The facilitating role of cerebrovascular disease in cognitive failure induced by diabetes
Dr. Edith Hamel, McGill University
Ernesto Schiffrin, Lady Davis Institute
Hélène Girouard, Université de Montréal
We propose to use a transgenic mouse model of cerebrovascular pathology, namely transforming growth factor-β1(TGF) mice originally developed to recapitulate the cerebrovascular pathology of Alzheimer’s disease (AD). Yet, while they display several features of the cerebrovascular pathology seen in vascular dementia (VD) and in AD, they have no amyloid-β pathology and no cognitive deficits even in old age, which make them an unsuitable model of AD.
Recently, we challenged TGF mice with a risk factor commonly associated with VD or AD (hypercholesterolemia), and they developed worsening of the cerebrovascular pathology and cognitive decline in an age-dependent manner while wild-type littermate controls showed no such predisposition. Hence, we suggest that TGF mice, due to their cerebrovascular pathology which by itself is not severe enough to trigger cognitive failure makes the mice more prone to develop cognitive deficits when combined to another risk factor. We trust that this observation is highly relevant to the human condition of vascular cognitive impairment (VCI) and, possibly, with increasing age, to VD due to the more widespread and severe vascular pathology. We thus propose to challenge TGF mice with diabetes (DB), and test if DB will trigger cognitive failure, worsen the vascular pathology, if age and gender influence this susceptibility and finally, if the resulting deficits can be normalized by therapy.
We trust that the proposal, which extends from our ongoing studies with hypercholesterolemia and hypertension, will establish that a dysfunctional cerebral circulation induced by DB increases predisposition to cognitive failure when combined to known risk factors for VCI and VD. We believe that new information on vascular and neuronal biomarkers that could become valid targets for therapeutic intervention will be generated. The project fits with the Research theme # 2, priorities 3 and 4.
Circulating MicroRNAs as Functional Biomarkers of Vascular Cognitive Impairment
Dr. Mansoor Husain, Toronto General Research Institute
Jason Fish, Toronto General Research Institute
Our proposal addresses TWO PRIORITIES of the Vascular Network: “Development of robust preclinical models of VCI” and “Development of novel biomarkers for detection/prognostication of VCI”. Epidemiology has revealed that cardiovascular diseases, such as diabetes, are associated with VCI. While enhanced cerebrovascular inflammation in diabetics likely plays a contributing role in the development of VCI, this is difficult to assess in a non-invasive fashion. Identifying patients at risk for VCI may enable interventions to slow disease progression. Sadly, circulating markers that are specific for VCI are not available. Our proposal will utilize a mouse model of type-2 diabetes (T2D), which develops VCI pathology that is similar in many respects to human disease. We will assess circulating microvesicles (MVs) and their microRNA (miR) contents during the course of VCI progression in this model to identify novel markers of the early stages of the disease. We recently obtained intriguing data that demonstrate that circulating MVs are anti-inflammatory in healthy mice, which is mediated in part by the transfer of anti-inflammatory miRs to recipient cells (e.g. endothelial cells and monocytes). We have developed a robust assay to assess the function of MVs that can be utilized to determine whether the anti-inflammatory function of MVs is compromised in mouse models of VCI. Importantly, we have found that MVs isolated from mice with advanced cardiovascular disease lose their anti-inflammatory properties, but the relationship between this observation and development of VCI is not known. Our project will combine the expertise of the Husain lab in murine diabetic disease models with the expertise of the Fish lab in the analysis of MVs and miR function. The proposed studies will allow us to explore whether circulating MVs/miRs might be useful functional markers of VCI.
Mechanisms of cerebral vascular pathology and potential reversal in a new animal model of age-related cognitive impairment.
Dr. Brian Bennett, Queen’s University
with Dr. Duncan Stewart, Ottawa Hospital Research Institute
Dr. David Andrew, Queen’s University
Dr. Greg Thatcher, University of Illinois at Chicago
Our laboratory has developed a novel oxidative stress-based mouse model of age-related cognitive impairment based on gene deletion of aldehyde dehydrogenase 2 (ALDH2). ALDH2 is important for the detoxification of endogenous aldehydes such as 4-hydroxynonenal (HNE), a lipid peroxidation product formed during periods of oxidative stress that can form DNA and protein adducts, altering cell function. Our working hypothesis is that the absence of ALDH2 creates conditions that promote HNE-induced oxidative damage, and subsequent pathological changes. These mice exhibit graded, age-related memory deficits beginning at 3 months and peaking at 7 months, and exhibit a number of vascular pathologies that are observed in other animal models of vascular cognitive impairment (VCI), such as blood-brain barrier alterations, microbleeds, altered vascular reactivity, and cognitive deficits. Priority 3 of Research Theme 2 relates to development of robust preclinical models of vascular cognitive impairment (VCI), and our project aims to undertake a detailed characterization of the time course for development of vascular pathological changes in Aldh2 null mice, and to what extent these changes correlate with the development of the observed cognitive deficits. In particular, seed funding will allow the establishment of methodologies for the measurement of cerebral blood flow, techniques not yet operationalized in my laboratory. In the second part of the project, a BBB impermeable HNE scavenger will be utilized to evaluate to what extent targeting vascular HNE adduct formation impacts vascular pathology and cognition.
Dr. Dale Corbett, University of Ottawa
Dr. Bojana Stefanovic, Sunnybrook Research Institute
Small vessel disease (SVD) is very common in the elderly and its incidence is likely to rise with an aging population and the increasing tendency of Canadians to adopt an unhealthy lifestyle characterized by physical inactivity and consumption of food high in fat, sugar and sodium. People with SVD display a progressive decline in cognition, culminating in vascular cognitive impairment (VCI). SVD also increases the risk of major stroke, vascular or mixed dementia, and Alzheimer’s disease. Consequently, better diagnosis and effective and practical therapies to prevent, halt, or at least delay the progression of VCI are urgently needed.
There is currently no agreed upon animal model of VCI that would allow testing of new therapeutic interventions and provide insights into the mechanisms of injury. In keeping with Canadian Vascular Network Theme II, priority area 3, we propose to develop a preclinical model of VCI, by modifying the rat 2-vessel occlusion (2-VO) model. Our 2-VO model incorporates several key clinical pathological features, namely hypoperfusion, white matter damage, dietary co-morbidity factors and progressive loss of cognitive function. We will use this model to examine the structural and functional changes in the cerebral microvasculature as assessed using two photon fluorescence microscopy, immunohistochemistry, and MRI that will be related, in turn, to deficits in cognition over time. Once we have characterized the vascular and behavioral abnormalities we will attempt to mitigate these changes through dietary reversal alone or in combination with other lifestyle interventions such as exercise and drug treatment.