Neurovascular regulation in the normal brain and in Alzheimer's disease

Iadecola, Costantino

doi:10.1038/nrn1387

Cited by 1,958 publications

(1,837 citation statements)

References 162 publications

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“…We reported previously that Aβ42 upregulates ECE2‐mediated production of EDN1 by neurons 45 and that Aβ40 upregulates ECE1‐mediated production of EDN1 by cerebrovascular endothelial cells, a process inhibited by the antioxidant superoxide dismutase 46, 48. Iadecola 24 showed that the transient modulation of arteriolar calibre needed for functional hyperaemia is impaired in mice transgenic for mutant human APP, that this is mediated by Aβ40 and dependent on the production of free radicals. Together these findings suggest that functional hyperaemia is impaired by Aβ40 as a result of a free radical‐mediated increase in ECE1 activity and EDN1 production.…”

Section: Discussionmentioning

confidence: 99%

“…The elevated production of EDN1 may be an unfortunate side effect of over‐activation of this pathway by excessive Aβ42. In contrast, endothelial production of EDN1, mediated by ECE1 and driven by Aβ40, is more likely to contribute to episodic, free radical‐dependent dysfunction of vascular regulation in AD 48 (Figure 7), including abnormalities of autoregulation and functional hyperaemia demonstrated initially in mouse models of cerebral Aβ accumulation 24, 39 and CAA 49, 54, and more recently in patients with AD 14 and probable CAA 50. It should be noted, in addition, that EDN1 is very unlikely to be the sole nonstructural mediator of hypoperfusion of the precuneus in early AD.…”

Section: Discussionmentioning

confidence: 99%

“…Reduction in cerebral blood flow precedes the development of dementia in AD 52 and occurs well before any behavioral or pathological abnormalities in animal models of the disease 24, 39. We still have only a limited understanding of the pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Pathophysiology of Hypoperfusion of the Precuneus in Early Alzheimer's Disease

2015

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The earliest decline in cerebral perfusion in Alzheimer's disease (AD) is in the medial parietal cortex (precuneus). We have analyzed precuneus in post‐mortem tissue from 70 AD and 37 control brains to explore the pathophysiology of the hypoperfusion: the contribution of arteriolosclerotic small vessel disease (SVD) and cerebral amyloid angiopathy (CAA), and of the vasoconstrictors endothelin‐1 (EDN1) and angiotensin II (Ang II), and the association with Aβ. The myelin‐associated glycoprotein:proteolipid protein‐1 ratio (MAG:PLP1) was used as an indicator of oxygenation of the precuneus prior to death. MAG:PLP1 was reduced ∼50% in early AD (Braak stage III–IV). Although MAG:PLP1 remained low in advanced AD (stage V–VI), the reduction was less pronounced, possibly reflecting falling oxygen demand. Reduction in cortical MAG:PLP1 correlated with elevation in vascular endothelial growth factor (VEGF), another marker of hypoperfusion. Cortical MAG:PLP1 declined nonsignificantly with increasing SVD and CAA, but significantly with the concentration of EDN1, which was elevated approximately 75% in AD. In contrast, with reduction in cortical MAG:PLP1, Ang II level and angiotensin‐converting enzyme (ACE) activity declined, showing a normal physiological response to hypoperfusion. MAG:PLP1 was reduced in the parietal white matter (WM) in AD but here the decline correlated positively (ie, physiologically) with WM EDN1. However, the decline of MAG:PLP1 in the WM was associated with increasing cortical EDN1 and perhaps reflected vasoconstriction of perforating arterioles, which traverse the cortex to perfuse the WM. EDN1 in the cortex correlated highly significantly with both soluble and insoluble Aβ42, shown previously to upregulate neuronal endothelin‐converting enzyme‐2 (ECE2), but not with Aβ40. Our findings demonstrate reduced oxygenation of the precuneus in early AD and suggest that elevated EDN1, resulting from Aβ42‐mediated upregulation of ECE2, is a contributor.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Pathophysiology of Hypoperfusion of the Precuneus in Early Alzheimer's Disease

2015

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“…The 'neurovascular unit' provides a conceptual framework that emphasizes cell-cell interactions between neuronal, glial, and vascular elements. [4][5][6][7][8][9][10] This concept primarily guides research in neuron-related cell-cell interaction mechanisms in gray matter. But cell-cell signaling between nonneuronal cells should also be critical for white-matter function.…”

Section: Introductionmentioning

confidence: 99%

Subcortical ischemic vascular disease: Roles of oligodendrocyte function in experimental models of subcortical white-matter injury

Shindo

Liang

Maki

et al. 2015

J Cereb Blood Flow Metab

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Oligodendrocytes are one of the major cell types in cerebral white matter. Under normal conditions, they form myelin sheaths that encircle axons to support fast nerve conduction. Under conditions of cerebral ischemia, oligodendrocytes tend to die, resulting in white-matter dysfunction. Repair of white matter involves the ability of oligodendrocyte precursors to proliferate and mature. However, replacement of lost oligodendrocytes may not be the only mechanism for white-matter recovery. Emerging data now suggest that coordinated signaling between neural, glial, and vascular cells in the entire neurovascular unit may be required. In this mini-review, we discuss how oligodendrocyte lineage cells participate in signaling and crosstalk with other cell types to underlie function and recovery in various experimental models of subcortical white-matter injury.

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“…Brain areas containing such Aβ plaques display neuroinflammation, featured by activated glial cells, and substantial loss of neurons. Not only neurons and glial cells are affected in AD, but also the vascular network appears to be altered and reduced vessel density, dysfunctional blood–brain barrier (BBB) and microbleeds are commonly seen in AD patients (Iadecola, 2004; Kalaria, 2002; Zlokovic, 2005). A recent study conducted by Sengillo and colleagues has further showed a marked loss of pericytes in AD patients compared to age‐matched nondemented controls (Sengillo et al., 2013).…”

Section: Introductionmentioning

confidence: 99%

Amyloid‐beta 1‐40 is associated with alterations in NG2+ pericyte population ex vivo and in vitro

et al. 2018

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SummaryThe population of brain pericytes, a cell type important for vessel stability and blood brain barrier function, has recently been shown altered in patients with Alzheimer's disease (AD). The underlying reason for this alteration is not fully understood, but progressive accumulation of the AD characteristic peptide amyloid‐beta (Aβ) has been suggested as a potential culprit. In the current study, we show reduced number of hippocampal NG2+ pericytes and an association between NG2+ pericyte numbers and Aβ1‐40 levels in AD patients. We further demonstrate, using in vitro studies, an aggregation‐dependent impact of Aβ1‐40 on human NG2+ pericytes. Fibril‐EP Aβ1‐40 exposure reduced pericyte viability and proliferation and increased caspase 3/7 activity. Monomer Aβ1‐40 had quite the opposite effect: increased pericyte viability and proliferation and reduced caspase 3/7 activity. Oligomer‐EP Aβ1‐40 had no impact on either of the cellular events. Our findings add to the growing number of studies suggesting a significant impact on pericytes in the brains of AD patients and suggest different aggregation forms of Aβ1‐40 as potential key regulators of the brain pericyte population size.

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Neurovascular regulation in the normal brain and in Alzheimer's disease

Cited by 1,958 publications

References 162 publications

Pathophysiology of Hypoperfusion of the Precuneus in Early Alzheimer's Disease

Pathophysiology of Hypoperfusion of the Precuneus in Early Alzheimer's Disease

Subcortical ischemic vascular disease: Roles of oligodendrocyte function in experimental models of subcortical white-matter injury

Amyloid‐beta 1‐40 is associated with alterations in NG2+ pericyte population ex vivo and in vitro

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