2010
DOI: 10.1038/jcbfm.2010.78
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Intact Memory in TGF-β1 Transgenic Mice Featuring Chronic Cerebrovascular Deficit: Recovery with Pioglitazone

Abstract: The roles of chronic brain hypoperfusion and transforming growth factor-beta 1 (TGF-b1) in Alzheimer's disease (AD) are unresolved. We investigated the interplay between TGF-b1, cerebrovascular function, and cognition using transgenic TGF mice featuring astrocytic TGF-b1 overexpression. We further assessed the impact of short, late therapy in elderly animals with the antioxidant N-acetyl-L-cysteine (NAC) or the peroxisome proliferator-activated receptor-c agonist pioglitazone. The latter was also administered … Show more

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Cited by 36 publications
(90 citation statements)
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“…In line with this idea, TGF mice feature increased capillary basement membrane thickness and endothelial cell degeneration (Wyss-Coray et al, 2000), resting hypoperfusion throughout the brain (Gaertner et al, 2005), impaired neurovascular coupling during whisker stimulation (Nicolakakis et al, 2011) (Table 1), and reduced basal CGU (Galea et al, 2006). The hemodynamic and metabolic changes may be related to glial activation in the TGF mouse brain (Wyss-Coray et al, 1995;Lacombe et al, 2004;Nicolakakis et al, 2011), but are mainly believed to have a vascular etiology, in view of the unaltered neuronal indices in old transgenic animals relative to age-matched WT littermates (18 to 22 months old). At this age, TGF mice featured preserved cortical cholinergic innervation, intact CGU increase during whisker stimulation, as measured by 18 F-fluorodeoxyglucose-positron emission tomography, and preserved spatial memory in the Morris water maze (Nicolakakis et al, 2011).…”
Section: Transgenic Mouse Modelsmentioning
confidence: 75%
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“…In line with this idea, TGF mice feature increased capillary basement membrane thickness and endothelial cell degeneration (Wyss-Coray et al, 2000), resting hypoperfusion throughout the brain (Gaertner et al, 2005), impaired neurovascular coupling during whisker stimulation (Nicolakakis et al, 2011) (Table 1), and reduced basal CGU (Galea et al, 2006). The hemodynamic and metabolic changes may be related to glial activation in the TGF mouse brain (Wyss-Coray et al, 1995;Lacombe et al, 2004;Nicolakakis et al, 2011), but are mainly believed to have a vascular etiology, in view of the unaltered neuronal indices in old transgenic animals relative to age-matched WT littermates (18 to 22 months old). At this age, TGF mice featured preserved cortical cholinergic innervation, intact CGU increase during whisker stimulation, as measured by 18 F-fluorodeoxyglucose-positron emission tomography, and preserved spatial memory in the Morris water maze (Nicolakakis et al, 2011).…”
Section: Transgenic Mouse Modelsmentioning
confidence: 75%
“…The latter is thickened (Mancardi et al, 1980;Vinters et al, 1994) as a result of accumulation of collagen IV (Kalaria and Pax, 1995) and that of other matrix proteins, a phenomenon associated with high levels of TGF-b1 in AD vessels (Grammas and Ovase, 2002). Transforming growth factor mice feature increased expression of vascular growth factors (vascular endothelial growth factor; connective tissue growth factor), and accumulation of perlecan, fibronectin, laminin, and collagen in the vascular basement membrane that contribute to its thickening (WyssCoray et al, 1995(WyssCoray et al, , 2000Tong et al, 2005;Nicolakakis et al, 2011). Not only do some of these proteins have the capacity to bind Ab, and potentially initiate CAA (Castillo et al, 1997), but also their accumulation in capillary basement membranes could hinder substrate delivery and waste elimination across the blood-brain barrier.…”
Section: Transgenic Mouse Modelsmentioning
confidence: 99%
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“…Candidate pharmacologic therapies targeted at improving cerebrovascular function include PDE‐5 inhibitors, 3‐hydroxy‐3‐methylglutaryl coenzyme‐A (HMG‐CoA) reductase inhibitors, high‐density lipoprotein (HDL) mimetics, and peroxisome proliferator‐activated receptor‐ gamma (PPAR‐ γ ) agonists, among others 27, 39. Non‐pharmacologic therapies targeted at improving vascular function include aerobic exercise, dietary interventions, and nutraceuticals such as omega‐3 fatty acids 28…”
Section: Discussionmentioning
confidence: 99%
“…Multiple pharmacologic and non‐pharmacologic therapies with well‐established medical indications promote blood vessel repair and may prove beneficial as therapy for TCVI in appropriately selected patients 27, 28, 29, 30. Sildenafil is a potent and specific inhibitor of cGMP‐specific phosphodiesterase (Phosphodiesterase 5, PDE5), thereby prolonging the elevation of cGMP resulting from the induction of guanylyl cyclase by nitric oxide (NO).…”
Section: Introductionmentioning
confidence: 99%