Neuronal activity regulates the regional vulnerability to amyloid-β deposition

Bero, Adam W.; Yan, Ping; Roh, Jee Hoon; Cirrito, John R.; Stewart, Floy R.; Raichle, Marcus E.; J, Lee; Holtzman, David M.

doi:10.1038/nn.2801

Cited by 796 publications

(739 citation statements)

References 48 publications

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“…2 A). This is similar to what we have observed previously (Cirrito et al, 2008;Bero et al, 2011). PTX decreased glucose by 33% and increased lactate by 342% (Fig.…”

Section: Results and Discussion Increasing Neuronal Activity Increasesupporting

confidence: 92%

Neuronal activity regulates extracellular tau in vivo

Yamada¹,

Holth²,

Liao³

et al. 2014

J Gen Physiol

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Tau is primarily a cytoplasmic protein that stabilizes microtubules. However, it is also found in the extracellular space of the brain at appreciable concentrations. Although its presence there may be relevant to the intercellular spread of tau pathology, the cellular mechanisms regulating tau release into the extracellular space are not well understood. To test this in the context of neuronal networks in vivo, we used in vivo microdialysis. Increasing neuronal activity rapidly increased the steady-state levels of extracellular tau in vivo. Importantly, presynaptic glutamate release is sufficient to drive tau release. Although tau release occurred within hours in response to neuronal activity, the elimination rate of tau from the extracellular compartment and the brain is slow (half-life of 11 d). The in vivo results provide one mechanism underlying neuronal tau release and may link trans-synaptic spread of tau pathology with synaptic activity itself.

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“…2 A). This is similar to what we have observed previously (Cirrito et al, 2008;Bero et al, 2011). PTX decreased glucose by 33% and increased lactate by 342% (Fig.…”

Section: Results and Discussion Increasing Neuronal Activity Increasesupporting

confidence: 92%

Neuronal activity regulates extracellular tau in vivo

Yamada¹,

Holth²,

Liao³

et al. 2014

J Gen Physiol

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“…This corroborates the recent finding of elevated MRS‐measured lactate in transgenic AD mice compared to wild‐type mice, in which it is associated with memory deficits 56. Whereas older MRS studies failed to show any discernable lactate differences in AD,57, 58 our finding and that of a recent study54 align with this very strong mechanistic data 55, 56. Despite the biological plausibility of the finding, we interpret our results on Lac with caution as quantitation of Lac can be affected by signals from macromolecules which partially overlap with the Lac signal in the J‐PRESS spectrum 24…”

Section: Discussionsupporting

confidence: 90%

Magnetic resonance spectroscopy reveals abnormalities of glucose metabolism in the Alzheimer's brain

Mullins

Reiter

Kapogiannis

2018

Ann Clin Transl Neurol

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ObjectiveBrain glucose hypometabolism is a prominent feature of Alzheimer's disease (AD), and in this case–control study we used Magnetic Resonance Spectroscopy (MRS) to assess AD‐related differences in the posterior cingulate/precuneal ratio of glucose, lactate, and other metabolites.MethodsJ‐modulated Point‐Resolved Spectroscopy (J‐PRESS) and Prior‐Knowledge Fitting (ProFit) software was used to measure glucose and other metabolites in the posterior cingulate/precuneus of 25 AD, 27 older controls, and 27 younger control participants. Clinical assessments for AD participants included cognitive performance measures, insulin resistance metrics and CSF biomarkers.Results AD participants showed substantially elevated glucose, lactate, and ascorbate levels compared to older (and younger) controls. In addition, the precuneal glucose elevation discriminated well between AD participants and older controls. Myo‐inositol correlated with CSF p‐Tau181P, total Tau, and the Clinical Dementia Rating (CDR) sum‐of‐boxes score within the AD group.InterpretationHigher glucose to creatine ratios in the AD brain likely reflect lower glucose utilization. Our findings reveal pronounced metabolic abnormalities in the AD brain and strongly suggest that brain glucose merits further investigation as a candidate AD biomarker.

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“…Confirmation of presynaptic localization of oligomers by electron microscope would be optimal; however, detection of intraneuronal, particularly oligomeric, Ab is limited by the technical difficulty of detecting Ab antigens, which are hydrophobic and difficult to detect by conventional immunocytochemical methods, especially in postmortem tissue. 67 On the basis of previous and current results, we posit that most synaptosomal Ab represents an intraterminal pool largely localized within endosomal and autophagic vesicles, consistent with a strong literature showing synaptic release of Ab 25,68,69 and disruption of autophagy in AD. 69e72 Relatively few examples in the literature have found cellular or pathologic factors associated with cognitive protection in subjects with AD pathology.…”

Section: Discussionsupporting

confidence: 88%

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

Bilousova

Miller

Poon

et al. 2016

The American Journal of Pathology

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Amyloid-b (Ab) and hyperphosphorylated tau (p-tau) aggregates form the two discrete pathologies of Alzheimer disease (AD), and oligomeric assemblies of each protein are localized to synapses. To determine the sequence by which pathology appears in synapses, Ab and p-tau were quantified across AD disease stages in parietal cortex. Nondemented cases with high levels of AD-related pathology were included to determine factors that confer protection from clinical symptoms. Flow cytometric analysis of synaptosome preparations was used to quantify Ab and p-tau in large populations of individual synaptic terminals. Soluble Ab oligomers were assayed by a single antibody sandwich enzyme-linked immunosorbent assay. Total in situ Ab was elevated in patients with early-and late-stage AD dementia, but not in high pathology nondemented controls compared with age-matched normal controls. However, soluble Ab oligomers were highest in early AD synapses, and this assay distinguished early AD cases from high pathology controls. Overall, synapse-associated p-tau did not increase until late-stage disease in human and transgenic rat cortex, and p-tau was elevated in individual Ab-positive synaptosomes in early AD. These results suggest that soluble oligomers in surviving neocortical synaptic terminals are associated with dementia onset and suggest an amyloid cascade hypothesis in which oligomeric Ab drives phosphorylated tau accumulation and synaptic spread. These results indicate that antiamyloid therapies will be less effective once p-tau pathology is developed. (Am J Pathol 2016, 186: 185e198; http://dx.doi.org/10.1016/j.ajpath.2015 A large body of evidence indicates that soluble oligomers of amyloid-b (Ab) are the primary toxic peptides that initiate downstream tau pathology in the amyloid cascade hypothesis of Alzheimer disease (AD). 1,2 However, the time course and severity of AD dementia have been generally found to correlate with neurofibrillary tangle development rather than plaque appearance, 3e8 although a few studies have linked plaques with early cognitive decline. 9e12 Soluble oligomeric

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Neuronal activity regulates the regional vulnerability to amyloid-β deposition

Cited by 796 publications

References 48 publications

Neuronal activity regulates extracellular tau in vivo

Neuronal activity regulates extracellular tau in vivo

Magnetic resonance spectroscopy reveals abnormalities of glucose metabolism in the Alzheimer's brain

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

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