Effects of ketone bodies in Alzheimer's disease in relation to neural hypometabolism, β-amyloid toxicity, and astrocyte function
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Standard
Effects of ketone bodies in Alzheimer's disease in relation to neural hypometabolism, β-amyloid toxicity, and astrocyte function. / Hertz, Leif; Chen, Ye; Waagepetersen, Helle S.
I: Journal of Neurochemistry, Bind 134, Nr. 1, 07.2015, s. 7-20.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Effects of ketone bodies in Alzheimer's disease in relation to neural hypometabolism, β-amyloid toxicity, and astrocyte function
AU - Hertz, Leif
AU - Chen, Ye
AU - Waagepetersen, Helle S
N1 - © 2015 International Society for Neurochemistry.
PY - 2015/7
Y1 - 2015/7
N2 - Diet supplementation with ketone bodies (acetoacetate and β-hydroxybuturate) or medium-length fatty acids generating ketone bodies has consistently been found to cause modest improvement of mental function in Alzheimer's patients. It was suggested that the therapeutic effect might be more pronounced if treatment was begun at a pre-clinical stage of the disease instead of well after its manifestation. The pre-clinical stage is characterized by decade-long glucose hypometabolism in brain, but ketone body metabolism is intact even initially after disease manifestation. One reason for the impaired glucose metabolism may be early destruction of the noradrenergic brain stem nucleus, locus coeruleus, which stimulates glucose metabolism, at least in astrocytes. These glial cells are essential in Alzheimer pathogenesis. The β-amyloid peptide Aβ interferes with their cholinergic innervation, which impairs synaptic function because of diminished astrocytic glutamate release. Aβ also reduces glucose metabolism and causes hyperexcitability. Ketone bodies are similarly used against seizures, but the effectively used concentrations are so high that they must interfere with glucose metabolism and de novo synthesis of neurotransmitter glutamate, reducing neuronal glutamatergic signaling. The lower ketone body concentrations used in Alzheimer's disease may owe their effect to support of energy metabolism, but might also inhibit release of gliotransmitter glutamate. Alzheimer's disease is a panglial-neuronal disorder with long-standing brain hypometabolism, aberrations in both neuronal and astrocytic glucose metabolism, inflammation, hyperexcitability, and dementia. Relatively low doses of β-hydroxybutyrate can have an ameliorating effect on cognitive function. This could be because of metabolic supplementation or inhibition of Aβ-induced release of glutamate as gliotransmitter, which is likely to reduce hyperexcitability and inflammation. The therapeutic β-hydroxybutyrate doses are too low to reduce neuronally released glutamate.
AB - Diet supplementation with ketone bodies (acetoacetate and β-hydroxybuturate) or medium-length fatty acids generating ketone bodies has consistently been found to cause modest improvement of mental function in Alzheimer's patients. It was suggested that the therapeutic effect might be more pronounced if treatment was begun at a pre-clinical stage of the disease instead of well after its manifestation. The pre-clinical stage is characterized by decade-long glucose hypometabolism in brain, but ketone body metabolism is intact even initially after disease manifestation. One reason for the impaired glucose metabolism may be early destruction of the noradrenergic brain stem nucleus, locus coeruleus, which stimulates glucose metabolism, at least in astrocytes. These glial cells are essential in Alzheimer pathogenesis. The β-amyloid peptide Aβ interferes with their cholinergic innervation, which impairs synaptic function because of diminished astrocytic glutamate release. Aβ also reduces glucose metabolism and causes hyperexcitability. Ketone bodies are similarly used against seizures, but the effectively used concentrations are so high that they must interfere with glucose metabolism and de novo synthesis of neurotransmitter glutamate, reducing neuronal glutamatergic signaling. The lower ketone body concentrations used in Alzheimer's disease may owe their effect to support of energy metabolism, but might also inhibit release of gliotransmitter glutamate. Alzheimer's disease is a panglial-neuronal disorder with long-standing brain hypometabolism, aberrations in both neuronal and astrocytic glucose metabolism, inflammation, hyperexcitability, and dementia. Relatively low doses of β-hydroxybutyrate can have an ameliorating effect on cognitive function. This could be because of metabolic supplementation or inhibition of Aβ-induced release of glutamate as gliotransmitter, which is likely to reduce hyperexcitability and inflammation. The therapeutic β-hydroxybutyrate doses are too low to reduce neuronally released glutamate.
KW - Alzheimer Disease
KW - Amyloid beta-Peptides
KW - Animals
KW - Astrocytes
KW - Brain
KW - Energy Metabolism
KW - Humans
KW - Ketogenic Diet
KW - Ketone Bodies
U2 - 10.1111/jnc.13107
DO - 10.1111/jnc.13107
M3 - Journal article
C2 - 25832906
VL - 134
SP - 7
EP - 20
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
IS - 1
ER -
ID: 161865230