Beta-amyloid pathology in human brain microvessel extracts from the parietal cortex: relation with cerebral amyloid angiopathy and Alzheimer’s disease

Bourassa, Philippe; Tremblay, Cyntia; Schneider, Julie A.; Bennett, David A.; Calon, Frédéric

doi:10.1007/s00401-019-01967-4

Cited by 67 publications

(97 citation statements)

References 111 publications

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“…We have extended these earlier findings with a more comprehensive Proteomics examination of proteins in cerebral MVs, with an emphasis not only on individual mitochondrial structural proteins and energy producing proteins but also on proteins known to modulate mitochondrial numbers and function. We studied cerebral MVs because of recent recognition that this vascular segment is more susceptible to dysfunction during aging and disease than large arteries and that MVs are a primary initiation site for development of severe neurological diseases such cognitive impairment, vascular dementia, and AD (Liu et al, 2018;Bourassa et al, 2019;Erdő & Krajcsi 2019). Although several current findings confirmed results of our earlier studies, the expansive and thorough nature of the present study has yielded novel and surprising findings.…”

Section: Discussionsupporting

confidence: 79%

Sexual Differences in Mitochondrial Proteins in Rat Cerebral Microvessels: A Proteomic Approach

Chandra

Čikić

Harman

et al. 2019

Preprint

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Sex differences in mitochondrial numbers and function are present in large cerebral arteries, but it is unclear whether these differences extend to the microcirculation. We performed an assessment of mitochondria-related proteins in cerebral microvessels (MVs) isolated from young, male and female, Sprague-Dawley rats. MVs composed of arterioles, capillaries, and venules were isolated from the cerebrum and used to perform a 3 vs. 3 quantitative, multiplexed proteomics experiment utilizing tandem mass tags (TMT), coupled with liquid chromatography/mass spectrometry (LC/MS). MS data and bioinformatic analyses were performed using Proteome Discoverer version 2.2 and Ingenuity Pathway Analysis. We identified a total of 1,969 proteins, of which 1,871 were quantified by TMT labels. Sixty-four proteins were expressed significantly (p < 0.05) higher in female samples compared with male samples. Females expressed more mitochondrial proteins involved in energy production, mitochondrial membrane structure, anti-oxidant enzyme proteins, and those involved in fatty acid oxidation. Conversely, males had higher expression levels of mitochondria-destructive proteins. We validated our key Proteomics results with western blotting. Our findings reveal, for the first time, the full extent of sexual dimorphism in the mitochondrial metabolic protein profiles of MVs, which may contribute to sex-dependent cerebrovascular and neurological pathologies. SynopsisEnergy-producing proteins in the cerebral microvessels (MVs) of male and female rats were examined by quantitative discovery-based proteomics to gain insight into the sex-dependent etiology of cardiovascular and neurological diseases. Females expressed more mitochondrial proteins involved in energy production, membrane structure, anti-oxidant activity, and fatty acid oxidation. In contrast, males exhibited more mitochondria-destructive proteins such as mitochondrial eating protein. Our findings reveal for the first time the sexual dimorphism of mitochondria-related proteins in cerebral MVs, which may explain functional sex-related differences in MVs during health and in the etiology of neurological pathologies of cerebrovascular origin. ACKNOWLEDGMENTSWe thank Nancy Busija, MA, for editing the manuscript. We thank Dana Liu for technical help.

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Section: Discussionsupporting

confidence: 79%

Sexual Differences in Mitochondrial Proteins in Rat Cerebral Microvessels: A Proteomic Approach

Chandra

Čikić

Harman

et al. 2019

Preprint

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“…through the proteolytic cleavage of longer Aβ isoforms by BACE1 or MMPs [19, 25]. In support of this hypothesis, elevated levels of vascular BACE1 were previously described in CAA-laden arteries [7, 13, 16]. Further studies focusing on CAA and vascular amyloidosis in samples including capCAA will be required to obtain a better understanding of the origin of Aβ34 in CAA-affected arteries.…”

Section: Discussionmentioning

confidence: 70%

The amyloid-β degradation intermediate Aβ34 is pericyte-associated and reduced in brain capillaries of patients with Alzheimer’s disease

Kirabali

Rigotti

Siccoli

et al. 2019

acta neuropathol commun

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An impairment of amyloid β-peptide (Aβ) clearance is suggested to play a key role in the pathogenesis of sporadic Alzheimer’s disease (AD). Amyloid degradation is mediated by various mechanisms including fragmentation by enzymes like neprilysin, matrix metalloproteinases (MMPs) and a recently identified amyloidolytic activity of β-site amyloid precursor protein cleaving enzyme 1 (BACE1). BACE1 cleavage of Aβ40 and Aβ42 results in the formation of a common Aβ34 intermediate which was found elevated in cerebrospinal fluid levels of patients at the earliest disease stages. To further investigate the role of Aβ34 as a marker for amyloid clearance in AD, we performed a systematic and comprehensive analysis of Aβ34 immunoreactivity in hippocampal and cortical post-mortem brain tissue from AD patients and non-demented elderly individuals. In early Braak stages, Aβ34 was predominantly detectable in a subset of brain capillaries associated with pericytes, while in later disease stages, in clinically diagnosed AD, this pericyte-associated Aβ34 immunoreactivity was largely lost. Aβ34 was also detected in isolated human cortical microvessels associated with brain pericytes and its levels correlated with Aβ40, but not with Aβ42 levels. Moreover, a significantly decreased Aβ34/Aβ40 ratio was observed in microvessels from AD patients in comparison to non-demented controls suggesting a reduced proteolytic degradation of Aβ40 to Aβ34 in AD. In line with the hypothesis that pericytes at the neurovascular unit are major producers of Aβ34, biochemical studies in cultured human primary pericytes revealed a time and dose dependent increase of Aβ34 levels upon treatment with recombinant Aβ40 peptides while Aβ34 production was impaired when Aβ40 uptake was reduced or BACE1 activity was inhibited. Collectively, our findings indicate that Aβ34 is generated by a novel BACE1-mediated Aβ clearance pathway in pericytes of brain capillaries. As amyloid clearance is significantly reduced in AD, impairment of this pathway might be a major driver of the pathogenesis in sporadic AD.

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“…The latter may be the result of deficiencies in Aβ clearance through the blood-brain barrier (BBB; Bourassa et al, 2019;Hecht et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Parallels between retinal and brain pathology and response to immunotherapy in old, late‐stage Alzheimer's disease mouse models

et al. 2020

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Beta-amyloid pathology in human brain microvessel extracts from the parietal cortex: relation with cerebral amyloid angiopathy and Alzheimer’s disease

Cited by 67 publications

References 111 publications

Sexual Differences in Mitochondrial Proteins in Rat Cerebral Microvessels: A Proteomic Approach

Sexual Differences in Mitochondrial Proteins in Rat Cerebral Microvessels: A Proteomic Approach

The amyloid-β degradation intermediate Aβ34 is pericyte-associated and reduced in brain capillaries of patients with Alzheimer’s disease

Parallels between retinal and brain pathology and response to immunotherapy in old, late‐stage Alzheimer's disease mouse models

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