Stabilized Low-n Amyloid-β Oligomers Induce Robust Novel Object Recognition Deficits Associated with Inflammatory, Synaptic, and GABAergic Dysfunction in the Rat

Watremez, William; Jackson, Joshua; Almari, Bushra; McLean, Samantha; Grayson, Ben; Neill, Joanna C.; Fischer, Nicolas; Allouche, Ahmad; Koziel, Violette; Pillot, Thierry; Harte, Michael K.

doi:10.3233/jad-170489

Cited by 4 publications

(63 citation statements)

References 45 publications

(63 reference statements)

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“…Cortical neurons were prepared from embryonic day 16–17 C57Bl6/J mouse fetuses and cultured at 50,000 cells/well in 48-well plates pre-coated with 1.5 μg/ml polyornithine at 35 °C in a humidified 6% CO 2 atmosphere. SynAging stable Aβ42O (consisting primarily of tetramers 43 , Supplementary Fig. 4) were pre-incubated for 30 min in the presence or absence of varying concentrations of muPMN310.…”

Section: Methodsmentioning

confidence: 99%

A Rationally Designed Humanized Antibody Selective for Amyloid Beta Oligomers in Alzheimer’s Disease

Gibbs

Silverman

Zhao

et al. 2019

Sci Rep

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Advances in the understanding of Alzheimer’s disease (AD) suggest that pathogenesis is not directly related to plaque burden, but rather to soluble toxic amyloid-beta oligomers (AßO). Therapeutic antibodies targeting Aß monomers and/or plaque have shown limited efficacy and dose-limiting adverse events in clinical trials. These findings suggest that antibodies capable of selectively neutralizing toxic AßO may achieve improved efficacy and safety. To this end, we generated monoclonal antibodies against a conformational Aß epitope predicted by computational modeling to be presented on toxic AßO but not monomers or fibrils. The resulting lead antibody, PMN310, showed the desired AßO-selective binding profile. In vitro , PMN310 inhibited AßO propagation and toxicity. In vivo , PMN310 prevented AßO-induced loss of memory formation and reduced synaptic loss and inflammation. A humanized version (huPMN310) compared favorably to other Aß-directed antibodies showing a lack of adverse event-associated binding to Aß deposits in AD brains, and greater selective binding to AßO-enriched AD brain fractions that contain synaptotoxic Aß species. Systemic administration of huPMN310 in mice resulted in brain exposure and kinetics comparable to those of other therapeutic human monoclonal antibodies. Greater selectivity for AßO and the potential to safely administer high doses of huPMN310 are expected to result in enhanced safety and therapeutic potency.

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Section: Methodsmentioning

confidence: 99%

A Rationally Designed Humanized Antibody Selective for Amyloid Beta Oligomers in Alzheimer’s Disease

Gibbs

Silverman

Zhao

et al. 2019

Sci Rep

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“…As a first step, we investigated the time frame necessary to achieve cognitive impairment in our rat model using NOR testing. The NOR test is used as a measure of short-term episodic memory, and we have previously used this test to show acute i.c.v administration of soluble amyloid β oligomers caused robust and enduring deficits ( Watremez et al, 2018 ). In line with the published literature, we found that 4 weeks of high-fat feeding results in cognitive impairment in Sprague Dawley rats ( Niepoetter et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

The Chemerin-CMKLR1 Axis is Functionally important for Central Regulation of Energy Homeostasis

Yun

Dumbell²,

Hanna³

et al. 2022

Front. Physiol.

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Chemerin is an adipokine involved in inflammation, adipogenesis, angiogenesis and energy metabolism, and has been hypothesized as a link between obesity and type II diabetes. In humans affected by obesity, chemerin gene expression in peripheral tissues and circulating levels are elevated. In mice, plasma levels of chemerin are upregulated by high-fat feeding and gain and loss of function studies show an association of chemerin with body weight, food intake and glucose homeostasis. Therefore, chemerin is an important blood-borne mediator that, amongst its other functions, controls appetite and body weight. Almost all studies of chemerin to date have focused on its release from adipose tissue and its effects on peripheral tissues with the central effects largely overlooked. To demonstrate a central role of chemerin, we manipulated chemerin signaling in the hypothalamus, a brain region associated with appetite regulation, using pharmacological and genetic manipulation approaches. Firstly, the selective chemerin receptor CMKLR1 antagonist α-NETA was administered i.c.v. to rats to test for an acute physiological effect. Secondly, we designed a short-hairpin-RNA (shRNA) lentivirus construct targeting expression of CMKLR1. This shRNA construct, or a control construct was injected bilaterally into the arcuate nucleus of male Sprague Dawley rats on high-fat diet (45%). After surgery, rats were maintained on high-fat diet for 2 weeks and then switched to chow diet for a further 2 weeks. We found a significant weight loss acutely and inhibition of weight gain chronically. This difference became apparent after diet switch in arcuate nucleus-CMKLR1 knockdown rats. This was not accompanied by a difference in blood glucose levels. Interestingly, appetite-regulating neuropeptides remained unaltered, however, we found a significant reduction of the inflammatory marker TNF-α suggesting reduced expression of CMKLR1 protects from high-fat diet induced neuroinflammation. In white and brown adipose tissue, mRNA expression of chemerin, its receptors and markers of adipogenesis, lipogenesis and brown adipocyte activation remained unchanged confirming that the effects are driven by the brain. Our behavioral analyses suggest that knockdown of CMKLR1 had an impact on object recognition. Our data demonstrate that CMKLR1 is functionally important for the central effects of chemerin on body weight regulation and neuroinflammation.

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“…For example, acute intracerebroventricular administration of soluble Aβ oligomers to rats caused sustained increases in inflammatory markers (tumor necrosis factor [TNF]-α, interleukin [IL]-1β), decreases in synaptic markers (PSD-95, SNAP-25) and loss of parvalbumin-positive interneurons in the frontal cortex [ 105 ]. Functionally, models of schizophrenia were not investigated, but Aβ treatment caused memory impairment in the rats.…”

Section: Chronic Inflammation Reduces Parvalbumin-positive Interneurons and Glutamatergic Pyramidal Cell Hyperexcitabilitymentioning

confidence: 99%

Relevance of 5-HT2A Receptor Modulation of Pyramidal Cell Excitability for Dementia-Related Psychosis: Implications for Pharmacotherapy

Burstein

2021

CNS Drugs

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Psychosis occurs across a wide variety of dementias with differing etiologies, including Alzheimer's dementia, Parkinson's dementia, Lewy body dementia, frontotemporal dementia, and vascular dementia. Pimavanserin, a selective serotonin 5-HT 2A receptor (5-HT 2A R) inverse agonist, has shown promising results in clinical trials by reducing the frequency and/or severity of hallucinations and delusions and the risk of relapse of these symptoms in patients with dementia-related psychosis. A literature review was conducted to identify mechanisms that explain the role of 5-HT 2A Rs in both the etiology and treatment of dementia-related psychosis. This review revealed that most pathological changes commonly associated with neurodegenerative diseases cause one or more of the following events to occur: reduced synaptic contact of gamma aminobutyric acid (GABA)-ergic interneurons with glutamatergic pyramidal cells, reduced cortical innervation from subcortical structures, and altered 5-HT 2A R expression levels. Each of these events promotes increased pyramidal cell hyperexcitability and disruption of excitatory/inhibitory balance, facilitating emergence of psychotic behaviors. The brain regions affected by these pathological changes largely coincide with areas expressing high levels of 5-HT 2A Rs. At the cellular level, 5-HT 2A Rs are most highly expressed on cortical glutamatergic pyramidal cells, where they regulate pyramidal cell excitability. The common effects of different neurodegenerative diseases on pyramidal cell excitability together with the close anatomical and functional connection of 5-HT 2A Rs to pyramidal cell excitability may explain why suppressing 5-HT 2A R activity could be an effective strategy to treat dementia-related psychosis.

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Stabilized Low-n Amyloid-β Oligomers Induce Robust Novel Object Recognition Deficits Associated with Inflammatory, Synaptic, and GABAergic Dysfunction in the Rat

Cited by 4 publications

References 45 publications

A Rationally Designed Humanized Antibody Selective for Amyloid Beta Oligomers in Alzheimer’s Disease

A Rationally Designed Humanized Antibody Selective for Amyloid Beta Oligomers in Alzheimer’s Disease

The Chemerin-CMKLR1 Axis is Functionally important for Central Regulation of Energy Homeostasis

Relevance of 5-HT2A Receptor Modulation of Pyramidal Cell Excitability for Dementia-Related Psychosis: Implications for Pharmacotherapy

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