Article

Thalidomide inhibition of perturbed vasculature and glial-derived tumor necrosis factor-alpha in an animal model of inflamed Alzheimer's disease brain.

Department of Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, The University of British Columbia, 2176 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3.
Neurobiology of Disease (impact factor: 5.4). 03/2008; 29(2):254-66. DOI:10.1016/j.nbd.2007.08.019 pp.254-66
Source: PubMed

ABSTRACT Injection of Abeta(1-42) peptide into rat hippocampus has been found to induce microglial reactivity and perturbed vasculature in an animal model of inflamed Alzheimer's disease (AD) brain. We report the anti-angiogenic and anti-inflammatory compound, thalidomide, to significantly inhibit peptide-induced vascular changes including endothelial cell proliferation (marker rat endothelial cell antigen-1, RECA-1), angiogenic activity (marker laminin) and leakiness of blood-brain barrier (BBB, marker albumin). Thalidomide also blocked microgliosis and astrogliosis with double immunostaining showing considerable regions of association of activated microglia with vascular remodeling and leaky BBB. Thalidomide inhibition of the glial-derived proinflammatory/angiogenic factor TNF-alpha (tumor necrosis factor-alpha) in Abeta(1-42)-injected brain and also in vitro from peptide-activated human microglia could underly the changes in vascular processes. Thalidomide treatment in vivo was also associated with a significant reduction in hippocampal neuronal loss. Our findings suggest altered cerebral vasculature as an integral component of inflammatory responses with thalidomide an effective inhibitor of gliosis, vascular changes and TNF-alpha leading to neuroprotection in an animal model of inflamed AD brain.

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    Article: Comparison of Vascular Perturbations in an Aβ-Injected Animal Model and in AD Brain.
    Nattinee Jantaratnotai, Jae K Ryu, Claudia Schwab, Patrick L McGeer, James G McLarnon
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    ABSTRACT: The validity of amyloid-β peptide (Aβ(1-42)) intrahippocampal injection, as an animal model of Alzheimer's disease (AD), has previously been considered in terms of inflammatory reactivity and neuronal damage. In this work, we have extended the testing of the animal model to vasculature by comparison of selected properties of microvessels in vivo with those in human AD brain tissue. The injection of Aβ(1-42), relative to control PBS (phosphate buffered saline), increased the mean number of microvessels and diminished the mean length of microvessels in the molecular layer of dentate gyrus. The animal model showed Aβ(1-42), but not PBS, injection was associated with abnormalities in morphology of microvessels which were characterized as looping, fragmented, knob-like, uneven, and constricted. In particular, numbers of constricted microvessels, defined as vessels with diameters less than 3 μm, were considerably enhanced for Aβ(1-42), compared to PBS, injection. In comparison, human AD brain demonstrated an elevated number of microvessels with a diminished mean length relative to nondemented (ND) brain. Additionally, microvessel perturbations in AD brain showed a similar pattern of morphological abnormalities to those observed in Aβ(1-42)-injected rat hippocampus. Constricted microvessels were a prominent feature of AD brain but were rarely observed in ND tissue. These results provide the first evidence that a peptide-injection animal model exhibits a commonality in perturbations of microvessels compared with those evident in AD brain.
    International journal of Alzheimer's disease. 01/2011; 2011:918280.
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Keywords

Abeta(1-42)-injected brain
 
animal model
 
double immunostaining
 
effective inhibitor
 
endothelial cell proliferation
 
glial-derived proinflammatory/angiogenic factor TNF-alpha
 
induce microglial reactivity
 
inflamed AD brain
 
inflamed Alzheimer's disease
 
inflammatory responses
 
leaky BBB
 
marker laminin
 
marker rat endothelial cell antigen-1
 
microgliosis
 
peptide-activated human microglia
 
peptide-induced vascular changes
 
Thalidomide treatment
 
tumor necrosis factor-alpha
 
vascular changes
 
vascular processes
 

Jae K Ryu