Vaishnavi SN, Vlassenko AG, Rundle MM, Snyder AZ, Mintun MA, Raichle ME.
Regional aerobic glycolysis in the human brain.
Proc Natl Acad Sci U S A. 2010 Oct 12;107(41):17757-62. Epub 2010 Sep 13
PubMed.
The studies on basic cerebral energy metabolism and its relationship to AD published in companion PNAS papers by Marc Raichle and colleagues at Washington University give us cause to stop and rethink—and dust off our copy of Lehninger. The details of the biochemistry are tedious and difficult to keep in working memory long enough to fully appreciate all of the relationships discussed in these papers. However, I think there are some manageable concepts here that could help move us forward in trying to understand AD and its treatment. First, the brain makes substantial use of aerobic glycolysis and does this in a regionally specific manner. Second, the metabolic fallout and vulnerabilities of cells—astrocytic or neuronal—that use aerobic glycolysis may be very different from those of cells that preferentially use oxidative phosphorylation. This fallout or vulnerability may be responsible for the regional overlap between high aerobic glycolysis and high amyloid-β deposition, not only in AD, but at the earliest stages of amyloid deposition in cognitively normal elderly controls. This has great importance. Perhaps these papers should be titled, “Amyloid Cascade Hypothesis—The Prequel.” That is, in our focus on the effects of amyloid-β (Aβ) accumulation, we seldom stop to discern why it is accumulating to begin with. The obvious exception to this is cases of autosomal dominant mutations in APP and presenilin. It is interesting that these forms of AD show a very different regional initiation of Aβ pathology in the striatum, another area of relatively high aerobic glycolysis.
As a field, we have been faced with serious challenges in translating the amyloid cascade hypothesis into effective therapies. By no means is this statement meant as evidence that that hypothesis is incorrect, just that the translation of that hypothesis into therapies may require some rethinking. Many have recently suggested that interventions in the amyloid cascade may need to occur early in the pathogenesis of AD, perhaps even at a presymptomatic stage. The ideas put forth by Raichle and colleagues push us even further, posing new challenges, but perhaps opening new possibilities as well. Perhaps relatively modest interventions that would regulate the rate of aerobic glycolysis throughout mid-life—even prior to the initiation of Aβ deposition—would have large payoffs in later life. These papers are one more reason to ask ourselves, “Are we not finding effective therapies for AD because we’re looking at the wrong therapies, or because we’re looking at too late a stage of the disease to expect to be successful?”
In these elegant and important studies, researchers from Washington University in St. Louis developed a novel strategy to characterize the resting pattern of “aerobic glycolysis” (reflecting the extent to which glucose metabolism exceeds that associated with oxygen metabolism) in the living human brain. To do so, they used PET measurements of cerebral blood flow, blood volume, oxygen metabolism and glucose metabolism and an innovative image-analysis strategy to compute a “glycolytic index” image in each person.
They have shown that a group of brain regions associated with elevated aerobic glycolysis in cognitively normal young adults corresponds remarkably well to both the default mode network. This is the group of brain regions that the same research group originally found to be more active when normal individuals are not engaged in attention-demanding, goal-directed task performance, and also the group of regions associated with the most fibrillar amyloid in symptomatic and asymptomatic older adults with PET evidence of amyloid pathology.
This study raises new questions about the different roles of glucose in neuronal synapses and peri-synaptic glial cells and the extent to which the cellular processes associated with aerobic glycolysis are related to the predisposition to amyloid pathology. Among other things, it will be interesting to characterize and compare the pattern of anaerobic metabolism in cognitively normal adults at differential risk for early- or late-onset AD to determine the extent to which alterations in these measures precede fibrillar amyloid deposition, and to identify molecular processes that could be targeted by novel treatments.
In my opinion, this study adds to the evidence that synaptic or peri-synaptic changes are involved in the earliest predisposition to AD, at least in those individuals with late-onset AD, even preceding the earliest measurable amyloid alterations that may be involved in the pathogenesis of AD.
I congratulate the researchers for their contributions. While I recognize the relative paucity of PET sites that are currently capable of conducting 150-based PET measurements of cerebral blood flow, blood volume and oxygen metabolism, I predict that the scientific importance of this work will continue to grow.
Drs. Raichle and Mintun have reported a very interesting phenomenon, that is, amyloid deposition is related to aerobic glycolysis. But they have not clarified the reason why amyloid preferably deposits in the glycolysis portions of brain.
I'd like to present some ideas about it. We have observed homocysteic acid as a pathogen for Alzheimer disease (1). HA induced Aβ42 (2). Also it is reported that HA induced strong glycolysis (3). Based on this evidence, we suggest that amyloid deposition in aerobic glycolysis is induced by HA.
This suggestion should be tested. The field should consider homocysteic acid toxicity in Alzheimer disease.
References:
Hasegawa T, Mikoda N, Kitazawa M, LaFerla FM.
Treatment of Alzheimer's disease with anti-homocysteic acid antibody in 3xTg-AD male mice.
PLoS One. 2010 Jan 20;5(1):e8593.
PubMed.
Hasegawa T, Ukai W, Jo DG, Xu X, Mattson MP, Nakagawa M, Araki W, Saito T, Yamada T.
Homocysteic acid induces intraneuronal accumulation of neurotoxic Abeta42: implications for the pathogenesis of Alzheimer's disease.
J Neurosci Res. 2005 Jun 15;80(6):869-76.
PubMed.
Folbergrová J, Haugvicová R, Mares P.
Attenuation of seizures induced by homocysteic acid in immature rats by metabotropic glutamate group II and group III receptor agonists.
Brain Res. 2001 Jul 27;908(2):120-9.
PubMed.
Comments
University of Pittsburgh
The studies on basic cerebral energy metabolism and its relationship to AD published in companion PNAS papers by Marc Raichle and colleagues at Washington University give us cause to stop and rethink—and dust off our copy of Lehninger. The details of the biochemistry are tedious and difficult to keep in working memory long enough to fully appreciate all of the relationships discussed in these papers. However, I think there are some manageable concepts here that could help move us forward in trying to understand AD and its treatment. First, the brain makes substantial use of aerobic glycolysis and does this in a regionally specific manner. Second, the metabolic fallout and vulnerabilities of cells—astrocytic or neuronal—that use aerobic glycolysis may be very different from those of cells that preferentially use oxidative phosphorylation. This fallout or vulnerability may be responsible for the regional overlap between high aerobic glycolysis and high amyloid-β deposition, not only in AD, but at the earliest stages of amyloid deposition in cognitively normal elderly controls. This has great importance. Perhaps these papers should be titled, “Amyloid Cascade Hypothesis—The Prequel.” That is, in our focus on the effects of amyloid-β (Aβ) accumulation, we seldom stop to discern why it is accumulating to begin with. The obvious exception to this is cases of autosomal dominant mutations in APP and presenilin. It is interesting that these forms of AD show a very different regional initiation of Aβ pathology in the striatum, another area of relatively high aerobic glycolysis.
As a field, we have been faced with serious challenges in translating the amyloid cascade hypothesis into effective therapies. By no means is this statement meant as evidence that that hypothesis is incorrect, just that the translation of that hypothesis into therapies may require some rethinking. Many have recently suggested that interventions in the amyloid cascade may need to occur early in the pathogenesis of AD, perhaps even at a presymptomatic stage. The ideas put forth by Raichle and colleagues push us even further, posing new challenges, but perhaps opening new possibilities as well. Perhaps relatively modest interventions that would regulate the rate of aerobic glycolysis throughout mid-life—even prior to the initiation of Aβ deposition—would have large payoffs in later life. These papers are one more reason to ask ourselves, “Are we not finding effective therapies for AD because we’re looking at the wrong therapies, or because we’re looking at too late a stage of the disease to expect to be successful?”
View all comments by William KlunkArizona Alzheimer's Consortium
In these elegant and important studies, researchers from Washington University in St. Louis developed a novel strategy to characterize the resting pattern of “aerobic glycolysis” (reflecting the extent to which glucose metabolism exceeds that associated with oxygen metabolism) in the living human brain. To do so, they used PET measurements of cerebral blood flow, blood volume, oxygen metabolism and glucose metabolism and an innovative image-analysis strategy to compute a “glycolytic index” image in each person.
They have shown that a group of brain regions associated with elevated aerobic glycolysis in cognitively normal young adults corresponds remarkably well to both the default mode network. This is the group of brain regions that the same research group originally found to be more active when normal individuals are not engaged in attention-demanding, goal-directed task performance, and also the group of regions associated with the most fibrillar amyloid in symptomatic and asymptomatic older adults with PET evidence of amyloid pathology.
This study raises new questions about the different roles of glucose in neuronal synapses and peri-synaptic glial cells and the extent to which the cellular processes associated with aerobic glycolysis are related to the predisposition to amyloid pathology. Among other things, it will be interesting to characterize and compare the pattern of anaerobic metabolism in cognitively normal adults at differential risk for early- or late-onset AD to determine the extent to which alterations in these measures precede fibrillar amyloid deposition, and to identify molecular processes that could be targeted by novel treatments.
In my opinion, this study adds to the evidence that synaptic or peri-synaptic changes are involved in the earliest predisposition to AD, at least in those individuals with late-onset AD, even preceding the earliest measurable amyloid alterations that may be involved in the pathogenesis of AD.
I congratulate the researchers for their contributions. While I recognize the relative paucity of PET sites that are currently capable of conducting 150-based PET measurements of cerebral blood flow, blood volume and oxygen metabolism, I predict that the scientific importance of this work will continue to grow.
View all comments by Eric M. ReimanSaga Woman Junior College
Drs. Raichle and Mintun have reported a very interesting phenomenon, that is, amyloid deposition is related to aerobic glycolysis. But they have not clarified the reason why amyloid preferably deposits in the glycolysis portions of brain.
I'd like to present some ideas about it. We have observed homocysteic acid as a pathogen for Alzheimer disease (1). HA induced Aβ42 (2). Also it is reported that HA induced strong glycolysis (3). Based on this evidence, we suggest that amyloid deposition in aerobic glycolysis is induced by HA.
This suggestion should be tested. The field should consider homocysteic acid toxicity in Alzheimer disease.
References:
Hasegawa T, Mikoda N, Kitazawa M, LaFerla FM. Treatment of Alzheimer's disease with anti-homocysteic acid antibody in 3xTg-AD male mice. PLoS One. 2010 Jan 20;5(1):e8593. PubMed.
Hasegawa T, Ukai W, Jo DG, Xu X, Mattson MP, Nakagawa M, Araki W, Saito T, Yamada T. Homocysteic acid induces intraneuronal accumulation of neurotoxic Abeta42: implications for the pathogenesis of Alzheimer's disease. J Neurosci Res. 2005 Jun 15;80(6):869-76. PubMed.
Folbergrová J, Haugvicová R, Mares P. Attenuation of seizures induced by homocysteic acid in immature rats by metabotropic glutamate group II and group III receptor agonists. Brain Res. 2001 Jul 27;908(2):120-9. PubMed.
View all comments by Tohru HasegawaMake a Comment
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