Compromised Hemodynamic Response in Amyloid Precursor Protein Transgenic Mice

Mueggler, Thomas; Stürchler-Pierrat, Christine; Baumann, Diana; Rausch, Martin; Staufenbiel, Matthias; Rudin, Markus

doi:10.1523/jneurosci.22-16-07218.2002

Cited by 96 publications

(80 citation statements)

References 38 publications

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“…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-dependent relaxation and cerebrovascular autoregulation, were altered before amyloid deposition (13-16).…”

mentioning

confidence: 99%

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

Meyer

Ulmann-Schuler

Staufenbiel

et al. 2008

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

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232

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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...

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mentioning

confidence: 99%

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

Meyer

Ulmann-Schuler

Staufenbiel

et al. 2008

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

Self Cite

232

215

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“…Ischemia commonly results in secondary injury, and can have significant acute effects in stroke (2,3) and traumatic brain injury (TBI) (4,5). Chronic effects of ischemia can also be observed in Alzheimer's disease (6,7). Similarly, hemorrhage (8) and brain tumors (9) can alter CBF, leading to deleterious neurological effects.…”

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confidence: 99%

Murine orthostatic response during prolonged vertical studies: Effect on cerebral blood flow measured by arterial spin‐labeled MRI

Foley

Hitchens

Kochanek

et al. 2005

Magnetic Resonance in Med

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“…As described above, Mueggler and co-workers (38,37) have reported reduced CBV response to pharmacological stimulation with bicuculline in aged APP23 mice, a model for human Alzheimer's disease. In an interesting approach, Small et al (141) analyzed contrast differences on T 2 Ã -weighted images, which vary with resting oxygen concentrations.…”

Section: Cognitive Studies With Fmri In Small Animalsmentioning

confidence: 80%

“…In the past, this was achieved with invasive blood sampling for repetitive blood gas analysis throughout the fMRI experiment. The drawbacks of limited blood sample availability and blindness to pCO 2 fluctuations between sampling periods have now been eliminated by using the continuous and non-invasive recording of transcutaneous pCO 2 (23,30,37,38) or end-tidal pCO 2 values with MRI-compatible capnometry in intubated animals (39)(40)(41) or simply with an inhalation mask (42) for which linear correlations with arterial pCO 2 have been established (43).…”

Section: Physiological Monitoringmentioning

confidence: 99%

“…In particular, plaque formation with increasing age has been described. Using CBV recording under somatosensory stimulation, Mueggler et al (37,38) noted an increasingly pronounced deterioration of the haemodynamic response with increasing age of the APP23 mice. This effect -relative to control or littermates -became most expressed with increasing stimulation amplitude.…”

Section: Cognitive Studies With Fmri In Small Animalsmentioning

confidence: 99%

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Current status of functional MRI on small animals: application to physiology, pathophysiology, and cognition

et al. 2007

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This review aims to make the reader aware of the potential of functional MRI (fMRI) in brain activation studies in small animal models. As small animals generally require anaesthesia for immobilization during MRI protocols, this is believed to be a serious limitation to the type of question that can be addressed with fMRI. We intend to introduce a fresh view with an in-depth overview of the surprising number of fMRI applications in a wide range of important research domains in neuroscience. These include the pathophysiology of brain functioning, the basic science of activity, and functional connectivity of different sensory circuits, including sensory brain mapping, the challenges when studying the hypothalamus as the major control centre in the central nervous system, and the limbic system as neural substrate for emotions and reward. Finally the contribution of small animal fMRI research to cognitive neuroscience is outlined. This review avoids focusing exclusively on traditional small laboratory animals such as rodents, but rather aims to broaden the scope by introducing alternative lissencephalic animal models such as songbirds and fish, as these are not yet well recognized as neuroimaging study subjects. These models are well established in many other neuroscience disciplines, and this review will show that their investigation with in vivo imaging tools will open new doors to cognitive neuroscience and the study of the autonomous nervous system in experimental animals.

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Compromised Hemodynamic Response in Amyloid Precursor Protein Transgenic Mice

Cited by 96 publications

References 38 publications

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

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

Murine orthostatic response during prolonged vertical studies: Effect on cerebral blood flow measured by arterial spin‐labeled MRI

Current status of functional MRI on small animals: application to physiology, pathophysiology, and cognition

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