Cerebrovascular alterations in the aging brain and AD: relations to ischemic injury.

The Neurovascular Research Unit (NRU, Dept. Pharmacology, Medical School, Univ. Complutense; Dr. Moro’s group) investigates how the cerebrovascular unit (neurons, glia and vascular cells) changes during aging and the effects of these changes on the response to cerebrovascular damage. Modifications at both central and peripheral levels are being studied. We are also interested in the effect of obesity as a cause of cerebrovascular dysfunction.  For that, we are identifying the alterations in the response of the aged brain to inflammation, angiogenesis and neurogenesis in ischemic conditions, the impact of aging on the integrity of the blood-brain barrier and the modifications induced by age on relevant signalling pathways. 

Specifically, the group investigates the effect of aging and on the extent of the damage after different ischemic insults, and on the resolution of the subsequent inflammatory response, that may affect on a later step the recovery of the damaged tissue. Transcription factors/nuclear receptors (PPARgamma, LXR, AhR, Oct2, Gcf2/Lrrfip1, HMGIY, CREB, etc.), membrane receptors (CBs, glutamate receptors, …), microRNAs (miR-347, …), epigenetic mechanisms (Sirt1-related; collaboration with Dr. Sanfeliu) and target genes involved are being identified, with special emphasis on the activation of pro- and anti-inflammatory phenotypes of both resident and circulating phagocytes (collaboration with Dr. De La Rosa on retina functional decline). We are also characterising age-induced alterations of the blood-brain barrier and of the extracellular matrix that may underlie abnormal clearance of Abeta and other substrates (collaboration with Dr. Dotti and Dr. Ledesma), as well as the process of haemorrhagic transformation of the ischemic stroke, with a particular focus on infiltrated blood-borne cells. An important effort is being devoted to the study of the response of different stem and progenitor cells (hematopoietic and neural) and other cellular precursors to the ischemic injury in the aged brain (some signalling pathways involved will be studied in collaboration with Dr. Nebreda). In addition, how obesity may be involved in cerebrovascular dysfunction is studied using young and aged obese/insulin resistant (JCR-LA corpulent) rats. The NRU also explores the effect of aging on lipid homeostasis and its impact on the response to cerebrovascular stress, in relation with the expression of membrane transporters associated to lipid rafts (collaboration with Dr. Dotti’s group).