Reboxetine Treatment Reduces Neuroinflammation and Neurodegeneration in the 5xFAD Mouse Model of Alzheimer’s Disease: Role of CCL2

Gutiérrez, Irene L.; González‐Prieto, Marta; Caso, Javier R.; García‐Bueno, Borja; Leza, Juan C.; Madrigal, José L. M.

doi:10.1007/s12035-019-01695-6

Cited by 26 publications

(24 citation statements)

References 44 publications

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“…The nature of these neuroglial interactions in our preplaque Tg rat model is, at present, unclear; however, they are likely time-and context-dependent. For example, CCL2 knockout or inhibition minimizes plaque pathology, diminishes inflammatory gene expression, and recovers cognitive performance in an AD Tg mouse model, but may have converse effects in otherwise WT animals (82,83). In an experimental animal model of encephalitis, neuronderived CCL2 promotes the recruitment of phagocytic macrophages and synaptic engulfment, resulting in significant motor deficits (84).…”

Section: Discussionmentioning

confidence: 99%

Early intraneuronal amyloid triggers neuron-derived inflammatory signaling in APP transgenic rats and human brain

Welikovitch

Carmo

Maglóczky

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Chronic inflammation during Alzheimer’s disease (AD) is most often attributed to sustained microglial activation in response to amyloid-β (Aβ) plaque deposits and cell death. However, cytokine release and microgliosis are consistently observed in AD transgenic animal models devoid of such pathologies, bringing into question the underlying processes that may be at play during the earliest AD-related immune response. We propose that this plaque-independent inflammatory reaction originates from neurons burdened with increasing levels of soluble and oligomeric Aβ, which are known to be the most toxic amyloid species within the brain. Laser microdissected neurons extracted from preplaque amyloid precursor protein (APP) transgenic rats were found to produce a variety of potent immune factors, both at the transcript and protein levels. Neuron-derived cytokines correlated with the extent of microglial activation and mobilization, even in the absence of extracellular plaques and cell death. Importantly, we identified an inflammatory profile unique to Aβ-burdened neurons, since neighboring glial cells did not express similar molecules. Moreover, we demonstrate within disease-vulnerable regions of the human brain that a neuron-specific inflammatory response may precede insoluble Aβ plaque and tau tangle formation. Thus, we reveal the Aβ-burdened neuron as a primary proinflammatory agent, implicating the intraneuronal accumulation of Aβ as a significant immunological component in the AD pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Early intraneuronal amyloid triggers neuron-derived inflammatory signaling in APP transgenic rats and human brain

Welikovitch

Carmo

Maglóczky

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…A contribution of an altered immune status within the brain parenchyma is not (yet) obvious from the here presented data. Expression of IL1β and CCL2 is increased in AD [61,62], and both have been discussed as pathogenicity factors and biomarkers for, e.g., progression from mild cognitive impairment (MCI) to AD [63][64][65]. Despite the increased CCL2 in the small intestine due to ingestion of ATIs, no increase of either immunological marker at the mRNA level was found in whole brain preparations.…”

Section: Discussionmentioning

confidence: 99%

Dietary Wheat Amylase Trypsin Inhibitors Impact Alzheimer’s Disease Pathology in 5xFAD Model Mice

Guilherme

Zevallos

Pesi

et al. 2020

IJMS

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Wheat amylase trypsin inhibitors (ATIs) represent a common dietary protein component of gluten-containing cereals (wheat, rye, and barley). They act as toll-like receptor 4 ligands, and are largely resistant to intestinal proteases, eliciting a mild inflammatory response within the intestine after oral ingestion. Importantly, nutritional ATIs exacerbated inflammatory bowel disease and features of fatty liver disease and the metabolic syndrome in mice. For Alzheimer’s disease (AD), both inflammation and altered insulin resistance are major contributing factors, impacting onset as well as progression of this devastating brain disorder in patients. In this study, we evaluated the impact of dietary ATIs on a well-known rodent model of AD (5xFAD). We assessed metabolic, behavioral, inflammatory, and microbial changes in mice consuming different dietary regimes with and without ATIs, consumed ad libitum for eight weeks. We demonstrate that ATIs, with or without a gluten matrix, had an impact on the metabolism and gut microbiota of 5xFAD mice, aggravating pathological hallmarks of AD. If these findings can be translated to patients, an ATI-depleted diet might offer an alternative therapeutic option for AD and warrants clinical intervention studies.

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“…Also, Gannon et al. (2015) stated that the loss of noradrenergic neurons and the subsequent reduction of brain noradrenaline (NA) levels are two alterations usually found in AD and usually aggravate the progression of neuroinflammation and neuronal damage (Gutiérrez et al., 2019). Regarding adrenaline, the present results go with the previous studies, which stated that AD patients have an exhibited loss of LC neuronal cells, reducing to as low as 70% in the rostral nuclei leading to reduced limbic and cortical epinephrine and norepinephrine levels (Gannon et al., 2015).…”

Section: Discussionmentioning

confidence: 99%

Glucagon‐like peptide‐1 analog improves neuronal and behavioral impairment and promotes neuroprotection in a rat model of aluminum‐induced dementia

et al. 2020

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Background Alzheimer's disease (AD) is a worldwide severe medical and social burden. Liraglutide (LIR) has neuroprotective effects in preclinical animal models. Aim: To explore the probable neuroprotective impact of Glucagon‐like peptide‐1 (GLP‐1) on rats' behavior and to elucidate its underlying mechanisms. Methods: A total of 24 male albino rats were assigned to control, LIR (300 µg/kg subcutaneously (s.c.)), AD only (100 mg/kg aluminum chloride (AlCl3) orally) and LIR + AD treated groups. Eight radial arm maze was performed. Serum blood glucose, proinflammatory cytokines, oxidative stress markers were measured and hippocampal tissue homogenate neurotransmitters were evaluated. Histopathological and immunofluorescent examinations were performed. Results: LIR prevents the impairment of learning and improves both working memory and reference memory through significant reduction of serum tumor necrosis factor (TNF‐α), interleukin 6 (IL‐6) and interferon‐γ (INF‐γ) and malondialdehyde (MDA) and through the increase of superoxide dismutase (SOD), dopamine, adrenaline, and noradrenaline. LIR also improves hippocampal histological features of ALCL3 administrated rats and decreases the percentage of neuronal loss. Conclusion: LIR normalizes ALCL3‐induced dementia. It improves cognitive dysfunction and ameliorates cerebral damage.

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Reboxetine Treatment Reduces Neuroinflammation and Neurodegeneration in the 5xFAD Mouse Model of Alzheimer’s Disease: Role of CCL2

Cited by 26 publications

References 44 publications

Early intraneuronal amyloid triggers neuron-derived inflammatory signaling in APP transgenic rats and human brain

Early intraneuronal amyloid triggers neuron-derived inflammatory signaling in APP transgenic rats and human brain

Dietary Wheat Amylase Trypsin Inhibitors Impact Alzheimer’s Disease Pathology in 5xFAD Model Mice

Glucagon‐like peptide‐1 analog improves neuronal and behavioral impairment and promotes neuroprotection in a rat model of aluminum‐induced dementia

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