Analysis of Cerebral Small Vessel Changes in AD Model Mice (original) (raw)
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The Journal of neuroscience : the official journal of the Society for Neuroscience, 2003
Neuropathological changes associated with Alzheimer's disease (AD) such as amyloidplaques, cerebral amyloid angiopathy, and related pathologies are reproduced in APP23 transgenic mice overexpressing amyloid precursor protein (APP) with the Swedish mutation. Magnetic resonance angiography (MRA) was applied to probe, in vivo, the cerebral arterial hemodynamics of these mice. Flow voids were detected at the internal carotid artery of 11-month-old APP23 mice. At the age of 20 months, additional flow disturbances were observed in large arteries at the circle of Willis. Vascular corrosion casts obtained from the same mice revealed that vessel elimination, deformation, or both had taken place at the sites where flow voids were detected by MRA. The detailed three-dimensional architecture of the vasculature visible in the casts assisted the identification of smaller vessels most likely formed as substitution or anastomosis within the circle of Willis. Angiograms and corrosion casts from ...
Age-Dependent Neurovascular Dysfunction and Damage in a Mouse Model of Cerebral Amyloid Angiopathy
Stroke, 2014
Background and Purpose— Accumulation of amyloid-β in cerebral blood vessels occurs in familial and sporadic forms of cerebral amyloid angiopathy and is a prominent feature of Alzheimer disease. However, the functional correlates of the vascular pathology induced by cerebral amyloid angiopathy and the mechanisms involved have not been fully established. Methods— We used male transgenic mice expressing the Swedish, Iowa, and Dutch mutations of the amyloid precursor protein (Tg-SwDI) to examine the effect of cerebral amyloid angiopathy on cerebrovascular structure and function. Somatosensory cortex cerebral blood flow was monitored by laser-Doppler flowmetry in anesthetized Tg-SwDI mice and wild-type littermates equipped with a cranial window. Results— Tg-SwDI mice exhibited reductions in cerebral blood flow responses to whisker stimulation, endothelium-dependent vasodilators, or hypercapnia at 3 months when compared with wild-type mice, whereas the response to adenosine was not attenu...
Progressive Vascular Abnormalities in the Aging 3xTg-AD Mouse Model of Alzheimer's Disease
2022
Vascular dysfunction and structural abnormalities in Alzheimer’s disease (AD) are known to contribute to the progression of the pathology, and studies have tended to ignore the role of the vasculature in AD progression. We utilized the 3xTg-AD mouse model of AD to examine individual cerebral vessels and the cortical vascular network across the lifespan. Our vessel painting approach was used to label the entire cortical vasculature, followed by epifluorescence microscopy. The middle cerebral artery (MCA) tree was assessed with confocal microscopy, and a new method was developed to assess branching patterns as a measure of aging-related changes. We found that vascular remodeling was profoundly altered at 4–6 months of age, when the 3xTg-AD mouse is known to transition to cognitive impairment and A deposition in both sexes. Analysis of vascular features (density, junctions, length) of the MCA territory highlighted sex-dependent differences across the 3xTg-AD mouse lifespan, with no alterations in branching patterns. Our current cerebrovascular angioarchitectural analyses demonstrate progressive alterations in individual cortical vessels, as well as in the vascular network of the cortex. These new findings advance our understanding of brain anatomy and physiology in the 3xTg-AD mouse, while potentially identifying unique diagnostic signatures of AD progression.
Cerebrovascular Pathology and Amyloid Plaque Formation in Alzheimer’s Disease
Current Alzheimer Research, 2014
Accumulation, aggregation and deposition of the amyloid-(A) peptides in the brain are widely accepted as the central events in the pathogenesis of Alzheimer's disease (AD). Any factor that is capable of causing these events is potentially a risk factor for AD. In the last decade, evidence has accumulated to support the association between cerebral vascular diseases (CVD) and AD. CVD is known to induce amyloid deposition and affects the age of onset for sporadic AD; whereas, amyloid deposition has been shown to cause cerebrovascular degeneration. In this review, we propose a positive feedback loop between CVD and amyloid deposition. The disease cycle could be triggered by aging and/or other environmental factor-associated CVD, as in late-onset sporadic AD patients, or by over production of A , as in the familial AD patients and amyloid precursor protein transgenic animals.
Reduction of the cerebrovascular volume in a transgenic mouse model of Alzheimer's disease
Neuropharmacology, 2009
Blood-brain barrier Brain perfusion Collagen a b s t r a c t Combined evidence from neuroimaging and neuropathological studies shows that signs of vascular pathology and brain hypoperfusion develop early in Alzheimer's disease (AD). To investigate the functional implication of these abnormalities, we have studied the cerebrovascular volume and selected markers of blood-brain barrier (BBB) integrity in 11-month-old 3ÂTg-AD mice, using the in situ brain perfusion technique. The cerebrovascular volume of distribution of two vascular space markers, [ 3 H]-inulin and [ 14 C]-sucrose, was significantly lower (À26% and À27%, respectively; p < 0.01) in the brain of 3ÂTg-AD mice compared to non-transgenic littermates. The vascular volume reduction was significant in the hippocampus (p < 0.01), but not in the frontal cortex and cerebellum. However, the brain transport coefficient (Clup) of [ 14 C]-D-glucose (1 mM) and [ 3 H]-diazepam was similar between 3ÂTg-AD mice and controls, suggesting no difference in the functional integrity of the BBB. We also report a 32% increase (p < 0.001) in the thickness of basement membranes surrounding cortical microvessels along with a 20% increase (p < 0.05) of brain collagen content in 3ÂTg-AD mice compared to controls. The present data indicate that the cerebrovascular space is reduced in a mouse model of Ab and tau accumulation, an observation consistent with the presence of cerebrovascular pathology in AD.
Alzheimer's Disease, Cerebrovascular Disease, and the β-amyloid Cascade
Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 2012
Alzheimer's disease (AD), considered the commonest neurodegenerative cause of dementia, is associated with hallmark pathologies including extracellular amyloid-β protein (Aβ) deposition in extracellular senile plaques and vessels, and intraneuronal tau deposition as neurofibrillary tangles. Although AD is usually categorized as neurodegeneration distinct from cerebrovascular disease (CVD), studies have shown strong links between AD and CVD. There is evidence that vascular risk factors and CVD may accelerate Aβ 40-42 production/ aggregation/deposition and contribute to the pathology and symptomatology of AD. Aβ deposited along vessels also causes cerebral amyloid angiopathy. Amyloid imaging allowsin vivodetection of AD pathology, opening the way for prevention and early treatment, if disease-modifying therapies in the pipeline show safety and efficacy. In this review, we review the role of vascular factors and Aβ, underlining that vascular risk factor management may be important ...
Journal of Alzheimer's Disease, 2002
Freshly prepared soluble amyloid (Aβ) peptide has been reported to have vascular actions both in vitro and in vivo. This study was designed to examine the in vivo microvascular effects of Aβ in two skin microvascular model systems that might reflect possible short and long-term vascular effects of this peptide. Short-term vascular effects were examined using freshly prepared soluble Aβ(1-40) peptide superfused over naive rat skin microvasculature for 15 min. Peripheral microvascular functional changes in 9-months-old transgenic (Tg) mice overexpressing soluble Aβ in the brain, peripheral circulation and other tissues, were also examined. Microvascular responses were monitored using laser Doppler flowmetry from the base of a blister raised on the hind footpad of the animals. Endothelial-dependent and independent vasodilatation responses (VD) were examined using acetylcholine (ACh) and sodium nitroprusside (SNP) respectively. The exposure of naïve rat skin microvasculature to Aβ(1-40) resulted in an immediate vasoconstriction (VC) that prevented ACh but not SNP from inducing a subsequent VD response. The vascular effects of Aβ(1-40) were reversed by antioxidants (superoxide dismutase and catalase) and an endothelin A (ETA) receptor antagonist (BQ-123). Tg mice overexpressing soluble Aβ and C100 showed significant reductions in both endothelial-dependent and endothelial-independent VD that were also reversed by antioxidants and BQ-123. In conclusion, this study provided evidence to support the notion of peripheral vascular effects of Aβ in vivo and present novel evidence for alterations in endothelial and smooth muscle cell function in peripheral skin microvasculature in Tg mice overexpressing Aβ and C100. We suggest that skin microvasculature is a useful model to examine the mechanisms underlying the vascular actions of the Aβ protein.
Neurobiology of Aging, 2021
Vascular perturbations and cerebral hypometabolism are emerging as important components of Alzheimer's disease (AD). While various in vivo imaging modalities have been designed to detect changes of cerebral perfusion and metabolism in AD patients and animal models, study results were often heterogenous with respect to imaging techniques and animal models. We therefore evaluated cerebral perfusion and glucose metabolism of two popular transgenic AD mouse strains, TgCRND8 and 5xFAD, at 7 and 12 months-of-age under identical conditions and analyzed possible molecular mechanisms underlying heterogeneous cerebrovascular phenotypes. Results revealed disparate findings in these two strains, displaying important aspects of AD progression. TgCRND8 mice showed significantly decreased cerebral blood flow and glucose metabolism *