Blood—Brain Barrier Permeability Precedes Senile Plaque Formation in an Alzheimer Disease Model

Ujiie, Maki; Dickstein, Dara L.; Carlow, Douglas A.; Jefferies, Wilfred A.

doi:10.1038/sj.mn.7800212

Cited by 227 publications

(248 citation statements)

References 26 publications

(41 reference statements)

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“…However, a growing body of evidence addresses alterations in BBB permeability (typically to large molecules). For example, increases in BBB permeability have been reported to accompany aging (Shah and Mooradian, 1997), Alzheimers dementia (Skoog et al, 1998;Ujiie et al, 2003), type II diabetes (Starr et al, 2003), and hypertension (Mooradian, 1988;Mayhan, 1990;Ueno et al, 2004). BBB permeability also increases with increasing plasma osmolarity (Tamaki et al, 1984), and after the administration of certain drugs (Boertje et al, 1992).…”

Section: Central Nervous Systemmentioning

confidence: 99%

Consensus meeting: monosodium glutamate – an update

et al. 2006

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Objective: Update of the Hohenheim consensus on monosodium glutamate from 1997: Summary and evaluation of recent knowledge with respect to physiology and safety of monosodium glutamate. Design: Experts from a range of relevant disciplines received and considered a series of questions related to aspects of the topic. Setting: University of Hohenheim, Stuttgart, Germany. Method: The experts met and discussed the questions and arrived at a consensus. Conclusion: Total intake of glutamate from food in European countries is generally stable and ranged from 5 to 12 g/day (free: ca. 1 g, protein-bound: ca. 10 g, added as flavor: ca. 0.4 g). L-Glutamate (GLU) from all sources is mainly used as energy fuel in enterocytes. A maximum intake of 16.000 mg/kg body weight is regarded as safe. The general use of glutamate salts (monosodium-L-glutamate and others) as food additive can, thus, be regarded as harmless for the whole population. Even in unphysiologically high doses GLU will not trespass into fetal circulation. Further research work should, however, be done concerning the effects of high doses of a bolus supply at presence of an impaired blood brain barrier function. In situations with decreased appetite (e.g., elderly persons) palatability can be improved by low dose use of monosodium-L-glutamate.

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Section: Central Nervous Systemmentioning

confidence: 99%

Consensus meeting: monosodium glutamate – an update

et al. 2006

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“…In an Alzheimer's disease mouse model, anticipation of an increase in BBB permeability behind the pathogenesis was found. 3 A persistent disruption of the BBB is causally related to progression of neuronal dysfunction, as in temporal lobe epilepsy. 4 These findings indicate that an alteration in the BBB participates in the pathogenesis and progression of neurodegenerative disorders.…”

Section: Introductionmentioning

confidence: 99%

Microvascular Sprouting, Extension, and Creation of New Capillary Connections with Adaptation of the Neighboring Astrocytes in Adult Mouse Cortex under Chronic Hypoxia

Masamoto

Takuwa²,

Seki³

et al. 2013

J Cereb Blood Flow Metab

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The present study aimed to determine the spatiotemporal dynamics of microvascular and astrocytic adaptation during hypoxiainduced cerebral angiogenesis. Adult C57BL/6J and Tie2-green fluorescent protein (GFP) mice with vascular endothelial cells expressing GFP were exposed to normobaric hypoxia for 3 weeks, whereas the three-dimensional microvessels and astrocytes were imaged repeatedly using two-photon microscopy. After 7 to14 days of hypoxia, a vessel sprout appeared from the capillaries with a bump-like head shape (mean diameter 14 mm), and stagnant blood cells were seen inside the sprout. However, no detectable changes in the astrocyte morphology were observed for this early phase of the hypoxia adaptation. More than 50% of the sprouts emerged from capillaries 60 mm away from the center penetrating arteries, which indicates that the capillary distant from the penetrating arteries is a favored site for sprouting. After 14 to 21 days of hypoxia, the sprouting vessels created a new connection with an existing capillary. In this phase, the shape of the new vessel and its blood flow were normalized, and the outside of the vessels were wrapped with numerous processes from the neighboring astrocytes. The findings indicate that hypoxia-induced cerebral angiogenesis provokes the adaptation of neighboring astrocytes, which may stabilize the blood-brain barrier in immature vessels.

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“…Among those factors, elevated levels of circulating LDL cholesterol, independent of APOE genotypes, is strongly linked to the pathogenesis of sporadic AD [6][7][8][9][10]. Of mechanistic importance, we have shown that elevated levels of LDL cholesterol, the essential lipoprotein transporting circulating cholesterol in blood, (1) induces blood-brain barrier (BBB) leakage [7,16] -an early pathological feature of sporadic AD that precedes brain deposition of Aβ [17], (2) disturbs neuronal endolysosome structure and function -another early pathological features of sporadic AD [18], and (3) promotes the development of pathological hallmarks of AD including disrupted synaptic integrity, brain deposition of Aβ, and tau pathology [7]. Furthermore, we have demonstrated in cultured neurons that treatment with LDL cholesterol increased cholesterol accumulation in endolysosomes, disturbed the structure and function of endolysosomes, promoted amyloidogenic processing of AβPP, increased levels of phosphorylated tau, and decreased levels of the presynaptic protein synaptophysin [8].…”

Section: Discussionmentioning

confidence: 99%

“…We have shown that the cholesterol-fed rabbits develop pathological hallmarks of AD including disrupted synaptic integrity, brain deposition of Aβ, and tau pathology [7]. In addition, we have reported that cholesterol-fed rabbits exhibit very early pathological features found in people with AD including increased blood-brain barrier (BBB) leakage [7,16,17] and disturbed neuronal endolysosome structure and function [18]. Furthermore, using primary cultured neurons we demonstrated that LDL cholesterol, the major lipoprotein particle responsible for cholesterol transport in the blood, promoted AβPP internalization, enhanced BACE-1 activity, and increased amyloidogenic processing of AβPP in endolysosomes [8].…”

Section: Introductionmentioning

confidence: 99%

Caffeine blocks cholesterol-enriched diet induced AD-like pathology in rabbits

Chen¹,

Tian²,

Ghribi³

et al. 2016

J Integr Syst Neurosci

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The pathogenesis of sporadic AD is believed to result from complex interactions between nutritional, environmental, epigenetic and genetic factors. Among those factors, elevated plasma cholesterol, independent of APOE genotypes, is strongly linked to the pathogenesis of sporadic AD, whereas chronic ingestion of caffeine is protective against sporadic AD. Others and we have shown that rabbits-fed cholesterol-enriched diet exhibit early AD-like pathological features including bloodbrain barrier (BBB) leakage and endolysosome dysfunction, as well as, AD-like pathological hallmarks including synaptic disruption, increased intraneuronal and brain deposition of amyloid beta (Aβ), and tau pathology. Further, we found that caffeine protects against the cholesterol-induced increases in BBB permeability. Here, we determined the extent to which caffeine affects cholesterol-enriched diet-induced increases in other pathological features of AD. We demonstrated that caffeine administration at low and moderate doses did not affect plasma levels of cholesterol, but did block significantly cholesterol-enriched diet-induced increases in brain levels of apoB and accumulation of apoB in neuronal endolysosomes. Furthermore, we demonstrated that caffeine administration at the two doses blocked cholesterol-enriched diet-induced abnormal accumulation of synaptophysin, Aβ, and phosphorylated tau in endolysosomes. Our findings suggest that caffeine exerts its protective effects against the development of sporadic AD-like pathological features, in part, by preventing the entrance of LDL cholesterol into brain parenchyma, the accumulation of LDL-cholesterol in neuronal endolysosomes, and structural and functional changes to endolysosomes.

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Blood—Brain Barrier Permeability Precedes Senile Plaque Formation in an Alzheimer Disease Model

Cited by 227 publications

References 26 publications

Consensus meeting: monosodium glutamate – an update

Consensus meeting: monosodium glutamate – an update

Microvascular Sprouting, Extension, and Creation of New Capillary Connections with Adaptation of the Neighboring Astrocytes in Adult Mouse Cortex under Chronic Hypoxia

Caffeine blocks cholesterol-enriched diet induced AD-like pathology in rabbits

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