Novel Control Mechanism of the Neurovascular Coupling in an Alzheimer’s Disease Model

Abstract

Alzheimer’s disease (AD) is a type of dementia related to age characterized by a progressive and irreversible deterioration of memory and general cognitive abilities. There is a consensus that the production of β‐amyloid protein (Aβ) aggregates correlates with neuronal alterations, triggering the characteristic neurodegeneration process of this disease. Furthermore, disease progression has been closely associated with cerebral vascular alterations, such as reduction in cerebral blood flow observed in patients and animal models of AD.It has been documented that Aβ not only has harmful effects at neuronal level but has also been associated with the alteration of astrocytes normal activity. One of the events modulated by astrocytes at cerebral level is its key role in the neurovascular coupling (NVC), mechanism that ensures nutrients and oxygen supply in proportion to the increase in neuronal activity. The NVC functions controlled by the astrocytes is mediated by vasodilator signals, a process that is dependent of intracellular calcium increase in astrocytes, which is propagated and coordinated by the release of paracrine and autocrine adenosine triphosphate (ATP).There is no consensus about the way of ATP release from astrocytes during NVC, but the description of a new channel, Calcium Homeostasis Modulator 1 (CALHM1) which permit the ATP release in some type of neurons, could be an important element in astrocyte signaling during this mechanism. In previous results we observed that ATP is released through CALHM1 in an astrocyte primary culture model stimulated with glutamate (a stimulus validated in NVC studies) and also was dependent of the CALHM1 activation by S‐nitrosylation through nitric oxide (NO) produced by the astrocytes.Considering that it has been reported that NVC is altered in AD, which contribute to the pathophysiological mechanisms of this disease, our main aim was to evaluate the ATP release in astrocytes primary cultures from a validated murine model of AD: B6C3‐Tg(APPswe,PSEN1dE9)85Dbo/Mmjax.Our results show that ATP release, and CALHM1 relative levels and expression are significatively reduced in astrocytes primary cultures from AD animals in comparing with cultures from wild type animals. These results suggest that calcium signaling could be diminished in the astrocytes in AD and could explicate the relation between the alteration of NVC in AD.Support or Funding InformationUniversidad del Desarrollo Intern Proyect 23.400.163