Spatiotemporal relationship between subthreshold amyloid accumulation and aerobic glycolysis in the human brain

Goyal, Manu; Gordon, Brian A.; Couture, Lars E.; Flores, Shaney; Xiong, Chengjie; Morris, John C.; Raichle, Marcus E.; Benzinger, Tammie L.S.; Vlassenko, Andrei G.

doi:10.1016/j.neurobiolaging.2020.08.019

Cited by 13 publications

(20 citation statements)

References 58 publications

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“…In a PET study of 33 neurologically healthy participants, Vaishnavi et al (2010) discovered that AG was significantly elevated in the medial, lateral, and prefrontal cortices, whereas the cerebellum and medial temporal lobes exhibited lower glycolysis when compared to the mean value of the brain. Follow-up studies reported that the regions with increased glycolysis in the resting state of healthy young adults closely mirror the later regional pattern where Aβ accumulates in the brains of AD patients ( Vaishnavi et al, 2010 ; Vlassenko et al, 2010 ; Goyal et al, 2020 ). The correlation observed in these studies is considered a compensatory mechanism in response to Aβ toxicity and mitochondrial dysfunction at a very early stage of AD.…”

Section: Glycolysis In Admentioning

confidence: 85%

Glycolytic Metabolism, Brain Resilience, and Alzheimer’s Disease

2021

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Alzheimer’s disease (AD) is the most common form of age-related dementia. Despite decades of research, the etiology and pathogenesis of AD are not well understood. Brain glucose hypometabolism has long been recognized as a prominent anomaly that occurs in the preclinical stage of AD. Recent studies suggest that glycolytic metabolism, the cytoplasmic pathway of the breakdown of glucose, may play a critical role in the development of AD. Glycolysis is essential for a variety of neural activities in the brain, including energy production, synaptic transmission, and redox homeostasis. Decreased glycolytic flux has been shown to correlate with the severity of amyloid and tau pathology in both preclinical and clinical AD patients. Moreover, increased glucose accumulation found in the brains of AD patients supports the hypothesis that glycolytic deficit may be a contributor to the development of this phenotype. Brain hyperglycemia also provides a plausible explanation for the well-documented link between AD and diabetes. Humans possess three primary variants of the apolipoprotein E (ApoE) gene – ApoE∗ϵ2, ApoE∗ϵ3, and ApoE∗ϵ4 – that confer differential susceptibility to AD. Recent findings indicate that neuronal glycolysis is significantly affected by human ApoE isoforms and glycolytic robustness may serve as a major mechanism that renders an ApoE2-bearing brain more resistant against the neurodegenerative risks for AD. In addition to AD, glycolytic dysfunction has been observed in other neurodegenerative diseases, including Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, strengthening the concept of glycolytic dysfunction as a common pathway leading to neurodegeneration. Taken together, these advances highlight a promising translational opportunity that involves targeting glycolysis to bolster brain metabolic resilience and by such to alter the course of brain aging or disease development to prevent or reduce the risks for not only AD but also other neurodegenerative diseases.

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Section: Glycolysis In Admentioning

confidence: 85%

Glycolytic Metabolism, Brain Resilience, and Alzheimer’s Disease

2021

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“…On the one hand, functional integration of high-order regions (e.g., default-mode and frontoparietal systems) requires high AG to support the metabolic demands of a large number of axon projections. On the other hand, elevated levels of AG are closely associated with higher risk of amyloid-β deposition (13,14). Previous works suggest that AG is critical for task-induced activity (10) and synaptic plasticity (11).…”

Section: Chen Et Almentioning

confidence: 99%

“…Brain AG is particularly crucial for biosynthesis (7,8), rapid production of ATP (9), taskinduced activity (10), synaptic plasticity (e.g., synapse formation and growth) (11), and neuroprotection against oxidative stress (12). However, research suggests that higher levels of brain AG could be associated with higher risk of pathological hallmarks such as amyloid-β deposition (10,13). Specifically, high-AG regions in young adults correspond to those regions that are later most vulnerable to amyloid-β deposition (14) and even subthreshold amyloid-β deposition (13).…”

mentioning

confidence: 99%

“…However, research suggests that higher levels of brain AG could be associated with higher risk of pathological hallmarks such as amyloid-β deposition (10,13). Specifically, high-AG regions in young adults correspond to those regions that are later most vulnerable to amyloid-β deposition (14) and even subthreshold amyloid-β deposition (13). Thus, brain AG appears to have a dual role, playing both a positive role in maintaining the metabolic requirements of normal function, while also at the same time presenting a risk of vulnerability.…”

mentioning

confidence: 99%

“…Meanwhile, as misfolded proteins are toxic to neurons, this may lead to a further loss of AG. Increasing evidence suggests that high-AG regions in healthy brains correspond to those regions that are highly vulnerable to amyloid-β deposition (14) and that may even constitute the main sites for early on-target subthreshold amyloid deposition (13). Therefore, from a risk control perspective, AG levels in these high-AG regions should not be further increased.…”

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confidence: 99%

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Association of aerobic glycolysis with the structural connectome reveals a benefit–risk balancing mechanism in the human brain

Chen

Lin

Liao

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Aerobic glycolysis (AG), that is, the nonoxidative metabolism of glucose, contributes significantly to anabolic pathways, rapid energy generation, task-induced activity, and neuroprotection; yet high AG is also associated with pathological hallmarks such as amyloid-β deposition. An important yet unresolved question is whether and how the metabolic benefits and risks of brain AG is structurally shaped by connectome wiring. Using positron emission tomography and magnetic resonance imaging techniques as well as computational models, we investigate the relationship between brain AG and the macroscopic connectome. Specifically, we propose a weighted regional distance-dependent model to estimate the total axonal projection length of a brain node. This model has been validated in a macaque connectome derived from tract-tracing data and shows a high correspondence between experimental and estimated axonal lengths. When applying this model to the human connectome, we find significant associations between the estimated total axonal projection length and AG across brain nodes, with higher levels primarily located in the default-mode and prefrontal regions. Moreover, brain AG significantly mediates the relationship between the structural and functional connectomes. Using a wiring optimization model, we find that the estimated total axonal projection length in these high-AG regions exhibits a high extent of wiring optimization. If these high-AG regions are randomly rewired, their total axonal length and vulnerability risk would substantially increase. Together, our results suggest that high-AG regions have expensive but still optimized wiring cost to fulfill metabolic requirements and simultaneously reduce vulnerability risk, thus revealing a benefit–risk balancing mechanism in the human brain.

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Physiological Roles of β-amyloid in Regulating Synaptic Function: Implications for AD Pathophysiology

Cai

Sang

et al. 2022

Neurosci. Bull.

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The physiological functions of endogenous amyloid-β (Aβ), which plays important role in the pathology of Alzheimer's disease (AD), have not been paid enough attention. Here, we review the multiple physiological effects of Aβ, particularly in regulating synaptic transmission, and the possible mechanisms, in order to decipher the real characters of Aβ under both physiological and pathological conditions. Some worthy studies have shown that the deprivation of endogenous Aβ gives rise to synaptic dysfunction and cognitive deficiency, while the moderate elevation of this peptide enhances long term potentiation and leads to neuronal hyperexcitability. In this review, we provide a new view for understanding the role of Aβ in AD pathophysiology from the perspective of physiological meaning.

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Spatiotemporal relationship between subthreshold amyloid accumulation and aerobic glycolysis in the human brain

Cited by 13 publications

References 58 publications

Glycolytic Metabolism, Brain Resilience, and Alzheimer’s Disease

Glycolytic Metabolism, Brain Resilience, and Alzheimer’s Disease

Association of aerobic glycolysis with the structural connectome reveals a benefit–risk balancing mechanism in the human brain

Physiological Roles of β-amyloid in Regulating Synaptic Function: Implications for AD Pathophysiology

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