Non-Alcoholic Fatty Liver Disease, and the Underlying Altered Fatty Acid Metabolism, Reveals Brain Hypoperfusion and Contributes to the Cognitive Decline in APP/PS1 Mice

Pinçon, Anthony; Montgolfier, Olivia de; Akkoyunlu, Nilay; Daneault, Caroline; Pouliot, Philippe; Villeneuve, Louis; Lesage, Frédéric; Lévy, Bernard; Thorin‐Trescases, Nathalie; Thorin, Éric; Ruiz, Matthieu

doi:10.3390/metabo9050104

Cited by 38 publications

(29 citation statements)

References 85 publications

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“…Their findings suggested an acceleration in neurodegeneration and in Aβ plaque formation after HFD-induced acute inflammation and NAFLD development [30]. The fact that HFD and fructose-rich diets may quicken AD cognitive decline has also been confirmed in recent experimental studies [32][33][34].…”

Section: Neurodegenerative Diseases: Alzheimer's Diseasementioning

confidence: 83%

Depression and Cognitive Impairment—Extrahepatic Manifestations of NAFLD and NASH

2020

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Non-alcoholic fatty liver disease (NAFLD) and its complication non-alcoholic steatohepatitis (NASH) are important causes of liver disease worldwide. Recently, a significant association between these hepatic diseases and different central nervous system (CNS) disorders has been observed in an increasing number of patients. NAFLD-related CNS dysfunctions include cognitive impairment, hippocampal-dependent memory impairment, and mood imbalances (in particular, depression and anxiety). This review aims at summarizing the main correlations observed between NAFLD development and these CNS dysfunctions, focusing on the studies investigating the mechanism(s) involved in this association. Growing evidences point at cerebrovascular alteration, neuroinflammation, and brain insulin resistance as NAFLD/NASH-related CNS manifestations. Since the pharmacological options available for the management of these conditions are still limited, further studies are needed to unravel the mechanism(s) of NAFLD/NASH and their central manifestations and identify effective pharmacological targets.

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Section: Neurodegenerative Diseases: Alzheimer's Diseasementioning

confidence: 83%

Depression and Cognitive Impairment—Extrahepatic Manifestations of NAFLD and NASH

2020

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“…Changes in rCBF occur earlier than rCBV during the disease course [98], where metabolic and vascular risk factors have been implicated as a driver of hemodynamic disturbances [102,103]. Consistent, experimental studies have shown that these risk factors compromises cerebral perfusion, contribute to cognitive impairment and enhances AD pathology [104,105]. The variability of hemodynamic read-outs in AD and the fact that hemodynamic changes are also common in other forms of dementia limits the utility of methods for the individual diagnosis of AD patients, but the methods remain pivotal research tools.…”

Section: Dysregulation Regional Rcbf and Volumementioning

confidence: 99%

An Integrated View on Vascular Dysfunction in Alzheimer’s Disease

Klohs

2019

Neurodegener Dis

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Background: Cerebrovascular disease is a common comorbidity in patients with Alzheimer's disease (AD). It is believed to contribute additively to the cognitive impairment and to lower the threshold for the development of dementia. However, accumulating evidence suggests that dysfunction of the cerebral vasculature and AD neuropathology interact in multiple ways. Vascular processes even proceed AD neuropathology, implicating a causal role in the etiology of AD. Thus, the review aims to provide an integrated view on vascular dysfunction in AD. Summary: In AD, the cerebral vasculature undergoes pronounced cellular, morphological and structural changes, which alters regulation of blood flow, vascular fluid dynamics and vessel integrity. Stiffening of central blood vessels lead to transmission of excessive pulsatile energy to the brain microvasculature, causing endorgan damage. Moreover, a dysregulated hemostasis and chronic vascular inflammation further impede vascular function, where its mediators interact synergistically. Changes of the cerebral vasculature are triggered and driven by systemic vascular abnormalities that are part of aging, and which can be accelerated and aggravated by cardiovascular diseas-es. Key Messages: In AD, the cerebral vasculature is the locus where multiple pathogenic processes converge and contribute to cognitive impairment. Understanding the molecular mechanism and pathophysiology of vascular dysfunction in AD and use of vascular blood-based and imaging biomarker in clinical studies may hold promise for future prevention and therapy of the disease.

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“…Oxidative phosphorylation and metabolic pathways appear disrupted at this early stage and have been associated with early stages of human AD [23,24]. In addition, non-alcoholic liver fatty liver disease (NAFLD) was also identified at this early stage and has been previously associated with AD [25,26]. NAFLD is generally characterized by excessive fat build up in the liver.…”

Section: Discussionmentioning

confidence: 99%

Staging Alzheimer’s disease in the brain and retina of B6.APP/PS1 mice by transcriptional profiling

Chintapaludi

Uyar

Jackson

et al. 2019

Preprint

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Alzheimer's disease (AD) is a common form of dementia characterized by amyloid plaque deposition, TAU pathology, neuroinflammation and neurodegeneration. Mouse models recapitulate some key features of AD. For instance, the B6.APP/PS1 model (carrying human transgenes for mutant forms of APP and PSEN1) shows plaque deposition and associated neuroinflammatory responses involving both astrocytes and microglia beginning around 6 months of age. However, in our colony, TAU pathology, significant neurodegeneration and cognitive decline are not apparent in this model even at older ages. Therefore, this model is ideal for studying neuroinflammatory responses to amyloid deposition. Here, RNA sequencing of brain and retinal tissue, generalized linear modeling (GLM), functional annotation followed by validation by immunofluorescence (IF) was performed in B6.APP/PS1 mice to determine the earliest molecular changes prior to and around the onset of plaque deposition (2-6 months of age). Multiple pathways were shown to be activated in response to amyloid deposition including the JAK/STAT and NALFD pathways. Putative, cell-specific targets of STAT3, a central component of the JAK/STAT pathway, were identified that we propose provide more precise options for assessing the potential for targeting activation of the JAK/STAT pathway as a treatment for human AD. In the retina, GLM predicted activation of vascular-related pathways. However, many of the gene expression changes comparing B6 with B6.APP/PS1 retina samples occurred prior to plaque onset (2 months of age). This suggests retinal changes in B6.APP/PS1 mice may be an artefact of overexpression of mutant forms of APP and PSEN1 providing limited translatability to human AD. Therefore, caution should be taken when using this mouse model to assess the potential of using the eye as a window to the brain for AD. 4

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Non-Alcoholic Fatty Liver Disease, and the Underlying Altered Fatty Acid Metabolism, Reveals Brain Hypoperfusion and Contributes to the Cognitive Decline in APP/PS1 Mice

Cited by 38 publications

References 85 publications

Depression and Cognitive Impairment—Extrahepatic Manifestations of NAFLD and NASH

Depression and Cognitive Impairment—Extrahepatic Manifestations of NAFLD and NASH

An Integrated View on Vascular Dysfunction in Alzheimer’s Disease

Staging Alzheimer’s disease in the brain and retina of B6.APP/PS1 mice by transcriptional profiling

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