Aging Exacerbates Obesity-induced Cerebromicrovascular Rarefaction, Neurovascular Uncoupling, and Cognitive Decline in Mice

Abstract

Epidemiological studies show that obesity has deleterious effects on the brain and cognitive function in the elderly population. However, the specific mechanisms through which aging and obesity interact to promote cognitive decline remain unclear. To test the hypothesis that aging exacerbates obesity-induced cerebromicrovascular impairment, we compared young (7 months) and aged (24 months) high-fat diet-fed obese C57BL/6 mice. We found that aging exacerbates the obesity-induced decline in microvascular density both in the hippocampus and in the cortex. The extent of hippocampal microvascular rarefaction and the extent of impairment of hippocampal-dependent cognitive function positively correlate. Aging exacerbates obesity-induced loss of pericyte coverage on cerebral microvessels and alters hippocampal angiogenic gene expression signature, which likely contributes to microvascular rarefaction. Aging also exacerbates obesity-induced oxidative stress and induction of NADPH oxidase and impairs cerebral blood flow responses to whisker stimulation. Collectively, obesity exerts deleterious cerebrovascular effects in aged mice, promoting cerebromicrovascular rarefaction and neurovascular uncoupling. The morphological and functional impairment of the cerebral microvasculature in association with increased blood-brain barrier disruption and neuroinflammation (Tucsek Z, Toth P, Sosnowsk D, et al. Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer's disease. J Gerontol Biol Med Sci. 2013. In press, PMID: 24269929) likely contribute to obesity-induced cognitive decline in aging.

Metabolic syndrome impairs reactivity and wall mechanics of cerebral resistance arteries in obese Zucker rats

“…In combination with microvessel rarefaction, these additional alterations may serve as physiological contributors to significant impairments in cerebral blood flow regulation and perfusion, which have been linked to cognitive decline with aging. Indeed, provocative recent work by Tucsek et al (51), who found that aging in combination with high-fat diet-induced obesity in mice led to an exacerbation of cerebrovascular rarefaction and neurovascular uncoupling previously observed in obese mice and associated cognitive impairments, may provide additional insight. MetS-associated cerebrovascular changes can also lead to elevated risk for ischemic stroke in MetS, as well as worsened stroke outcomes in patients in whom MetS is a preexisting condition, through compromised processes of mass transport and exchange, leading to an increased risk for areas of ischemic damage.…”

Cerebromicrovascular dysfunction predicts cognitive decline and gait abnormalities in a mouse model of whole brain irradiation-induced accelerated brain senescence

“…During periods of intense neuronal activity, there is a requirement for rapid increases in oxygen and glucose delivery. This is ensured by neurovascular coupling (functional hyperemia), a vital mechanism of regulation of CBF that maintains optimal microenvironment of cerebral tissue by adjusting local blood flow to local neuronal activity in a moment-to-moment manner (Attwell et al 2010;Tarantini et al 2015Tarantini et al , 2016Toth et al 2016;Toth et al 2014aToth et al , 2015aToth et al , 2015bToth et al , 2017Tucsek et al 2014). There is increasing evidence that neurovascular dysfunction is causally related to cognitive decline in models of aging (Tarantini et al 2015(Tarantini et al , 2016), yet, the effects of WBI on cerebromicrovascular function have never been investigated.…”

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

“…A wide range of pathophysiological conditions in the elderly was shown to adversely affect the synthesis and/or release of NO and astrocyte-derived vasoactive eicosanoid mediators, promoting neurovascular uncoupling (Girouard and Iadecola 2006;Kazama et al 2004;Tucsek et al 2014). Cardiovascular risk factors, including hypertension (Kazama et al 2003(Kazama et al , 2004, dyslipidemia, smoking, low circulating IGF-1 levels (Toth et al 2015a), and obesity (Tucsek et al 2014b), which are all important risk factors for cognitive decline in elderly patients (Gorelick et al 2011;Iadecola et al 2009;Miralbell et al 2013), also inhibit NO mediation of neurovascular coupling and microvascular dilations by promoting oxidative stress, uncoupling endothelial NO synthase and/or by upregulating asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase. In that regard, it is important that a significant association between serum ADMA level and slower gait speed was demonstrated among elderly individuals (Obayashi et al 2016).…”

“…Functional hyperemia is not only responsible for increased delivery of oxygen and nutrients, it also enables effective washout of noxious substances, ensuring an optimal humoral microenvironment in the cerebral tissue. The cellular mechanisms underlying neurovascular coupling include synthesis of nitric oxide (NO) by activated neurons and/or endothelial of nitric oxide (NO) and astrocytic production of vasodilator eicosanoid metabolites, including epoxygenase-derived epoxyeicosatrienoic acids (EETs) and cyclooxygenase-derived prostaglandins (Chen et al 2014;Ma et al 1996;Peng et al 2002;Stobart et al 2013;Takano et al 2006;Tarantini et al 2015Tarantini et al , 2016Tarantini et al , 2017Toth et al 2014Toth et al , 2015aToth et al , b, 2017Tucsek et al 2014b;Ungvari et al 2017a;Zonta et al 2003). There is strong evidence that aging is associated with impairment of functional hyperemia (termed Bneurovascular uncoupling^) due to dysregulated release and/or increased degradation of NO, EETs, and prostaglandins (Stefanova et al 2013;Tarantini et al 2016;Topcuoglu et al 2009;Toth et al 2014).…”