Animal Models of Metabolic Disorders in the Study of Neurodegenerative Diseases: An Overview

de, Andreza Fabro; Krolow, Rachel; Farias, Hémelin Resende; Rezende, Victória Linden De; Gelain, Daniel Pens; Moreira, José Cláudio Fonseca; Duarte, João Miguel das Neves; Oliveira, Jade de

doi:10.3389/fnins.2020.604150

Cited by 44 publications

(40 citation statements)

References 274 publications

(386 reference statements)

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“…Although aging is the leading risk factor for the development of Alzheimer’s disease, growing evidence, also from animal models, indicates that metabolic dysfunctions may have a crucial role in the etiology of AD [ 2 , 3 ]. Obesity and type 2 diabetes mellitus (T2DM) are reported to be related to AD [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Inflammasome NLRP3 Potentially Links Obesity-Associated Low-Grade Systemic Inflammation and Insulin Resistance with Alzheimer’s Disease

Litwiniuk

Bik

Kalisz

et al. 2021

IJMS

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Alzheimer’s disease (AD) is the most common form of neurodegenerative dementia. Metabolic disorders including obesity and type 2 diabetes mellitus (T2DM) may stimulate amyloid β (Aβ) aggregate formation. AD, obesity, and T2DM share similar features such as chronic inflammation, increased oxidative stress, insulin resistance, and impaired energy metabolism. Adiposity is associated with the pro-inflammatory phenotype. Adiposity-related inflammatory factors lead to the formation of inflammasome complexes, which are responsible for the activation, maturation, and release of the pro-inflammatory cytokines including interleukin-1β (IL-1β) and interleukin-18 (IL-18). Activation of the inflammasome complex, particularly NLRP3, has a crucial role in obesity-induced inflammation, insulin resistance, and T2DM. The abnormal activation of the NLRP3 signaling pathway influences neuroinflammatory processes. NLRP3/IL-1β signaling could underlie the association between adiposity and cognitive impairment in humans. The review includes a broadened approach to the role of obesity-related diseases (obesity, low-grade chronic inflammation, type 2 diabetes, insulin resistance, and enhanced NLRP3 activity) in AD. Moreover, we also discuss the mechanisms by which the NLRP3 activation potentially links inflammation, peripheral and central insulin resistance, and metabolic changes with AD.

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Section: Introductionmentioning

confidence: 99%

Inflammasome NLRP3 Potentially Links Obesity-Associated Low-Grade Systemic Inflammation and Insulin Resistance with Alzheimer’s Disease

Litwiniuk

Bik

Kalisz

et al. 2021

IJMS

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“…Nevertheless, due to the species differences between humans and mice, the existing AD mouse models cannot fully simulate the pathologic and clinical features of human AD, which limits their application in preclinical studies of AD ( de Bem et al, 2020 ). Therefore, it is necessary to develop animal models more similar to human AD to test the safety and efficacy of these agents ( Medina and Avila, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Effects of Natural Compounds and Small Molecule Inhibitors Targeting Endoplasmic Reticulum Stress in Alzheimer’s Disease

Gao

2021

Front. Cell Dev. Biol.

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Alzheimer’s disease (AD) is the most common neurodegenerative disease, characterized by progressive cognitive impairment and memory loss. So far, the pathogenesis of AD has not been fully understood. Research have shown that endoplasmic reticulum (ER) stress and unfolded protein response (UPR) participate in the occurrence and development of AD. Furthermore, various studies, both in vivo and in vitro, have shown that targeting ER stress and ER stress-mediated apoptosis contribute to the recovery of AD. Thus, targeting ER stress and ER stress-mediated apoptosis may be effective for treating AD. In this review, the molecular mechanism of ER stress and ER stress-mediated apoptosis, as well as the therapeutic effects of some natural compounds and small molecule inhibitors targeting ER stress and ER stress-mediated apoptosis in AD will be introduced.

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“…Neuroinflammation is a key process by which lipid metabolism disorders and obesity impact brain function (de Bem et al, 2021). HSL-/-mice show low grade neuroinflammation characterized by higher expression of pro-inflammatory cytokines than wild-type littermates.…”

Section: Discussionmentioning

confidence: 99%

“…As a first step to investigate the impact of HSL deletion on brain metabolism, we measured the expression of a panel of genes coding for proteins involved in glucose and lipid metabolism and genes encoding enzymes involved in the endocannabinoid system. Since neuroinflammation is known to be involved in a number of neurological and metabolic disorders (de Bem et al, 2021), this gene panel also included the master regulator of inflammatory processes NF-κB and cytokines. Transcriptomics data from the hippocampus and cortex was analysed with a 2-component partial least-squares discriminant analysis (PLS-DA), and allowed good separation of HSL-/-and wild-type mice (figure 4A), with PC1 and PC2 accounting for 72% and 16% of the variance in gene expression.…”

Section: Hsl Deletion Impacts Genes Involved In Glucose Metabolism and Inflammationmentioning

confidence: 99%

Central hormone-sensitive lipase is located at synapses and is necessary for normal memory performance in mice

Skoug

Holm

Duarte

2021

Preprint

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Hormone-sensitive lipase (HSL) is mainly present in the adipose tissue where it hydrolyses diacylglycerol. Although brain expression of HSL has been reported, its presence in different cellular compartments is uncertain, and its role in regulating brain lipid metabolism remains hitherto unexplored. We propose that HSL has a role in regulating the availability of bioactive lipids necessary for adequate neuronal function. Therefore, we tested the hypothesis that dampening HSL activity leads to brain dysfunction. We found HSL protein and activity throughout all the mouse brain, localised in neurons and especially enriched in synapses. HSL null mice were then analysed using a battery of behavioural tests. Relative to wild-type littermates, HSL null mice showed impaired short- and long-term memory, but preserved exploratory behaviours. Molecular analysis of the cortex and hippocampus showed increased expression of genes involved in glucose utilization in the hippocampus but not cortex of HSL null mice compared to controls. Lipidomics analyses indicated an impact of HSL deletion on the profile of bioactive lipids, including endocannabinoids and eicosanoids that are known to modulate neuronal activity, cerebral blood blow and inflammation processes. Accordingly, mild increases in expression of pro-inflammatory cytokines suggest low grade inflammation in HSL null mice compared to littermates. We conclude that HSL has a homeostatic role in maintaining pools of lipids that are needed for brain function. It remains to be tested, however, whether the recruitment of HSL for the synthesis of these lipids occurs during increased neuronal activity, or whether HSL participates in neuroinflammatory responses.

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Animal Models of Metabolic Disorders in the Study of Neurodegenerative Diseases: An Overview

Cited by 44 publications

References 274 publications

Inflammasome NLRP3 Potentially Links Obesity-Associated Low-Grade Systemic Inflammation and Insulin Resistance with Alzheimer’s Disease

Inflammasome NLRP3 Potentially Links Obesity-Associated Low-Grade Systemic Inflammation and Insulin Resistance with Alzheimer’s Disease

Therapeutic Effects of Natural Compounds and Small Molecule Inhibitors Targeting Endoplasmic Reticulum Stress in Alzheimer’s Disease

Central hormone-sensitive lipase is located at synapses and is necessary for normal memory performance in mice

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