Disturbances in the control of capillary flow in an aged APPswe/PS1ΔE9 model of Alzheimer's disease

Gutiérrez‐Jiménez, Eugenio; Angleys, Hugo; Rasmussen, Peter Mondrup; West, Mark J.; Catalini, Laura; Iversen, Nina; Jensen, Morten Skovgaard; Frische, Sebastian; Østergaard, Leif

doi:10.1016/j.neurobiolaging.2017.10.006

Cited by 32 publications

(28 citation statements)

References 76 publications

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“…Functional indications that capillary pericyte-mediated control of CBF is disrupted in AD have been provided by measurements of the capillary transit time of the blood, and its heterogeneity. Magnetic resonance imaging (MRI) experiments on humans and optical imaging experiments on AD mice have found that AD leads to both a prolongation of the capillary transit time and an increase in its heterogeneity, as if some capillary pericytes became more constricted than others [38,54]. Furthermore, in humans, these changes correlate with cognitive decline (Fig.…”

Section: Cerebral Blood Flow Decreases In Ad Largely Reflect Pericytementioning

confidence: 99%

“…The discoveries that the decrease of CBF in AD occurs early in the disease [76], and is caused by impaired capillary regulation of CBF [26,54,128,133], are consistent with the proposal that impaired capillary blood flow contributes to the onset of AD [31] made soon after the amyloid hypothesis of AD was proposed [59]. These data, including the demonstration that Aβ itself can trigger pericyte-mediated capillary constriction [133], reconcile genetic evidence for the involvement of Aβ in AD with the fact that the first change seen in AD is a decrease of cerebral blood flow [76], and open up new potential therapeutic approaches for this disease.…”

Section: Implications For Therapeutic Approaches To Alzheimer's Diseasementioning

confidence: 99%

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Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease

2020

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Therapies targeting late events in Alzheimer's disease (AD), including aggregation of amyloid beta (Aβ) and hyperphosphorylated tau, have largely failed, probably because they are given after significant neuronal damage has occurred. Biomarkers suggest that the earliest event in AD is a decrease of cerebral blood flow (CBF). This is caused by constriction of capillaries by contractile pericytes, probably evoked by oligomeric Aβ. CBF is also reduced by neutrophil trapping in capillaries and clot formation, perhaps secondary to the capillary constriction. The fall in CBF potentiates neurodegeneration by upregulating the BACE1 enzyme that makes Aβ and by promoting tau hyperphosphorylation. Surprisingly, therefore, CBF reduction may play a crucial role in driving cognitive decline by initiating the amyloid cascade itself, or being caused by and amplifying Aβ production. Here, we review developments in this area that are neglected in current approaches to AD, with the aim of promoting novel mechanism-based therapeutic approaches.

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Section: Cerebral Blood Flow Decreases In Ad Largely Reflect Pericytementioning

confidence: 99%

Section: Implications For Therapeutic Approaches To Alzheimer's Diseasementioning

confidence: 99%

Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease

2020

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“…Vessel diameter was defined as the FWHM value of the profile. 29,30,31 Arterioles and venules were distinguished on the basis of their diameters, positions, orientations, and values of StO 2 before LISW application. In addition, we carefully distinguished cortical surface arterioles from the vessels in the dura matter on the basis of their diameters; the diameter of cortical surface arterioles is about two to three times larger than that of dural vessels (∼25 μm) in their proximal portion in rats.…”

Section: Evaluation Of Cortical Vessel Diametersmentioning

confidence: 99%

Multispectral imaging of cortical vascular and hemodynamic responses to a shock wave: observation of spreading depolarization and oxygen supply-demand mismatch

et al. 2019

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imaging of cortical vascular and hemodynamic responses to a shock wave: observation of spreading depolarization and oxygen supply-demand mismatch," J.Abstract. Blast-induced traumatic brain injury has been a recent major concern in neurotraumatology.However, its pathophysiology and mechanism are not understood partly due to insufficient information on the brain pathophysiology during/immediately after shock wave exposure. We transcranially applied a laserinduced shock wave (LISW, ∼19 Pa · s) to the left frontal region in a rat and performed multispectral imaging of the ipsilateral cortex through a cranial window (n ¼ 4). For the spectral data obtained, we conducted multiple regression analysis aided by Monte Carlo simulation to evaluate vascular diameters, regional hemoglobin concentration (rC Hb ), tissue oxygen saturation (StO 2 ), oxygen extraction fraction, and light-scattering signals as a signature of cortical spreading depolarization (CSD). Immediately after LISW exposure, rC Hb and StO 2 were significantly decreased with distinct venular constriction. CSD was then generated and was accompanied by distinct hyperemia/hyperoxemia. This was followed by oligemia with arteriolar constriction, but it soon recovered (within ∼20 min). However, severe hypoxemia was persistently observed during the post-CSD period (∼1 h). These observations indicate that inadequate oxygen supply and/or excessive oxygen consumption continued even after blood supply was restored in the cortex. Such a hypoxemic state and/or a hypermetabolic state might be associated with brain damage caused by a shock wave.

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“…Smooth muscle atrophy and general disorganization of these cells was consistently observed in AD subjects although these features seemed unrelated to the deposition of A␤ [193]. These structural changes translate into a decreased capillary flow in aged (16 months old) compared to young (2 months old) mice [194] as well as aggravated loss of blood flow rate in an aged APP swe /PS1 E9 transgenic mouse model [195]. The observed structural and functional changes in the microvascular organization thus lead to hypoperfusion and a general inability of the cerebral vasculature to meet the metabolic needs of the brain while this was partly compensated for by an increased ability to extract oxygen from the remaining blood flow [196].…”

Section: A Vascular Componentmentioning

confidence: 94%

Molecular Mechanisms and Genetics of Oxidative Stress in Alzheimer’s Disease

Cioffi

Adam

Broersen

2019

JAD

126

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Alzheimer's disease is the most common neurodegenerative disorder that can cause dementia in elderly over 60 years of age. One of the disease hallmarks is oxidative stress which interconnects with other processes such as amyloid-␤ deposition, tau hyperphosphorylation, and tangle formation. This review discusses current thoughts on molecular mechanisms that may relate oxidative stress to Alzheimer's disease and identifies genetic factors observed from in vitro, in vivo, and clinical studies that may be associated with Alzheimer's disease-related oxidative stress.

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Disturbances in the control of capillary flow in an aged APPswe/PS1ΔE9 model of Alzheimer's disease

Cited by 32 publications

References 76 publications

Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease

Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease

Multispectral imaging of cortical vascular and hemodynamic responses to a shock wave: observation of spreading depolarization and oxygen supply-demand mismatch

Molecular Mechanisms and Genetics of Oxidative Stress in Alzheimer’s Disease

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