Proteomic differences in brain vessels of Alzheimer’s disease mice: Normalization by PPARγ agonist pioglitazone

Badhwar, AmanPreet; Brown, Rebecca; Stanimirovic, Danica; Haqqani, Arsalan S.; Hamel, Edith

doi:10.1177/0271678x16655172

Cited by 33 publications

(32 citation statements)

References 53 publications

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“…As such, we hypothesize that microvascular loss is greatest in the white matter and areas that experience a decline in CBF with age. Revealing such differences will be useful for future "omic" research that seeks to understand regional diversity in aging processes at a molecular level (Badhwar et al, 2017;Mattson and Arumugam, 2018).…”

Section: Introductionmentioning

confidence: 99%

Susceptibility to capillary plugging can predict brain region specific vessel loss with aging

Schager

Brown

2020

J Cereb Blood Flow Metab

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Vessel loss in the aging brain is commonly reported, yet important questions remain concerning whether there are regional vulnerabilities and what mechanisms could account for these regional differences, if they exist. Here we imaged and quantified vessel length, tortuosity and width in 15 brain regions in young adult and aged mice. Our data indicate that vessel loss was most pronounced in white matter followed by cortical, then subcortical grey matter regions, while some regions (visual cortex, amygdala, thalamus) showed no decline with aging. Regions supplied by the anterior cerebral artery were more vulnerable to loss than those supplied by middle or posterior cerebral arteries. Vessel width and tortuosity generally increased with age but neither reliably predicted regional vessel loss. Since capillaries are naturally prone to plugging and prolonged obstructions often lead to vessel pruning, we hypothesized that regional susceptibilities to plugging could help predict vessel loss. By mapping the distribution of microsphere-induced capillary obstructions, we discovered that regions with a higher density of persistent obstructions were more likely to show vessel loss with aging and vice versa. These findings indicate that age-related vessel loss is region specific and can be explained, at least partially, by regional susceptibilities to capillary plugging.

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Section: Introductionmentioning

confidence: 99%

Susceptibility to capillary plugging can predict brain region specific vessel loss with aging

Schager

Brown

2020

J Cereb Blood Flow Metab

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“…Comparative proteomic analysis has revealed changes in protein networks following experimental subarachnoid hemorrhage of rat cerebral arteries (4) and in ischemic brain of permanent middle cerebral artery occlusion in a mouse model (5). In addition, changes in brain vessel proteome were described in Alzheimer's disease mice (6). A growing body of evidence strongly suggests that the cerebral circulation is a critical target of prenatal alcohol exposure (7)(8)(9)(10)(11).…”

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confidence: 99%

Proteomic Analysis of Baboon Cerebral Artery Reveals Potential Pathways of Damage by Prenatal Alcohol Exposure*

Bisen¹,

Kakhniashvili²,

Johnson³

et al. 2019

Molecular & Cellular Proteomics

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In BriefProteome analysis was performed to determine whether fetal alcohol exposure during mid-pregnancy would evoke changes in protein profile of fetal cerebral artery in baboons. We detected that levels of 238 proteins differed significantly between control and alcoholexposed fetuses. Proteins of metabolic pathways represented one of the major targets of alcohol. The differences were detected near term, long after alcohol exposure took place. Our findings point at novel targets of alcohol within developing brain vessels. Graphical Abstract Highlights• We studied mid-pregnancy alcohol exposure and baboon fetal cerebral artery.• 238 proteins differed between control and alcohol-exposed fetuses near-term.• Proteins of metabolic pathways represented one of the major targets of alcohol.• Alcohol effect on the development of fetal brain vessels is persistent.Alcohol is one of the most widely misused substances in the world. Alcohol consumption by pregnant women often results in an array of fetal developmental abnormalities, but the damage to the fetus by alcohol remains poorly understood. The limited knowledge regarding the molecular targets of alcohol in the developing fetus constitutes one of the major obstacles in developing effective pharmacological interventions that could prevent fetal damage after alcohol consumption by pregnant women. The fetal cerebral artery is emerging as an important mediator of fetal cerebral damage by maternal alcohol drinking. In the present work, we conduct proteomics analysis of cerebral (basilar) artery lysates of near-term fetal baboons to search for protein targets of fetal alcohol exposure. Our study demonstrates that 3 episodes of binge alcohol exposure during the second trimester-equivalent of human pregnancy are sufficient to render profound changes in fetal cerebral artery proteome. These changes persisted, as they were detected in near-term fetuses. In particular, the relative abundance of 238 proteins differed significantly between control and alcohol-exposed fetuses. Enrichment analysis pointed at the group of metabolic activity proteins as a major class targeted by alcohol. Western blotting confirmed upregulation of the aldehyde dehydrogenase 6 family member A1 (ALDH6A1) in cerebral artery lysates from alcohol-exposed fetuses. This upregulation translated to greater ALDH activity of cerebral artery lysate of near-term fetuses following prenatal alcohol exposure when compared with controls. Molecular

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“…This was further correlated with reduced AGO2-GW182 interaction and dysregulated miRISC assembly (Lewkowicz et al, 2015). In fact, miRISC protein GW182 was first identified from the serum auto-antibodies of patients with neuropathic symptoms (Eystathioy et al, 2002(Eystathioy et al, , 2003, and changes in its levels are implicated in Alzheimer's disease (Rouillard et al, 2016;Badhwar et al, 2017). Altered localization and trafficking of miRISC was recently reported in a cell culture model of amyotrophic lateral sclerosis (ALS) (Gershoni-Emek et al, 2018).…”

Section: Discussionmentioning

confidence: 98%

The Role of Dynamic miRISC During Neuronal Development

Nawalpuri

Ravindran

Muddashetty

2020

Front. Mol. Biosci.

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Activity-dependent protein synthesis plays an important role during neuronal development by fine-tuning the formation and function of neuronal circuits. Recent studies have shown that miRNAs are integral to this regulation because of their ability to control protein synthesis in a rapid, specific and potentially reversible manner. miRNA mediated regulation is a multistep process that involves inhibition of translation before degradation of targeted mRNA, which provides the possibility to store and reverse the inhibition at multiple stages. This flexibility is primarily thought to be derived from the composition of miRNA induced silencing complex (miRISC). AGO2 is likely the only obligatory component of miRISC, while multiple RBPs are shown to be associated with this core miRISC to form diverse miRISC complexes. The formation of these heterogeneous miRISC complexes is intricately regulated by various extracellular signals and cell-specific contexts. In this review, we discuss the composition of miRISC and its functions during neuronal development. Neurodevelopment is guided by both internal programs and external cues. Neuronal activity and external signals play an important role in the formation and refining of the neuronal network. miRISC composition and diversity have a critical role at distinct stages of neurodevelopment. Even though there is a good amount of literature available on the role of miRNAs mediated regulation of neuronal development, surprisingly the role of miRISC composition and its functional dynamics in neuronal development is not much discussed. In this article, we review the available literature on the heterogeneity of the neuronal miRISC composition and how this may influence translation regulation in the context of neuronal development.

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Proteomic differences in brain vessels of Alzheimer’s disease mice: Normalization by PPARγ agonist pioglitazone

Cited by 33 publications

References 53 publications

Susceptibility to capillary plugging can predict brain region specific vessel loss with aging

Susceptibility to capillary plugging can predict brain region specific vessel loss with aging

Proteomic Analysis of Baboon Cerebral Artery Reveals Potential Pathways of Damage by Prenatal Alcohol Exposure*

The Role of Dynamic miRISC During Neuronal Development

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