Abstract
Aging is associated with marked deficiency in circulating IGF-1, which has been shown to contribute to age-related cognitive decline. Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling is thought to play a critical role in the genesis of age-related cognitive impairment. To establish the link between IGF-1 deficiency and cerebromicrovascular impairment, neurovascular coupling mechanisms were studied in a novel mouse model of IGF-1 deficiency (Igf1(f/f) -TBG-Cre-AAV8) and accelerated vascular aging. We found that IGF-1-deficient mice exhibit neurovascular uncoupling and show a deficit in hippocampal-dependent spatial memory test, mimicking the aging phenotype. IGF-1 deficiency significantly impaired cerebromicrovascular endothelial function decreasing NO mediation of neurovascular coupling. IGF-1 deficiency also impaired glutamate-mediated CBF responses, likely due to dysregulation of astrocytic expression of metabotropic glutamate receptors and impairing mediation of CBF responses by eicosanoid gliotransmitters. Collectively, we demonstrate that IGF-1 deficiency promotes cerebromicrovascular dysfunction and neurovascular uncoupling mimicking the aging phenotype, which are likely to contribute to cognitive impairment.
Highlights
Vascular cognitive impairment (VCI) in the aging population poses a serious challenge to developed countries around the world
insulin-like growth factor-1 (IGF-1) deficiency impairs neurovascular coupling and cognitive function Figure 1A shows that mice receiving thyroxine-binding globulin (TBG)-Cre-AAV8 had significantly lower serum IGF-1 levels compared with control mice receiving TBGeGFP-AAV8
Toth et al IGF-1 levels in the brain (Nishijima et al, 2010), we found that mice receiving TBG-Cre-AAV8 had significantly lower tissue IGF-1 levels in the cerebral cortex compared with control mice receiving TBG-eGFP-AAV8 (4.8 Æ 1.7 and 11.4 Æ 2.4 pg mgÀ1 of tissue, respectively; P = 0.03)
Summary
Vascular cognitive impairment (VCI) in the aging population poses a serious challenge to developed countries around the world. With the expansion of the aging population, understanding potentially reversible and preventable vascular contributions to age-related cognitive impairment and dementia is of critical importance. Age-related functional changes in the neurovascular unit that have the potential to impair local regulation of cerebral blood flow are of great importance (Iadecola et al, 2009). The brain contains little energy reserves and, during neuronal activation, there is a need for rapid increases in oxygen and glucose delivery. This is ensured by neurovascular coupling, a vital feedforward control mechanism involving neuronal signaling via neurotransmitters, which adjusts local cerebral blood flow (CBF) to the energy requirements of activated neurons. The specific age-related mechanisms responsible for neurovascular uncoupling are not yet understood
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