A ketogenic diet accelerates neurodegeneration in mice with induced mitochondrial DNA toxicity in the forebrain

Lauritzen, Knut H.; Hasan‐Olive, Mahdi; Regnell, Christine Elisabeth; Kleppa, Liv; Scheibye‐Knudsen, Morten; Gjedde, Albert; Klungland, Arne; Bohr, Vilhelm A.; Storm‐Mathisen, Jon; Bergersen, Linda Hildegard

doi:10.1016/j.neurobiolaging.2016.08.005

Cited by 34 publications

(25 citation statements)

References 60 publications

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“…The method combines manual segmentation of cell membranes with automated gold particle detection with high precision and a low false‐positive detection rate (Enger, ). Comparing with another immunogold analysis method based on ImageJ (Lauritzen et al, ), the MATLAB based automated gold particle detection method added precision and efficiency to the analysis of the big data set in question.…”

Section: Discussionmentioning

confidence: 99%

Loss of perivascular aquaporin‐4 in idiopathic normal pressure hydrocephalus

Hasan‐Olive

Enger

Hansson

et al. 2018

Glia

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Idiopathic normal pressure hydrocephalus (iNPH) is a subtype of dementia that may be successfully treated with cerebrospinal fluid (CSF) diversion. Recently, magnetic resonance imaging (MRI) using a MRI contrast agent as a CSF tracer revealed impaired clearance of the CSF tracer from various brain regions such as the entorhinal cortex of iNPH patients. Hampered clearance of waste solutes, for example, soluble amyloid‐β, may underlie neurodegeneration and dementia in iNPH. The goal of the present study was to explore whether iNPH is associated with altered subcellular distribution of aquaporin‐4 (AQP4) water channels, which is reported to facilitate CSF circulation and paravascular glymphatic drainage of metabolites from the brain parenchyma. Cortical brain biopsies of 30 iNPH patients and 12 reference individuals were subjected to AQP4 immunogold cytochemistry. Electron microscopy revealed significantly reduced density of AQP4 water channels in astrocytic endfoot membranes along cortical microvessels in patients with iNPH versus reference subjects. There was a significant positive correlation between density of AQP4 toward endothelial cells (perivascular) and toward parenchyma, but the reduced density of AQP4 toward parenchyma was not significant in iNPH. We conclude that perivascular AQP4 expression is attenuated in iNPH, potentially contributing to impaired glymphatic circulation, and waste clearance, and subsequent neurodegeneration. Hence, restoring normal perivascular AQP4 distribution may emerge as a novel treatment strategy for iNPH.

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Section: Discussionmentioning

confidence: 99%

Loss of perivascular aquaporin‐4 in idiopathic normal pressure hydrocephalus

Hasan‐Olive

Enger

Hansson

et al. 2018

Glia

Self Cite

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“…Conversely, a recent report demonstrated histopathological evidence of neurodegenerative progression by a ketogenic diet in a transgenic mouse model of abnormal mitochondrial DNA repair, despite increases in mitochondrial biogenesis and antioxidant signatures (Lauritzen et al, 2016). Other conflicting reports suggest that exposure to high ketone body concentrations elicits oxidative stress.…”

Section: Ketone Bodies Oxidative Stress and Neuroprotectionmentioning

confidence: 99%

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

2017

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Ketone body metabolism is a central node in physiological homeostasis. In this review, we discuss how ketones serve discrete fine-tuning metabolic roles that optimize organ and organism performance in varying nutrient states, and protect from inflammation and injury in multiple organ systems. Traditionally viewed as metabolic substrates enlisted only in carbohydrate restriction, recent observations underscore the importance of ketone bodies as vital metabolic and signaling mediators when carbohydrates are abundant. Complementing a repertoire of known therapeutic options for diseases of the nervous system, prospective roles for ketone bodies in cancer have arisen, as have intriguing protective roles in heart and liver, opening therapeutic options in obesity-related and cardiovascular disease. Controversies in ketone metabolism and signaling are discussed to reconcile classical dogma with contemporary observations.

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“…Mitochondrial dysfunction and oxidative stress play a significant role in neurodegeneration. Both processes are known to generate higher concentrations of ROS, which are harmful to all cellular macromolecules, including nucleic acid, lipid, and protein damage [87]. Therefore, KD may provide neuroprotective benefit by improving mitochondrial function through biochemical changes resulting from glycolysis inhibition and increased KBs formation.…”

Section: Ketogenic Dietmentioning

confidence: 99%

Ketogenic Diet in Alzheimer’s Disease

Rusek

Pluta

Ułamek-Kozioł

et al. 2019

IJMS

248

165

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At present, the prevalence of Alzheimer’s disease, a devastating neurodegenerative disorder, is increasing. Although the mechanism of the underlying pathology is not fully uncovered, in the last years, there has been significant progress in its understanding. This includes: Progressive deposition of amyloid β-peptides in amyloid plaques and hyperphosphorylated tau protein in intracellular as neurofibrillary tangles; neuronal loss; and impaired glucose metabolism. Due to a lack of effective prevention and treatment strategy, emerging evidence suggests that dietary and metabolic interventions could potentially target these issues. The ketogenic diet is a very high-fat, low-carbohydrate diet, which has a fasting-like effect bringing the body into a state of ketosis. The presence of ketone bodies has a neuroprotective impact on aging brain cells. Moreover, their production may enhance mitochondrial function, reduce the expression of inflammatory and apoptotic mediators. Thus, it has gained interest as a potential therapy for neurodegenerative disorders like Alzheimer’s disease. This review aims to examine the role of the ketogenic diet in Alzheimer’s disease progression and to outline specific aspects of the nutritional profile providing a rationale for the implementation of dietary interventions as a therapeutic strategy for Alzheimer’s disease.

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A ketogenic diet accelerates neurodegeneration in mice with induced mitochondrial DNA toxicity in the forebrain

Cited by 34 publications

References 60 publications

Loss of perivascular aquaporin‐4 in idiopathic normal pressure hydrocephalus

Loss of perivascular aquaporin‐4 in idiopathic normal pressure hydrocephalus

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

Ketogenic Diet in Alzheimer’s Disease

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