Sporadic Alzheimer's Disease: The Starving Brain

Mamelak, Mortimer

doi:10.3233/jad-2012-120370

Cited by 49 publications

(39 citation statements)

References 155 publications

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“…We hypothesized that areas that show lower levels of GLUT and insulin signaling genes are less able to adapt to energetic challenges and are more vulnerable to AD pathology (Mamelak, 2012). We derived values of double-blinded rater assessments of the density of plaques and tangles from a seminal histological study on their topography in AD (Arnold et al, 1991) and converted them into 3D spatial map in Montreal Neuroimaging Institute (MNI) space (Figure 1).…”

Section: Spatial Correlation Of Ir-related Genes and Ad Pathologymentioning

confidence: 99%

Insulin Resistance as a Link between Amyloid-Beta and Tau Pathologies in Alzheimer’s Disease

Mullins

Diehl

Chia

et al. 2017

Front. Aging Neurosci.

134

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Current hypotheses and theories regarding the pathogenesis of Alzheimer’s disease (AD) heavily implicate brain insulin resistance (IR) as a key factor. Despite the many well-validated metrics for systemic IR, the absence of biomarkers for brain-specific IR represents a translational gap that has hindered its study in living humans. In our lab, we have been working to develop biomarkers that reflect the common mechanisms of brain IR and AD that may be used to follow their engagement by experimental treatments. We present two promising biomarkers for brain IR in AD: insulin cascade mediators probed in extracellular vesicles (EVs) enriched for neuronal origin, and two-dimensional magnetic resonance spectroscopy (MRS) measures of brain glucose. As further evidence for a fundamental link between brain IR and AD, we provide a novel analysis demonstrating the close spatial correlation between brain expression of genes implicated in IR (using Allen Human Brain Atlas data) and tau and beta-amyloid pathologies. We proceed to propose the bold hypotheses that baseline differences in the metabolic reliance on glycolysis, and the expression of glucose transporters (GLUT) and insulin signaling genes determine the vulnerability of different brain regions to Tau and/or Amyloid beta (Aβ) pathology, and that IR is a critical link between these two pathologies that define AD. Lastly, we provide an overview of ongoing clinical trials that target IR as an angle to treat AD, and suggest how biomarkers may be used to evaluate treatment efficacy and target engagement.

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Section: Spatial Correlation Of Ir-related Genes and Ad Pathologymentioning

confidence: 99%

Insulin Resistance as a Link between Amyloid-Beta and Tau Pathologies in Alzheimer’s Disease

Mullins

Diehl

Chia

et al. 2017

Front. Aging Neurosci.

134

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“…The multiple reasons for cerebral glucose hypometabolism in AD, its relationship with oxidative stress and the use of alternative substrates under such condition have been well reviewed [43,44]. The metabolic implications of AD pathogenesis in the context of brain insulin deficiency and insulin resistance have been extensively discussed in several recent publications [45,46].…”

Section: Metabolic and Endocrine Components In Ad Pathogenesismentioning

confidence: 99%

“…One of the earliest manifestations of AD is the decreased cerebral utilization of glucose as evidenced by PET imaging of 18 F -2 deoxyglucose uptake in the AD brain, and the phenomenon is progressive with the disease and well correlated with the degree of cognitive decline in AD brain [43,44]. The multiple reasons for cerebral glucose hypometabolism in AD, its relationship with oxidative stress and the use of alternative substrates under such condition have been well reviewed [43,44].…”

Section: Metabolic and Endocrine Components In Ad Pathogenesismentioning

confidence: 99%

Metabolic Risk Factors of Sporadic Alzheimer's Disease: Implications in the Pathology, Pathogenesis and Treatment

Chakrabarti¹,

Khemka²,

Banerjee³

et al. 2015

Aging and disease

111

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Alzheimer's disease (AD), the major cause of dementia among the elderly world-wide, manifests in familial and sporadic forms, and the latter variety accounts for the majority of the patients affected by this disease. The etiopathogenesis of sporadic AD is complex and uncertain. The autopsy studies of AD brain have provided limited understanding of the antemortem pathogenesis of the disease. Experimental AD research with transgenic animal or various cell based models has so far failed to explain the complex and varied spectrum of AD dementia. The review, therefore, emphasizes the importance of AD related risk factors, especially those with metabolic implications, identified from various epidemiological studies, in providing clues to the pathogenesis of this complex disorder. Several metabolic risk factors of AD like hypercholesterolemia, hyperhomocysteinemia and type 2 diabetes have been studied extensively both in epidemiology and experimental research, while much less is known about the role of adipokines, proinflammatory cytokines and vitamin D in this context. Moreover, the results from many of these studies have shown a degree of variability which has hindered our understanding of the role of AD related risk factors in the disease progression. The review also encompasses the recent recommendations regarding clinical and neuropathological diagnosis of AD and brings out the inherent uncertainty and ambiguity in this area which may have a distinct impact on the outcome of various population-based studies on AD-related risk factors.

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“…Reciprocally, restoration of GLUT1 reduced Aβ levels in AD mice brains (Winkler et al , 2015). In addition, alternative energy substrates such as ketogenetic diet and enhancement glucose uptake by intranasal insulin have demonstrated beneficial effects (Mamelak, 2012; Stafstrom and Rho, 2012; Yarchoan and Arnold, 2014). …”

Section: Brain Energy Metabolismmentioning

confidence: 99%

Alternative mitochondrial electron transfer for the treatment of neurodegenerative diseases and cancers: Methylene blue connects the dots

Yang

Sumien

et al. 2017

Progress in Neurobiology

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Brain has exceptional high requirement for energy metabolism with glucose as the exclusive energy source. Decrease of brain energy metabolism and glucose uptake has been found in patients of Alzheimer’s, Parkinson’s and other neurodegenerative diseases, providing a clear link between neurodegenerative disorders and energy metabolism. On the other hand, cancers, including glioblastoma, have increased glucose uptake and rely on aerobic glycolysis for energy metabolism. The switch of high efficient oxidative phosphorylation to low efficient aerobic glycolysis pathway (Warburg effect) provides macromolecule for biosynthesis and proliferation. Current research indicate that methylene blue, a century old drug, can receive electron from NADH in the presence of complex I and donates it to cytochrome C, providing an alternative electron transfer pathway. Methylene blue increases oxygen consumption, decrease glycolysis, and increases glucose uptake in vitro. Methylene blue enhances glucose uptake and regional cerebral blood flow in rats upon acute treatment. In addition, methylene blue provides protective effect in neuron and astrocyte against various insults in vitro and in rodent models of Alzheimer’s, Parkinson’s, and Huntington’s disease. In glioblastoma cells, methylene blue reverses Warburg effect by enhancing mitochondrial oxidative phosphorylation, arrests glioma cell cycle at s-phase, and inhibits glioma cell proliferation. Accordingly, methylene blue activates AMP-activated protein kinase, inhibits downstream acetyl-coA carboxylase and cyclin-dependent kinases. In summary, there is accumulating evidence providing a proof of concept that enhancement of mitochondrial oxidative phosphorylation via alternative mitochondrial electron transfer may offer protective action against neurodegenerative diseases and inhibit cancers proliferation.

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Sporadic Alzheimer's Disease: The Starving Brain

Cited by 49 publications

References 155 publications

Insulin Resistance as a Link between Amyloid-Beta and Tau Pathologies in Alzheimer’s Disease

Insulin Resistance as a Link between Amyloid-Beta and Tau Pathologies in Alzheimer’s Disease

Metabolic Risk Factors of Sporadic Alzheimer's Disease: Implications in the Pathology, Pathogenesis and Treatment

Alternative mitochondrial electron transfer for the treatment of neurodegenerative diseases and cancers: Methylene blue connects the dots

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