as well as functionally linked as part of a cortical network that controls higher-order cognitive functions. Together, these observations demonstrate the central functional importance of rodent mPFC as well as the validity of QA-induced mPFC damage as a preclinical rodent model of the early stages of neurodegeneration.
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http://dx.doi.org/10.1038/srep36489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5098239PMC
November 2016

Early pathologic amyloid induces hypersynchrony of BOLD resting-state networks in transgenic mice and provides an early therapeutic window before amyloid plaque deposition.

Alzheimers Dement 2016 09 21;12(9):964-976. Epub 2016 Apr 21.

Bio-Imaging Lab, Department of Biomedical Sciences, University of Antwerp, Wilrijk, Antwerp, Belgium.

Introduction: In Alzheimer's disease (AD), pathologic amyloid-beta (Aβ) is synaptotoxic and impairs neuronal function at the microscale, influencing brain networks at the macroscale before Aβ deposition. The latter can be detected noninvasively, in vivo, using resting-state functional MRI (rsfMRI), a technique used to assess brain functional connectivity (FC).

Methods: RsfMRI was performed longitudinally in TG2576 and PDAPP mice, starting before Aβ deposition to determine the earliest FC changes. Additionally, the role of pathologic Aβ on early FC alterations was investigated by treating TG2576 mice with the 3D6 anti-Aβ-antibody.

Results: Both transgenic models showed hypersynchronized FC before Aβ deposition and hyposynchronized FC at later stages. Early anti-Aβ treatment in TG2576 mice prevented hypersynchronous FC and the associated synaptic impairments and excitatory/inhibitory disbalances.

Discussion: Hypersynchrony of FC may be used as a new noninvasive read out of early AD and can be recovered by anti-Aβ treatment, encouraging preventive treatment strategies in familial AD.
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http://dx.doi.org/10.1016/j.jalz.2016.03.010DOI Listing
September 2016