This paper describes impressive experimentation with convincing results, though I would be interested in seeing more discussion of chronic glutamate toxicity in AD. Before investing further in therapeutic strategies targeting reduction of Aβ-oligomers, there must be evaluation of compensatory processes for gradual increases in hyperexcitability in aging. This is beyond the scope of this work, but relevant to the overall translatability of the research. Neurotoxicity of glutamargeric hyperexcitation is typically an acute event, though there is an existing body of research for chronic cases (reviewed by Lewerenz & Maher, 2015).
This new story is noteworthy not only for the findings but also for the lack of adequate exposition [or the significance] of the downstream sequels to a neuron ‘driven’ into an “…hyperactive frenzy…”. One of the longstanding challenges for all the major theories on putative mechanisms of neurodegeneration or dementia or Alzheimer’s disease [AD], including the ‘amyloid’ hypothesis, has been the lack of compelling explanation on how the particular hypothesis influences the functioning/performance of a neuron; as a constituent of a network or a system. The significance of this question stems from the premise that progressive decline in the performance/functioning of various neural networks is the most proximal and crucial event that accounts for the clinical features of chronic brain disorders associated with neurodegeneration; including dementia and AD. Although various theories on the origins of these conditions usually start with differing assumptions, virtually all models of pathogenesis invoke some form of deficit in the functional connectivity of neural networks. However, the precise molecular mechanism for linking the putative biological mechanism of the ‘disease’ with its ‘clinical’ expression or special features of the condition has remained an ill-defined ‘black box’. Recent studies from groups such as those headed by Cindy Lemere and Dennis Selkoe groups’ [see- Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q, Rosenthal A, Barres BA, Lemere CA, Selkoe DJ, Stevens B. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016 Mar 31] have begun to shed light on this ‘black box’ by providing explanations for plausible mechanistic links between upstream events and neuronal function by proposing the possibility of a compliment/microglia mediated neuronal dysfunction. In this context, the finding by Zott et al that soluble Aβ dimers induce hyperexcitability in neurons, similar to those caused by blocking glutamate reuptake, is very significant. This study provides yet another important insight about the workings of the ‘Black Box.’ In light of the sequential failure of therapy development paradigms [e.g., clinical trials] or, based on the ‘amyloid hypothesis,’ the urgency of uncovering and considering alternative plausible mechanisms that mediate neuronal function-dysfunction has become more vital than ever. Until recently, alternative ideas on the origins of dementia-AD and/or potential targets for therapy development were largely overshadowed by the amyloid hypothesis. But, now with the changing climate for drug discovery-development, along with the search for better or more precise explanations of molecular mechanism that mediate neuronal functioning, hitherto overlooked ideas or theories may get more attention and flourish. The Calcium Hypothesis [1, 2] is a good case-study to illustrate this point. The relationship between ‘amyloid’ and calcium dyshomeostasis has been known for some time [see Arispe N, Pollard HB, Rojas E. The ability of amyloid b-protein [AbP (1-40)] to form Ca2+ channels provides a mechanism for neuronal death in Alzheimer’s disease. Ann N Y Acad Sci 1994; 747:256–66]. Now, Zott et al provide further evidence that the so called ‘amyloid toxicity’ is actually mediated by calcium dysregulation. Perhaps, this will generate greater interest in the ‘Calcium Hypothesis and the proposition that cytosol calcium dyshomeostasis is represents the final common path for neuronal dysfunction [i.e., continued pruning of dendritic arbors, loss of synapses, and decrements in repair and restoration]. Thus, provides the most proximal mechanism [and most plausible explanation] for the expression of clinical features of l neurodegenerative disorders such as dementia and AD [3]. References: 1. Khachaturian ZS. Calcium hypothesis of Alzheimer’s disease and brain aging. In: Calcium hypothesis of aging and dementia. Disterhoft JF, Willem HG, Treber J, Khachaturian ZS. Eds. Ann N Y Acad Sci 1994;747:1–11. 2. Alzheimer’s Association Calcium Hypothesis Workgroup. Calcium Hypothesis of Alzheimer’s disease and brain aging: A framework for integrating new evidence into a comprehensive theory of pathogenesis’. Alzheimers Dement 2017;13:178–82. 3. Khachaturian ZS, Kuller LH, Khachaturian AK. Editorial: Strategic goals and roadmap for dementia prevention by stroke Prevention. Alzheimers Dementia 2019;15: 865-869.
This paper suggests that defects in GLT-1 (also known as EAAT2) in astrocytes lead to accumulation of synaptic glutamate, which causes hyperactivity, leading to excitotoxicity of and Ca2+ entry to neurons. Nearly two decades ago, our laboratory demonstrated that, in AD brain, GLT-1 was oxidatively modified by the lipid peroxidation product, 4-hydroxynonenal (HNE) to more than 70% more than that in control brain (Lauderback et al., 2001). Moreover, this paper showed that addition of Abeta1-42 to synaptic preparations containing pre- and post-synaptic membranes reproduced the same finding as in AD brain. Our prior studies had shown that HNE covalent modification of Cys, His, or Lys residues of synaptic proteins following Michael addition reactions alters their conformation (Subramaniam et al.,1997). This, essentially, always led to decreased function (Butterfield and Halliwell, 2019). Masliah and colleagues showed that GLT-1 activity was decreased in AD brain (Masliah et al., 1996). Therefore, we hypothesize that the elegant studies led by Prof. Konnerth have a basis derived from HNE-oxidative modification of GLT-1 structure and function.
References:
Lauderback CM, Hackett JM, Huang FF, Keller JN, Szweda LI, Markesbery WR, Butterfield DA.
The glial glutamate transporter, GLT-1, is oxidatively modified by 4-hydroxy-2-nonenal in the Alzheimer's disease brain: the role of Abeta1-42.
J Neurochem. 2001 Jul;78(2):413-6.
PubMed.
Subramaniam R, Roediger F, Jordan B, Mattson MP, Keller JN, Waeg G, Butterfield DA.
The lipid peroxidation product, 4-hydroxy-2-trans-nonenal, alters the conformation of cortical synaptosomal membrane proteins.
J Neurochem. 1997 Sep;69(3):1161-9.
PubMed.
Butterfield DA, Halliwell B.
Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease.
Nat Rev Neurosci. 2019 Mar;20(3):148-160.
PubMed.
Masliah E, Alford M, DeTeresa R, Mallory M, Hansen L.
Deficient glutamate transport is associated with neurodegeneration in Alzheimer's disease.
Ann Neurol. 1996 Nov;40(5):759-66.
PubMed.
Comments
BrightFocus Foundation
This paper describes impressive experimentation with convincing results, though I would be interested in seeing more discussion of chronic glutamate toxicity in AD. Before investing further in therapeutic strategies targeting reduction of Aβ-oligomers, there must be evaluation of compensatory processes for gradual increases in hyperexcitability in aging. This is beyond the scope of this work, but relevant to the overall translatability of the research. Neurotoxicity of glutamargeric hyperexcitation is typically an acute event, though there is an existing body of research for chronic cases (reviewed by Lewerenz & Maher, 2015).
View all comments by Keith WhitakerAlzheimer's & Dementia
This new story is noteworthy not only for the findings but also for the lack of adequate exposition [or the significance] of the downstream sequels to a neuron ‘driven’ into an “…hyperactive frenzy…”. One of the longstanding challenges for all the major theories on putative mechanisms of neurodegeneration or dementia or Alzheimer’s disease [AD], including the ‘amyloid’ hypothesis, has been the lack of compelling explanation on how the particular hypothesis influences the functioning/performance of a neuron; as a constituent of a network or a system. The significance of this question stems from the premise that progressive decline in the performance/functioning of various neural networks is the most proximal and crucial event that accounts for the clinical features of chronic brain disorders associated with neurodegeneration; including dementia and AD. Although various theories on the origins of these conditions usually start with differing assumptions, virtually all models of pathogenesis invoke some form of deficit in the functional connectivity of neural networks. However, the precise molecular mechanism for linking the putative biological mechanism of the ‘disease’ with its ‘clinical’ expression or special features of the condition has remained an ill-defined ‘black box’. Recent studies from groups such as those headed by Cindy Lemere and Dennis Selkoe groups’ [see- Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q, Rosenthal A, Barres BA, Lemere CA, Selkoe DJ, Stevens B. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016 Mar 31] have begun to shed light on this ‘black box’ by providing explanations for plausible mechanistic links between upstream events and neuronal function by proposing the possibility of a compliment/microglia mediated neuronal dysfunction. In this context, the finding by Zott et al that soluble Aβ dimers induce hyperexcitability in neurons, similar to those caused by blocking glutamate reuptake, is very significant. This study provides yet another important insight about the workings of the ‘Black Box.’ In light of the sequential failure of therapy development paradigms [e.g., clinical trials] or, based on the ‘amyloid hypothesis,’ the urgency of uncovering and considering alternative plausible mechanisms that mediate neuronal function-dysfunction has become more vital than ever. Until recently, alternative ideas on the origins of dementia-AD and/or potential targets for therapy development were largely overshadowed by the amyloid hypothesis. But, now with the changing climate for drug discovery-development, along with the search for better or more precise explanations of molecular mechanism that mediate neuronal functioning, hitherto overlooked ideas or theories may get more attention and flourish. The Calcium Hypothesis [1, 2] is a good case-study to illustrate this point. The relationship between ‘amyloid’ and calcium dyshomeostasis has been known for some time [see Arispe N, Pollard HB, Rojas E. The ability of amyloid b-protein [AbP (1-40)] to form Ca2+ channels provides a mechanism for neuronal death in Alzheimer’s disease. Ann N Y Acad Sci 1994; 747:256–66]. Now, Zott et al provide further evidence that the so called ‘amyloid toxicity’ is actually mediated by calcium dysregulation. Perhaps, this will generate greater interest in the ‘Calcium Hypothesis and the proposition that cytosol calcium dyshomeostasis is represents the final common path for neuronal dysfunction [i.e., continued pruning of dendritic arbors, loss of synapses, and decrements in repair and restoration]. Thus, provides the most proximal mechanism [and most plausible explanation] for the expression of clinical features of l neurodegenerative disorders such as dementia and AD [3]. References: 1. Khachaturian ZS. Calcium hypothesis of Alzheimer’s disease and brain aging. In: Calcium hypothesis of aging and dementia. Disterhoft JF, Willem HG, Treber J, Khachaturian ZS. Eds. Ann N Y Acad Sci 1994;747:1–11. 2. Alzheimer’s Association Calcium Hypothesis Workgroup. Calcium Hypothesis of Alzheimer’s disease and brain aging: A framework for integrating new evidence into a comprehensive theory of pathogenesis’. Alzheimers Dement 2017;13:178–82. 3. Khachaturian ZS, Kuller LH, Khachaturian AK. Editorial: Strategic goals and roadmap for dementia prevention by stroke Prevention. Alzheimers Dementia 2019;15: 865-869.
View all comments by Zaven KhachaturianUniversity of Kentucky
This paper suggests that defects in GLT-1 (also known as EAAT2) in astrocytes lead to accumulation of synaptic glutamate, which causes hyperactivity, leading to excitotoxicity of and Ca2+ entry to neurons. Nearly two decades ago, our laboratory demonstrated that, in AD brain, GLT-1 was oxidatively modified by the lipid peroxidation product, 4-hydroxynonenal (HNE) to more than 70% more than that in control brain (Lauderback et al., 2001). Moreover, this paper showed that addition of Abeta1-42 to synaptic preparations containing pre- and post-synaptic membranes reproduced the same finding as in AD brain. Our prior studies had shown that HNE covalent modification of Cys, His, or Lys residues of synaptic proteins following Michael addition reactions alters their conformation (Subramaniam et al.,1997). This, essentially, always led to decreased function (Butterfield and Halliwell, 2019). Masliah and colleagues showed that GLT-1 activity was decreased in AD brain (Masliah et al., 1996). Therefore, we hypothesize that the elegant studies led by Prof. Konnerth have a basis derived from HNE-oxidative modification of GLT-1 structure and function.
References:
Lauderback CM, Hackett JM, Huang FF, Keller JN, Szweda LI, Markesbery WR, Butterfield DA. The glial glutamate transporter, GLT-1, is oxidatively modified by 4-hydroxy-2-nonenal in the Alzheimer's disease brain: the role of Abeta1-42. J Neurochem. 2001 Jul;78(2):413-6. PubMed.
Subramaniam R, Roediger F, Jordan B, Mattson MP, Keller JN, Waeg G, Butterfield DA. The lipid peroxidation product, 4-hydroxy-2-trans-nonenal, alters the conformation of cortical synaptosomal membrane proteins. J Neurochem. 1997 Sep;69(3):1161-9. PubMed.
Butterfield DA, Halliwell B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat Rev Neurosci. 2019 Mar;20(3):148-160. PubMed.
Masliah E, Alford M, DeTeresa R, Mallory M, Hansen L. Deficient glutamate transport is associated with neurodegeneration in Alzheimer's disease. Ann Neurol. 1996 Nov;40(5):759-66. PubMed.
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