Alzheimer’s Disease as the Product of a Progressive Energy Deficiency Syndrome in the Central Nervous System: The Neuroenergetic Hypothesis

Blonz, Edward R.

doi:10.3233/jad-170549

Cited by 33 publications

(27 citation statements)

References 72 publications

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“…Under euglycemic conditions, lactate increases brain energy content and therefore is a potential therapeutic approach for diseases beyond hypoglycemic periods in diabetes. These include diseases associated with reduced cerebral energy levels, such as obesity or Alzheimer's disease …”

Section: Discussionmentioning

confidence: 99%

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Lactate infusion increases brain energy content during euglycemia but not hypoglycemia in healthy men

Richter¹,

Rabe²,

Duysen³

et al. 2019

NMR in Biomedicine

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A special characteristic of the brain is the usage of lactate as alternative fuel instead of glucose to preserve its energy homeostasis. This physiological function is valid for sufficient cerebral glucose supply, as well as presumably during hypoglycemia, given that exogenous lactate infusion suppresses hormonal counterregulation. However, it is not yet clarified whether this effect is mediated by the use of lactate as an alternative cerebral energy substrate or any other mechanism. We hypothesized that under conditions of limited access to glucose (ie, during experimental hypoglycemia) lactate infusion would prevent hypoglycemia‐induced neuroenergetic deficits in a neuroprotective way. In a randomized, double‐blind, crossover study, lactate vs placebo infusion was compared during hyperinsulinemic‐hypoglycemic clamps in 16 healthy young men. We measured the cerebral high‐energy phosphate content — ie, adenosine triphosphate (ATP), phosphocreatine (PCr) and inorganic phosphate (Pi) levels — by 31P‐magnetic resonance spectroscopy as well as the neuroendocrine stress response. During euglycemia, lactate infusion increased ATP/Pi as well as PCr/Pi ratios compared with baseline values and placebo infusion. During hypoglycemia, there were no differences between the lactate and the placebo condition in both ratios. Hormonal counterregulation was significantly diminished upon lactate infusion. Our data demonstrate an elevated cerebral high‐energy phosphate content upon lactate infusion during euglycemia, whereas there was no such effect during experimental hypoglycemia. Nevertheless, lactate infusion suppressed hypoglycemic hormonal counterregulation. Lactate thus adds to cerebral energy provision during euglycemia and may contribute to an increase in ATP reserves, which in turn protects the brain against neuroglucopenia under recurrent hypopglycemic conditions, eg, in diabetic patients.

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Section: Discussionmentioning

confidence: 99%

“…These include diseases associated with reduced cerebral energy levels, such as obesity 29,52 or Alzheimer's disease. 53…”

Section: Figurementioning

confidence: 99%

Lactate infusion increases brain energy content during euglycemia but not hypoglycemia in healthy men

Richter¹,

Rabe²,

Duysen³

et al. 2019

NMR in Biomedicine

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“…These findings shed doubt on the assumption that the amyloid plaques are the primary mandatory cause of dementia. Probably these results were relevant for upcoming concepts, which relate AD to inflammatory processes of the brain (Neuhaus et al, 2011;Hommet et al, 2014;Blonz, 2017). Although treatment of inflammation seems to be a manageable task, the situation is different and by far more complex with chronic inflammation of unproven origin (Dominy et al, 2019).…”

Section: Inflammation Of Bbb Cellsmentioning

confidence: 90%

Dysfunction of the Blood-Brain Barrier—A Key Step in Neurodegeneration and Dementia

Noe

Noe-Letschnig²,

Handschuh

et al. 2020

Front. Aging Neurosci.

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The vascular endothelium in the brain is an essential part of the blood-brain-barrier (BBB) because of its very tight structure to secure a functional and molecular separation of the brain from the rest of the body and to protect neurons from pathogens and toxins. Impaired transport of metabolites across the BBB due to its increasing dysfunction affects brain health and cognitive functioning, thus providing a starting point of neurodegenerative diseases. The term "cerebral metabolic syndrome" is proposed to highlight the importance of lifestyle factors in neurodegeneration and to describe the impact of increasing BBB dysfunction on neurodegeneration and dementia, especially in elderly patients. If untreated, the cerebral metabolic syndrome may evolve into dementia. Due to the high energy demand of the brain, impaired glucose transport across the BBB via glucose transporters as GLUT1 renders the brain increasingly susceptible to neurodegeneration. Apoptotic processes are further supported by the lack of essential metabolites of the phosphocholine synthesis. In Alzheimer's disease (AD), inflammatory and infectious processes at the BBB increase the dysfunction and might be pace-making events. At this point, the potentially highly relevant role of the thrombocytic amyloid precursor protein (APP) in endothelial inflammation of the BBB is discussed. Chronic inflammatory processes of the BBB transmitted to an increasing number of brain areas might cause a lasting build-up of spreading, pore-forming β-amyloid fragments explaining the dramatic progression of the disease. In the view of the essential requirement of an early diagnosis to investigate and implement causal therapeutic strategies against dementia, brain imaging methods are of great importance. Therefore, status and opportunities in the field of diagnostic imaging of the living human brain will be portrayed, comprising diverse techniques such as positron emissions tomography (PET) and functional magnetic resonance imaging (fMRI) to uncover the patterns of atrophy, protein deposits, hypometabolism, and molecular as well as functional alterations in AD.

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“…It is also the link between sporadic AD and its risk factor of diabetes [42]. Furthermore, age-related decline in the ability of glucose to cross the BBB might lead to the production of Aβ plaques and tau-containing neurofibrillary tangles (neuro-energetic hypothesis) [43]. Moreover, insulin resistance in type 2 diabetes mellitus and obesity is a risk factor for AD, as insulin resistance might contribute to neurodegeneration [44].…”

Section: Pathophysiological Hypotheses and Associated Biomarkersmentioning

confidence: 99%

Utility of Animal Models to Understand Human Alzheimer’s Disease, Using the Mastermind Research Approach to Avoid Unnecessary Further Sacrifices of Animals

Qin

Prins

Groeneveld

et al. 2020

IJMS

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To diagnose and treat early-stage (preclinical) Alzheimer’s disease (AD) patients, we need body-fluid-based biomarkers that reflect the processes that occur in this stage, but current knowledge on associated processes is lacking. As human studies on (possible) onset and early-stage AD would be extremely expensive and time-consuming, we investigate the potential value of animal AD models to help to fill this knowledge gap. We provide a comprehensive overview of processes associated with AD pathogenesis and biomarkers, current knowledge on AD-related biomarkers derived from on human and animal brains and body fluids, comparisons of biomarkers obtained in human AD and frequently used animal AD models, and emerging body-fluid-based biomarkers. In human studies, amyloid beta (Aβ), hyperphosphorylated tau (P-tau), total tau (T-tau), neurogranin, SNAP-25, glial fibrillary acidic protein (GFAP), YKL-40, and especially neurofilament light (NfL) are frequently measured. In animal studies, the emphasis has been mostly on Aβ. Although a direct comparison between human (familial and sporadic) AD and (mostly genetic) animal AD models cannot be made, still, in brain, cerebrospinal fluid (CSF), and blood, a majority of similar trends are observed for human AD stage and animal AD model life stage. This indicates the potential value of animal AD models in understanding of the onset and early stage of AD. Moreover, animal studies can be smartly designed to provide mechanistic information on the interrelationships between the different AD processes in a longitudinal fashion and may also include the combinations of different conditions that may reflect comorbidities in human AD, according to the Mastermind Research approach.

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Alzheimer’s Disease as the Product of a Progressive Energy Deficiency Syndrome in the Central Nervous System: The Neuroenergetic Hypothesis

Cited by 33 publications

References 72 publications

Lactate infusion increases brain energy content during euglycemia but not hypoglycemia in healthy men

Lactate infusion increases brain energy content during euglycemia but not hypoglycemia in healthy men

Dysfunction of the Blood-Brain Barrier—A Key Step in Neurodegeneration and Dementia

Utility of Animal Models to Understand Human Alzheimer’s Disease, Using the Mastermind Research Approach to Avoid Unnecessary Further Sacrifices of Animals

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