Cerebral atherosclerosis contributes to Alzheimer’s dementia independently of its hallmark amyloid and tau pathologies

Wingo, Aliza P.; Fan, Wen; Duong, Duc; Gerasimov, Ekaterina S.; Dammer, Eric B.; White, Bartholomew; Thambisetty, Madhav; Troncoso, Juan C.; Schneider, Julie A.; Lah, James J.; Bennett, David A.; Seyfried, Nicholas T.; Levey, Aĺlan I.; Wingo, Thomas S.

doi:10.1101/793349

Cited by 3 publications

(3 citation statements)

References 59 publications

(88 reference statements)

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“…Tandem mass tag proteomics analysis was conducted on frozen tissue samples of the DLPFC (eAppendix 1 and eFigures 6 and 7 in the Supplement). Details on the mass spectrometry–based proteomics, database searches, and quality control have been previously described . In brief, the samples were homogenized, and the protein concentration was determined.…”

Section: Methodssupporting

confidence: 76%

“…Details on the mass spectrometrybased proteomics, database searches, and quality control have been previously described. 14 In brief, the samples were homogenized, and the protein concentration was determined. After protein digestion, isobaric TMT peptide labeling and high pH fractionation were performed.…”

Section: Mass Spectrometry-based Proteomics Using Isobaric Tmtmentioning

confidence: 99%

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Cortical Proteins Associated With Cognitive Resilience in Community-Dwelling Older Persons

et al. 2020

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Identifying genes and proteins for cognitive resilience (ie, targets that may be associated with slowing or preventing cognitive decline regardless of the presence, number, or combination of common neuropathologic conditions) provides a complementary approach to developing novel therapeutics for the treatment and prevention of Alzheimer disease and related dementias.OBJECTIVE To identify proteins associated with cognitive resilience via a proteome-wide association study of the human dorsolateral prefrontal cortex. DESIGN, SETTING, AND PARTICIPANTSThis study used data from 391 community-dwelling older persons who participated in the Religious Orders Study and the Rush Memory and Aging Project.

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Section: Methodssupporting

confidence: 76%

Section: Mass Spectrometry-based Proteomics Using Isobaric Tmtmentioning

confidence: 99%

Cortical Proteins Associated With Cognitive Resilience in Community-Dwelling Older Persons

et al. 2020

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“…Due to the variance in location, size and composition of the plaque, atherosclerosis can cause different abnormalities throughout the body and as such is the most prominent cause of CVD [ 16 , 17 ]. For example, cerebral atherosclerosis can lead to strokes and cause neurodegeneration [ 18 ]. Atherosclerosis is believed to be caused by a combination of both environmental and genetic factors.…”

Section: Mural Cells and Cardiovascular Diseasementioning

confidence: 99%

Mural Cells: Potential Therapeutic Targets to Bridge Cardiovascular Disease and Neurodegeneration

Lin

Peiris

Dhaliwal

et al. 2021

Cells

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Mural cells collectively refer to the smooth muscle cells and pericytes of the vasculature. This heterogenous population of cells play a crucial role in the regulation of blood pressure, distribution, and the structural integrity of the vascular wall. As such, dysfunction of mural cells can lead to the pathogenesis and progression of a number of diseases pertaining to the vascular system. Cardiovascular diseases, particularly atherosclerosis, are perhaps the most well-described mural cell-centric case. For instance, atherosclerotic plaques are most often described as being composed of a proliferative smooth muscle cap accompanied by a necrotic core. More recently, the role of dysfunctional mural cells in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, is being recognized. In this review, we begin with an exploration of the mechanisms underlying atherosclerosis and neurodegenerative diseases, such as mural cell plasticity. Next, we highlight a selection of signaling pathways (PDGF, Notch and inflammatory signaling) that are conserved across both diseases. We propose that conserved mural cell signaling mechanisms can be exploited for the identification or development of dual-pronged therapeutics that impart both cardio- and neuroprotective qualities.

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Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation

Johnson

Dammer

Duong

et al. 2020

Nat Med

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Our understanding of the biological changes in the brain associated with Alzheimer's disease (AD) pathology and cognitive impairment remains incomplete. To increase our understanding of these changes, we analyzed dorsolateral prefrontal cortex of control, asymptomatic AD, and AD brains from four different centers by label-free quantitative mass spectrometry and weighted protein co-expression analysis to obtain a consensus protein co-expression network of AD brain. This network consisted of 13 protein co-expression modules. Six of these modules correlated with amyloid-β plaque burden, tau neurofibrillary tangle burden, cognitive function, and clinical functional status, and were altered in asymptomatic AD, AD, or in both disease states. These six modules reflected synaptic, mitochondrial, sugar metabolism, extracellular matrix, cytoskeletal, and RNA binding/splicing biological functions. The identified protein network modules were preserved in a community-based cohort analyzed by a different quantitative mass spectrometry approach. They were also preserved in temporal lobe and precuneus brain regions. Some of the modules were influenced by aging, and showed changes in other neurodegenerative diseases such as frontotemporal dementia and corticobasal degeneration. The module most strongly associated with AD pathology and cognitive impairment was the sugar metabolism module. This module was enriched in AD genetic risk factors, and was also highly enriched in microglia and astrocyte protein markers associated with an anti-inflammatory state, suggesting that the biological functions it represents serve a protective role in AD. Proteins from the sugar metabolism module were increased in cerebrospinal fluid from asymptomatic AD and AD cases, highlighting their potential as biomarkers of the altered brain network. In this study of >2000 brains and nearly 400 cerebrospinal fluid samples by quantitative proteomics, we identify proteins and biological processes in AD brain that may serve as therapeutic targets and fluid biomarkers for the disease.

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Cerebral atherosclerosis contributes to Alzheimer’s dementia independently of its hallmark amyloid and tau pathologies

Cited by 3 publications

References 59 publications

Cortical Proteins Associated With Cognitive Resilience in Community-Dwelling Older Persons

Cortical Proteins Associated With Cognitive Resilience in Community-Dwelling Older Persons

Mural Cells: Potential Therapeutic Targets to Bridge Cardiovascular Disease and Neurodegeneration

Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation

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