Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer’s disease

Bennett, Rachel E.; Robbins, Ashley B.; Hu, Miwei; Cao, Xinrui; Betensky, Rebecca A.; Clark, Tim W.; Das, Sudeshna; Hyman, Bradley T.

doi:10.1073/pnas.1710329115

Cited by 249 publications

(288 citation statements)

References 56 publications

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“…In line with this, pericyte loss is accelerated in humans carrying the APOE4 allele [88]. In a recent study, expression of tau in neurons of mice (the Tg4510 mouse model) resulted in an altered cortical microvasculature, with elevated numbers of small-diameter blood vessels [161].…”

Section: Cerebrovascular Diseases Affecting the Cnsmentioning

confidence: 77%

“…ATP and adenosine from neurons act on adenosine receptors on the vascular cells, and arachidonic acid derivatives (including 20-HETE, see below) from astrocytes also influence the vascular cells. In a recent study, expression of tau in neurons of mice (the Tg4510 mouse model) resulted in an altered cortical microvasculature, with elevated numbers of small-diameter blood vessels [161]. In line with this, pericyte loss is accelerated in humans carrying the APOE4 allele [88].…”

Section: Cerebrovascular Diseases Affecting the Cnsmentioning

confidence: 82%

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Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

2019

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Neurodegenerative and cerebrovascular diseases cause considerable human suffering, and therapy options for these two disease categories are limited or non-existing. It is an emerging notion that neurodegenerative and cerebrovascular diseases are linked in several ways, and in this review, we discuss the current status regarding vascular dysregulation in neurodegenerative disease, and conversely, how cerebrovascular diseases are associated with central nervous system (CNS) degeneration and dysfunction. The emerging links between neurodegenerative and cerebrovascular diseases are reviewed with a particular focus on pericytes-important cells that ensheath the endothelium in the microvasculature and which are pivotal for blood-brain barrier function and cerebral blood flow. Finally, we address how novel molecular and cellular insights into pericytes and other vascular cell types may open new avenues for diagnosis and therapy development for these important diseases.

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Section: Cerebrovascular Diseases Affecting the Cnsmentioning

confidence: 77%

Section: Cerebrovascular Diseases Affecting the Cnsmentioning

confidence: 82%

Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

2019

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“…Among the results, these investigations have highlighted the importance of immune/inflammatory and neuronal/synaptic changes (Boisvert et al, 2018;Cummings et al, 2015;Gjoneska et al, 2015;Matarin et al, 2015;Rothman et al, 2018;Stephenson et al, 2018;Swartzlander et al, 2018). While some reports have identified selected overlaps between expression changes in AD mouse models and human brains (Bennett et al, 2018a;Castillo et al, 2017;Mostafavi et al, 2018;Neuner et al, 2019;Rojo et al, 2017), other studies have questioned the overall degree of conservation (Burns et al, 2015;Galatro et al, 2017;Hargis and Blalock, 2017).…”

Section: Introductionmentioning

confidence: 99%

Functional dissection of Alzheimer’s disease brain gene expression signatures in humans and mouse models

Wan

Al‐Ouran

et al. 2019

Preprint

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Human brain transcriptomes can highlight biological pathways associated with Alzheimer's disease (AD); however, challenges remain to link expression changes with causal triggers. We have examined 30 ADassociated, gene coexpression modules from human brains for overlap with 251 differentially-expressed gene sets from mouse brain RNA-sequencing experiments, including from models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus neurofibrillary tangle pathology and further reveal age-and sex-dependent expression signatures for AD progression. Human coexpression modules enriched for neuronal and/or microglial genes overlap broadly with signatures from mouse models of AD, Huntington's disease, Amyotrophic Lateral Sclerosis, and also aging. Several human AD coexpression modules, including those implicated in the unfolded protein response and oxidative phosphorylation, were not activated in AD models, but instead were detected following other, unexpected mouse genetic manipulations. Our results comprise a powerful, cross-species resource and pinpoint experimental models for diverse features of AD pathophysiology from human brain transcriptomes.

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“…Indeed, previous studies in aged APP mice show structural abnormalities in amyloid laden blood vessels, supporting a potential link between abnormal amyloid peptide deposition and bloodbrain barrier alterations (18,19). Furthermore, a recent paper showed significant morphologic alterations in cerebral microvessels in the brains of aged mutant tau Tg4510 mice (46). These changes were accompanied by increased expression of angiogenesis-related genes in CD31-positive ECs.…”

Section: Discussionmentioning

confidence: 66%

“…These changes were accompanied by increased expression of angiogenesis-related genes in CD31-positive ECs. Interestingly, in the same study (46), mice overexpressing nonmutant forms of tau (Tg21221 mice) also showed increased production of angiogenesis-related proteins in ECs, but without overt neurodegeneration. The authors interpret this to mean that changes in angiogenesisrelated gene expression precede the microvessel alterations and suggest that frank neurodegeneration may not be a required stimulus for this phenotype but rather the presence of soluble tau "oligomeric" species in the Tg21221 mouse brain could directly induce the aberrant angiogenesis effects seen in the ECs, leading to alterations in the brain microvessels.…”

Section: Discussionmentioning

confidence: 77%

VEGF receptor‐1 modulates amyloid β 1–42 oligomer‐induced senescence in brain endothelial cells

Angom¹,

Wang²,

Wang³

et al. 2018

FASEB j.

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Aggregated amyloid β (Aβ) peptides in the Alzheimer's disease (AD) brain are hypothesized to trigger several downstream pathologies, including cerebrovascular dysfunction. Previous studies have shown that Aβ peptides can have antiangiogenic properties, which may contribute to vascular dysfunction in the early stages of the disease process. We have generated data showing that brain endothelial cells (ECs) exposed to toxic Aβ1‐42 oligomers can readily enter a senescence phenotype. To determine the effect of Aβ oligomers on brain ECs, we treated early passaged human brain microvascular ECs and HUVECs with high MW Aβ1‐42 oligomers (5 µM, for 72 h). For controls, we used no peptide treatment, 5 µM Aβ1‐42 monomers, and 5 µM Aβ1‐42 fibrils, respectively. Brain ECs treated with Aβ1‐42 oligomers showed increased senescence‐associated β‐galactosidase staining and increased senescence‐associated p21/ p53 expression. Treatment with either Aβ1‐42 monomer or Aβ1‐42 fibrils did not induce senescence in this assay. We then measured vascular endothelial growth factor receptor (VEGFR) expression in the Aβ1‐42 oligomer‐treated ECs, and these cells showed significantly increased VEGFR‐1 expression and decreased VEGFR‐2 levels. Overexpression of VEGFR‐1 in brain ECs readily induced senescence, suggesting a direct role of VEGFR‐1 signaling events in this paradigm. More importantly, small interfering RNA‐mediated knockdown of VEGFR‐1 expression in brain ECs was able to prevent up‐regulation of p21 protein expression and significantly reduced induction of senescence following Aβ1‐42 oligomer treatment. Our studies show that exposure to Aβ1‐42 oligomers may impair vascular functions by altering VEGFR‐1 expression and causing ECs to enter a senescent phenotype. Altered VEGFR expression has been documented in brains of AD patients and suggests that this pathway may play a role in AD disease pathogenesis. These studies suggest that modulating VEGFR‐1 expression and signaling events could potentially prevent senescence and rejuvenate EC functions, and provides us with a novel target to pursue for prevention and treatment of cerebrovascular dysfunction in AD.—Angom, R. S., Wang, Y., Wang, E., Pal, K., Bhattacharya, S., Watzlawik, J. O., Rosenberry, T. L., Das, P., Mukhopadhyay, D. VEGF receptor‐1 modulates amyloid β 1–42 oligomer‐induced senescence in brain endothelial cells. FASEB J. 33, 4626–4637 (2019). http://www.fasebj.org

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Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer’s disease

Abstract: SignificanceThis work provides evidence that the protein tau induces changes in blood vessels distinct from the effects of amyloid beta on vasculature and indicates a previously unknown pathway by which pathological tau may accelerate cognitive decline in Alzheimer’s disease.

Cited by 249 publications

References 56 publications

Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

Functional dissection of Alzheimer’s disease brain gene expression signatures in humans and mouse models

VEGF receptor‐1 modulates amyloid β 1–42 oligomer‐induced senescence in brain endothelial cells

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