Role of the MEOX2 homeobox gene in neurovascular dysfunction in Alzheimer disease

Maslov

Proc. Natl. Acad. Sci. U.S.A.

2013

189

153

Label-free functional imaging of single red blood cells (RBCs) in vivo holds the key to uncovering the fundamental mechanism of oxygen metabolism in cells. To this end, we developed single-RBC photoacoustic flowoxigraphy (FOG), which can image oxygen delivery from single flowing RBCs in vivo with millisecond-scale temporal resolution and micrometer-scale spatial resolution. Using intrinsic optical absorption contrast from oxyhemoglobin (HbO 2 ) and deoxyhemoglobin (HbR), FOG allows label-free imaging. Multiple single-RBC functional parameters, including total hemoglobin concentration (C Hb ), oxygen saturation (sO 2 ), sO 2 gradient (∇sO 2 ), flow speed (v f ), and oxygen release rate (rO 2 ), have been quantified simultaneously in real time. Working in reflection instead of transmission mode, the system allows minimally invasive imaging at more anatomical sites. We showed the capability to measure relationships among sO 2 , ∇sO 2 , v f , and rO 2 in a living mouse brain. We also demonstrated that single-RBC oxygen delivery was modulated by changing either the inhalation gas or blood glucose. Furthermore, we showed that the coupling between neural activity and oxygen delivery could be imaged at the single-RBC level in the brain. The single-RBC functional imaging capability of FOG enables numerous biomedical studies and clinical applications. Although individual parameters such as oxygen saturation (sO 2 ) (1, 2), partial oxygen pressure (pO 2 ) (3, 4), or blood flow speed (v f ) (4-7) may partially indicate tissue oxygenation, none of them can provide a complete description of oxygen transport. To quantify tissue oxygenation in vivo, three primary imaging modalities have been applied: positron emission tomography (PET) (8), functional magnetic resonance imaging (fMRI) (9, 10), and diffuse optical tomography (DOT) (11). Although these methods may provide deep functional imaging, they all suffer from millimeter-scale spatial resolutions. Recently, photoacoustic (PA) microscopy was proposed to measure the oxygen metabolic rate at feeding and draining blood vessels (12). However, the assessment is limited to a relatively large region; moreover, the feeding and draining blood vesselsespecially those surrounding a tumor-may be numerous and difficult to identify. Because micrometer-sized RBCs are the basic elements for delivering most of the oxygen to cells and tissues, the need for direct imaging of oxygen release from flowing single RBCs in vivo is imperative. A molecular imaging method based on the measurement of ground-state recovery time has been investigated for hemoglobin sensing (13), but in vivo measurement of oxygen saturation has not been implemented. Dual-wavelength spectrophotometry has been applied to measure oxygen release for decades (14), but transmission-mode imaging limits its application to very thin tissue. Many biomedical problems-for example, tumor or neuroscience studies-require minimally invasive imaging at various anatomical sites. A new method for in vivo imaging of single-RBC oxygen release...

Section: Quantitative Measurement Of Oxygen Release From Single Rbcs Inmentioning

confidence: 77%

Single-cell label-free photoacoustic flowoxigraphy in vivo

Maslov

Proc. Natl. Acad. Sci. U.S.A.

2013

189

153

Proc. Natl. Acad. Sci. U.S.A.

“…In vivo studies showed the effect of A␤ on cerebral blood flow and vessel architecture in a mouse model for AD (11,12). In other models, cerebrovascular regulatory mechanisms, such as endothelium-dependent relaxation and cerebrovascular autoregulation, were altered before amyloid deposition (13)(14)(15)(16). It also has been shown that A␤ in vivo and in vitro inhibits angiogenesis and at high dose can stimulate vascular degeneration (17), further strengthening the link between A␤ and the cerebrovascular abnormalities in AD.…”

mentioning

confidence: 94%

Altered morphology and 3D architecture of brain vasculature in a mouse model for Alzheimer's disease

Meyer

Ulmann-Schuler

Staufenbiel

et al. 2008

231

215

Substantial evidence from epidemiological, pathological, and clinical reports suggests that vascular factors are critical in the pathogenesis of Alzheimer's disease (AD), and changes in blood flow are currently the most reliable indicators of the disease. We previously reported that older APP23 transgenic (tg) mice have significant blood flow alterations correlated with structural modifications of blood vessels. For the present study, our objective was to analyze the age-dependent morphological and architectural changes of the cerebral vasculature of APP23 tg mice. To visualize the 3D arrangement of the entire brain vasculature, we used vascular corrosion casts. Already at young ages, when typically parenchymal amyloid plaques are not yet present, APP23 tg mice had significant alterations, particularly of the microvasculature, often accompanied by small deposits attached to the vessels. In older animals, vasculature abruptly ended at amyloid plaques, resulting in holes. Often, small deposits were sitting near or at the end of truncated vessels. Between such holes, the surrounding vascular array appeared more dense and showed features typical for angiogenesis. We propose that small amyloid aggregates associated with the microvasculature lead to morphological and architectural alterations of the vasculature, resulting in altered local blood flow. The characteristic early onset of vascular alterations suggests that imaging blood flow and/or vasculature architecture could be used as a tool for early diagnosis of the disease and to monitor therapies. amyloid precursor protein ͉ cerebral blood flow ͉ scanning electron microscopy ͉ vascular corrosion casting T he typical clinical picture of Alzheimer's disease (AD) includes a progressive decline of memory function, often accompanied by other clinical signs such as agitation, aggression, sleep disturbances, and social withdrawal. Nonetheless, brain autopsy is needed to positively confirm the diagnosis (1). A high density of neuritic plaques, neurofibrillary tangles, and vascular amyloid (A␤) is a characteristic neuropathological marker of AD (2, 3). Plaques and tangles in the neuropil may affect neuronal function and also contribute to the neuronal damage; however, it is unclear whether their incidence correlates with the clinical signs and symptoms of cognitive impairment characteristic of the disease (4). Evidence suggests that cerebrovascular pathologies, such as structural alterations (5), atherosclerotic lesions (6), and impaired hemodynamic responses (7), are early features of AD (for review, see ref. 8). Reduced blood flow has been reported as one of the most consistent physiological deficits in AD (9, 10); however, it remains unclear whether the reduced cerebral blood flow is a response to neuronal damage or a factor initiating the characteristic neuropathology. In vivo studies showed the effect of A␤ on cerebral blood flow and vessel architecture in a mouse model for AD (11,12). In other models, cerebrovascular regulatory mechanisms, such as endothelium-depende...

J Cereb Blood Flow Metab

“…Available evidence indicates that failure of nitric oxide (NO)-induced, endotheliumdependent vasodilation is causal to vascular aging, 11 which has been linked to age-associated dysfunction in various organs and tissues including brain. 12,13 Endothelial cells and vascular smooth muscle cells dysfunction are prominent in AD [14][15][16] and have a negative impact on CBF. The target-of-rapamycin (TOR) is a major signaling hub that integrates nutrient and growth factor availability with cell metabolism.…”

Section: Introductionmentioning

confidence: 99%

Chronic Rapamycin Restores Brain Vascular Integrity and Function Through NO Synthase Activation and Improves Memory in Symptomatic Mice Modeling Alzheimer’s Disease

Lin¹,

Zheng

Halloran

et al. 2013

180

204

Vascular pathology is a major feature of Alzheimer's disease (AD) and other dementias. We recently showed that chronic administration of the target-of-rapamycin (TOR) inhibitor rapamycin, which extends lifespan and delays aging, halts the progression of AD-like disease in transgenic human (h)APP mice modeling AD when administered before disease onset. Here we demonstrate that chronic reduction of TOR activity by rapamycin treatment started after disease onset restored cerebral blood flow (CBF) and brain vascular density, reduced cerebral amyloid angiopathy and microhemorrhages, decreased amyloid burden, and improved cognitive function in symptomatic hAPP (AD) mice. Like acetylcholine (ACh), a potent vasodilator, acute rapamycin treatment induced the phosphorylation of endothelial nitric oxide (NO) synthase (eNOS) and NO release in brain endothelium. Administration of the NOS inhibitor L-NG-Nitroarginine methyl ester reversed vasodilation as well as the protective effects of rapamycin on CBF and vasculature integrity, indicating that rapamycin preserves vascular density and CBF in AD mouse brains through NOS activation. Taken together, our data suggest that chronic reduction of TOR activity by rapamycin blocked the progression of AD-like cognitive and histopathological deficits by preserving brain vascular integrity and function. Drugs that inhibit the TOR pathway may have promise as a therapy for AD and possibly for vascular dementias.