Angiotensin II type 1 receptor blocker losartan prevents and rescues cerebrovascular, neuropathological and cognitive deficits in an Alzheimer’s disease model

Ongali, Brice; Nicolakakis, Nektaria; Tong, Xin‐Kang; Aboulkassim, Tahar; Papadopoulos, Panayiota; Rosa‐Neto, Pedro; Lecrux, Clotilde; Imboden, Hans; Hamel, Édith

doi:10.1016/j.nbd.2014.04.018

Cited by 127 publications

(127 citation statements)

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“…The results of this study provide experimental evidence in support of the concept that neurovascular uncoupling per se promotes subclinical gait abnormalities. Our findings, taken together with the results of earlier studies (Hamel et al 2016;Ongali et al 2014;Papadopoulos et al 2017;Tong et al 2012), point to potential benefits of pharmacological and nonpharmacological (e.g., dietary (Sorond et al 2013)) interventions targeting neurovascular coupling pathways and promoting microvascular health to preserve gait function in aging.…”

Section: Discussionsupporting

confidence: 76%

Pharmacologically induced impairment of neurovascular coupling responses alters gait coordination in mice

et al. 2017

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There is correlative evidence that impaired cerebral blood flow (CBF) regulation, in addition to promoting cognitive impairment, is also associated with alterations in gait and development of falls in elderly people. CBF is adjusted to neuronal activity via neurovascular coupling (NVC) and this mechanism becomes progressively impaired with age. To establish a direct cause-andeffect relationship between impaired NVC and gait abnormalities, we induced neurovascular uncoupling pharmacologically in young C57BL/6 mice by inhibiting the synthesis of vasodilator mediators involved in NVC. Treatment of mice with the epoxygenase inhibitor MSPPOH, the NO synthase inhibitor L-NAME, and the COX inhibitor indomethacin significantly decreased NVC mimicking the aging phenotype. Pharmacologically induced neurovascular uncoupling significantly decreased the dynamic gait parameter duty cycle, altered footfall patterns, and significantly increased phase dispersion, indicating impaired interlimb coordination. Impaired NVC also tended to increase gait variability. Thus, selective experimental disruption of NVC causes subclinical gait abnormalities, supporting the importance of CBF in both cognitive function and gait regulation.

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Section: Discussionsupporting

confidence: 76%

Pharmacologically induced impairment of neurovascular coupling responses alters gait coordination in mice

et al. 2017

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“…Vascular dysregulation in AD includes deficiencies in cerebrovascular reactivity, CBF, and neurovascular coupling responses (Girouard and Iadecola 2006;Gorelick et al 2011;Hock et al 1997;Rombouts et al 2000). Neurovascular coupling dysfunction of AD has been replicated in experimental studies showing that in mouse models of AD, neurovascular coupling is also significantly impaired (Rancillac et al 2012;Shin et al 2007;Royea et al 2017), at least in part, due to enhanced oxidative stress (Nicolakakis et al 2008;Park et al 2008;Park et al 2005) arising from mitochondrial dysfunction and inflammation (Lacoste et al 2013;Ongali et al 2014). Importantly, recent evidence suggests that pharmacological interventions that rescue functional hyperemia result in improved cognitive function in mice with AD pathologies (Tong et al 2012;Nicolakakis et al 2008).…”

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confidence: 92%

“…Importantly, recent evidence suggests that pharmacological interventions that rescue functional hyperemia result in improved cognitive function in mice with AD pathologies (Tong et al 2012;Nicolakakis et al 2008). Due to the increased realization that understanding of the mechanisms underlying neurovascular dysfunction is critical for developing novel therapeutic interventions to prevent or treat AD, there is an increasing need in many laboratories to adapt methodologies to investigate neurovascular coupling responses in mouse models of aging and AD (Lacoste et al 2013;Ongali et al 2014;Papadopoulos et al 2016;Hamel et al 2016;Nicolakakis and Hamel 2011;Papadopoulos et al 2014). In this paper, published as part of the BMethods for Geroscience^series in the BTranslational Geroscience^initiative of the journal (Callisaya et al 2017;Kane et al 2017;Kim et al 2017;Liu et al 2017;Meschiari et al 2017;Perrott et al 2017;Shobin et al 2017;Ashpole et al 2017;Bennis et al 2017;Deepa et al 2017;Grimmig et al 2017;Hancock et al 2017;Konopka et al 2017;Podlutsky et al 2017;Sierra and Kohanski 2017;Tenk et al 2017;Ungvari et al 2017a;Ungvari et al 2017b;Urfer et al 2017a;Urfer et al 2017b), we present an easy-to-adapt protocol for assessment of neurovascular coupling responses in mice in both geroscience and AD research.…”

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confidence: 99%

Demonstration of impaired neurovascular coupling responses in TG2576 mouse model of Alzheimer’s disease using functional laser speckle contrast imaging

et al. 2017

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Increasing evidence from epidemiological, clinical, and experimental studies indicates that cerebromicrovascular dysfunction and microcirculatory damage play critical roles in the pathogenesis of many types of dementia in the elderly, including both vascular cognitive impairment (VCI) and Alzheimer's disease. Vascular contributions to cognitive impairment and dementia (VCID) include impairment of neurovascular coupling responses/functional hyperemia (Bneurovascular uncoupling^). Due to the growing interest in understanding and pharmacologically targeting pathophysiological mechanisms of VCID, there is an increasing need for sensitive, easy-to-establish methods to assess neurovascular coupling responses. Laser speckle contrast imaging (LSCI) is a technique that allows rapid and minimally invasive visualization of changes in regional cerebromicrovascular blood perfusion. This type of imaging technique combines high resolution and speed to provide great spatiotemporal accuracy to measure moment-to-moment changes in cerebral blood flow induced by neuronal activation. Here, we provide detailed protocols for the successful measurement in neurovascular coupling responses in anesthetized mice equipped with a thinned-skull cranial window using LSCI. This method can be used to evaluate the effects of anti-aging or anti-AD treatments on cerebromicrovascular health.Keywords Neurovascular coupling . Functional hyperemia . Laser speckle contrast imaging . Laser speckle contrast analysis . LASCA . Laser speckle imaging . LSI Neurovascular uncoupling in aging and Alzheimer's diseaseIt is well recognized that the brain consumes more energy than any other human organ. Over 20% of the body's total energy requirements are spent to fuel the brain, which in turn only accounts for 2% of the total body mass. Moment-to-moment regulation of cerebral blood flow (CBF) is crucial since inadequate supply of glucose and oxygen to an active region of the brain GeroScience (2017) 39:465-473

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“…The transforming growth factor beta-1 (TGF-β1), a downstream effector of the RAS system, is a key cytokine regulator (Bye et al 2001) that is increased in the brain and cerebral vessels of AD and VCID patients (Grammas and 19 month-old WT and TGF mice treated for 12 weeks with the same medications, no effect was detected on arterial blood pressure, heart rate, respiratory rate, blood gases (pO2, pCO2), and blood pH measured according to Tong and colleagues (Tong et al 2012) (Supplementary Table 1). Similar doses of losartan and enalapril were previously shown to be equipotent for lowering blood-pressure (Sasaki et al 2004), and to exert benefits on cerebrovascular or cognitive deficits in a transgenic AD mouse model (Ongali et al 2014). Mice were housed under a 12 h light-dark cycle in a room with controlled temperature (25°C) and humidity (50%); food and water were available ad libitum.…”

Section: Introductionmentioning

confidence: 76%

Transforming growth factor-β1 induces cerebrovascular dysfunction and astrogliosis through angiotensin II type 1 receptor-mediated signaling pathways

Ongali

Nicolakakis

Tong

et al. 2018

Can. J. Physiol. Pharmacol.

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Transgenic mice constitutively overexpressing the cytokine transforming growth factor-β1 (TGF-β1) (TGF mice) display cerebrovascular alterations as seen in Alzheimer’s disease (AD) and vascular cognitive impairment and dementia (VCID), but no or only subtle cognitive deficits. TGF-β1 may exert part of its deleterious effects through interactions with angiotensin II (AngII) type 1 receptor (AT1R) signaling pathways. We test such interactions in the brain and cerebral vessels of TGF mice by measuring cerebrovascular reactivity, levels of protein markers of vascular fibrosis, nitric oxide synthase activity, astrogliosis, and mnemonic performance in mice treated (6 months) with the AT1R blocker losartan (10 mg/kg per day) or the angiotensin converting enzyme inhibitor enalapril (3 mg/kg per day). Both treatments restored the severely impaired cerebrovascular reactivity to acetylcholine, calcitonin gene-related peptide, endothelin-1, and the baseline availability of nitric oxide in aged TGF mice. Losartan, but not enalapril, significantly reduced astrogliosis and cerebrovascular levels of profibrotic protein connective tissue growth factor while raising levels of antifibrotic enzyme matrix metallopeptidase-9. Memory was unaffected by aging and treatments. The results suggest a pivotal role for AngII in TGF-β1-induced cerebrovascular dysfunction and neuroinflammation through AT1R-mediated mechanisms. Further, they suggest that AngII blockers could be appropriate against vasculopathies and astrogliosis associated with AD and VCID.

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Angiotensin II type 1 receptor blocker losartan prevents and rescues cerebrovascular, neuropathological and cognitive deficits in an Alzheimer’s disease model

Cited by 127 publications

References 59 publications

Pharmacologically induced impairment of neurovascular coupling responses alters gait coordination in mice

Pharmacologically induced impairment of neurovascular coupling responses alters gait coordination in mice

Demonstration of impaired neurovascular coupling responses in TG2576 mouse model of Alzheimer’s disease using functional laser speckle contrast imaging

Transforming growth factor-β1 induces cerebrovascular dysfunction and astrogliosis through angiotensin II type 1 receptor-mediated signaling pathways

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